ࡱ> Kx%z%-%.%/%0%1%2%3%4%5%6%7%8%9%:%;%<%=%>%?%@%A%B%C%D%E%F%G%H%I%J%K%L%M%N%O%P%Q%R%S%T%U%V%W%X%Y%Z%[%\%]%^%_%`%a%b%c%d%e%f%g%h%i%j%k%l%m%n%o%p%q%r%s%t%u%v%w%#` k#bjbjmm 9t#.N N N N N N N b )))8)4+Ub t:2""2"2"23TU\0-* J j$hn N 23N N "2"2_N "2N "2/%\"N N F "2t phK )n`4$u0!$kkFFkN HOds  OOORdOOOb b b Fdb b b Fb b b N N N N N N    HYPERLINK "http://www.mdtruth.com/" MDtruth.com Note: the following material is for personal use only (see below for  HYPERLINK \l "disclaimer" full disclaimer).  HYPERLINK \l "cardio" Cardio  HYPERLINK \l "hematology" Heme/ HYPERLINK \l "oncology" Onc  HYPERLINK \l "endocrine" Endo HYPERLINK \l "infectious"ID  HYPERLINK \l "neuro" Neuro HYPERLINK \l "renal"Renal   HYPERLINK \l "lungs" Pulmonary HYPERLINK \l "gi"GI HYPERLINK \l "liver"Liver  HYPERLINK \l "Rheumatology" Rheum  HYPERLINK \l "bone" Bone /  HYPERLINK \l "joint" Joint / HYPERLINK \l "myopathy"Muscle  HYPERLINK \l "male" Male / HYPERLINK \l "female"Female  HYPERLINK \l "allergy" Allergy  HYPERLINK \l "immunology" Immunology  HYPERLINK \l "dermatology" Derm  HYPERLINK \l "surgery" Surgery /  HYPERLINK \l "orthopedics" Ortho  HYPERLINK \l "acidbase" Acid-Base /  HYPERLINK \l "metabolic" Metabolic /  HYPERLINK \l "electrolytes" Electrolytes HYPERLINK \l "ophthalmology"Ophtho HYPERLINK \l "environmental"Environment/ HYPERLINK \l "nutrition" Nutrition/Vitamins HYPERLINK \l "development"Pediatrics  HYPERLINK \l "emergency" Emergency  HYPERLINK "pharm.doc" Pharm  HYPERLINK "micro.doc" Micro  HYPERLINK "ddx.doc" Ddx  HYPERLINK "procedurevids/" Procedure vids! ICU Guide One [HYPERLINK "pics/icu1.jpg"pic] cardiac / pulmonary equations ICU Guide Two [HYPERLINK "pics/icu2.jpg"pic] intubation / respiratory physiology / creatinine clearance / drug levels Immunology  HYPERLINK \l "immunology" General Immunology  HYPERLINK \l "immunoglobulins" Immunoglobulins,  HYPERLINK \l "complement" complement cascade  HYPERLINK \l "immunodeficiencies" Immunodeficiencies  HYPERLINK \l "tcells" T-cells  HYPERLINK \l "digeorge" DiGeorge,  HYPERLINK \l "cmc" CMC  HYPERLINK \l "bcells" B-cells  HYPERLINK \l "cvid" CVID, IgA deficiency,  HYPERLINK \l "brutons" Brutons,  HYPERLINK \l "duncans" Duncans  HYPERLINK \l "bt" B&T-cells  HYPERLINK \l "scids" SCIDS,  HYPERLINK \l "ada" ADA,  HYPERLINK \l "wiskottaldrich" Wiskott-Aldrich,  HYPERLINK \l "ataxiatelangiectasia" ataxia telangiectasia  HYPERLINK \l "phagocytes" Phagocytes  HYPERLINK \l "cyclicneutropenia" cyclic neutropenia,  HYPERLINK \l "cd18" CD18,  HYPERLINK \l "jobs" Jobs,  HYPERLINK \l "chediakhigashi" Chediak-Higashi  HYPERLINK \l "connective" Connective Tissue Disorders  HYPERLINK \l "ra" RA,  HYPERLINK \l "sle" SLE,  HYPERLINK \l "sjrogrens" Sjgrens,  HYPERLINK \l "polymyositis" Polymyositis,  HYPERLINK \l "scleroderma" Scleroderma,  HYPERLINK \l "sarcoidosis" Sarcoidosis  HYPERLINK \l "vasculitides" Systemic Vascultides  HYPERLINK \l "giantcell" Giant cell arteritis,  HYPERLINK \l "takayasus" Takayasus,  HYPERLINK \l "kawasakis" Kawasakis,  HYPERLINK \l "pan" PAN,  HYPERLINK \l "wegeners" Wegeners,  HYPERLINK \l "buergers" Buergers,  HYPERLINK \l "churg" Churg-Strauss B-cell surface markers [HYPERLINK "pics/bsl-tcellsurface.jpg"diagram] T-cell surface markers [HYPERLINK "pics/bsl-tcellsurface.jpg"diagram] Immunoglobulins [HYPERLINK "pics/bsl-antibody1.jpg"diagram] 20% of plasma proteins / 2 light chains (kappa or lambda) and 4 heavy chains (gamma, alpha, mu, delta, epsilon) IgA (15%) secretions / 2 IgA molecules linked by J-segment (secreted by epithelial cells) IgG (75%) crosses placenta / major antibody IgM (10%) most efficient activator of compliment IgE (trace) hypersensitivity reactions / bound to Fc receptors on mast cells and basophils IgD (1%) surface of B-cells 4 major types of immune-response Type I: hypersensitivity Type II: cell-mediated Type III: immune-complex Type IV: delayed-type hypersensitivity Type I hypersensitivity ( HYPERLINK \l "typeonederm" derm) IgE, mast cells (his, 5HT, TNF-a, TGF-B, IL-4), Th2, (y-IFN is inhibitory) urticaria,  HYPERLINK \l "atopicdermatitis" atopic dermatitis, anaphylactic shock Treatment of acute anaphylactic shock: 0.3 mg epinephrine SC Long term: avoidance, drugs, allergen immunotherapy (how does that work?) Insect stings: reaction in < 15 mins / venom immunotherapy may help / note: honeybee stings different from other stinging insects Type II cell-mediated ( HYPERLINK \l "typetwoderm" derm) IgM > IgG / complement / ADCC / organ-specific (Goodpastures,  HYPERLINK \l "pemphigus" pemphigus) / receptor-specific (Graves, Myasthenia gravis) /  HYPERLINK \l "hemolyticanemia" hemolytic anemia / Derm: pemphigus, HYPERLINK \l "bullouspemphigoid"bullous pemphigus, HYPERLINK \l "herpesgestationis"herpes gestationis,  HYPERLINK \l "epidermolysisbullosa" epidermolysis bullosa Treatment: immunosuppression, plasmapheresis Type III immune-complex ( HYPERLINK \l "typethreederm" derm) leukoclastic vasculitis (PAN) / fibrinoid necrosis / polyarthritis, skin,  HYPERLINK \l "serumsickness" serum sickness, arthus reaction Treatment: anti-inflammatory agents, immunosuppression Type IV delayed-type hypersensitivity Th-1 - contact dermatitis, Tb, sarcoidosis, Wegeners, IBD Treatment: corticosteroids, cytotoxic agents, antimicrobials GVHD Affects: skin, liver, GI tract, eye, kidney (reports) Occurs following transplantation (e.g.  HYPERLINK \l "bmt" BMT) / patients at high-risk for fungal infections for several weeks/months after engraftment (current debate over when and what to use for prophylaxis 1/07) / immunosuppressive agents used to prevent GVHD can look like EM [HYPERLINK "pics/hymes-gvhd1.jpg"pic] [ HYPERLINK "http://dermis.net/dermisroot/en/33214/diagnose.htm" dermis] Immunodeficiencies Systemic Diseases Causing Defects of: T-cells:  HYPERLINK "micro.doc" \l "hiv" HIV,  HYPERLINK \l "sarcoidosis" sarcoidosis, steroids B-cells: asplenia,  HYPERLINK \l "sle" SLE,  HYPERLINK \l "cll" CLL, steroids Some genetic Immunodeficiencies may present in adulthood:  HYPERLINK \l "cvid" CVID,  HYPERLINK \l "cmc" CMC, more. Defects of mainly T Cells DiGeorge no thymus (no T-cells), no parathyroids / failure of 3rd (upper parathyroids), 4th pharyngeal (lower parathyroids) pouches / presents with tetany owing to hypocalcemia Chronic Mucocutaneous Candidiasis (CMC) T-cells do not respond to Candida albicans Defects of mainly B Cells IgA deficiency 1 in 500 (most common immunodeficiency) / B-cells have it, but cant secrete it / risk factor for celiac sprue Presentation: recurrent  HYPERLINK \l "sinusitis" sinusitis, GI infection (giardia), otitis media Note: do NOT give IVIG due to presence of anti-IgA antibodies (44%) Common variable immunodeficiency (CVID) Most common primary immune deficiency requiring medical attention / 1 in 50,000 sporadic / 10% familial / 15-35 yrs Mechanism: hypo-IgG from various defects (CD27+ memory B-cells cannot differentiate into plasma cells) / suspected genes involved (BAFF, APRIL, TACI, ICOS) Presentation: pyogenic infections (e.g. respiratory), chronic diarrhea (e.g. giardia), and increased incidence of autoimmune diseases (sprue-like syndrome, gastric atrophy, bronchiectasis,  HYPERLINK \l "pernicious" pernicious anemia) / associated T-cell abnormalities (10%) Diagnosis: can test for response to Ag (e.g. tetanus,  HYPERLINK "pharm.doc" \l "pneumovax" pneumovax) Related syndromes: hyper IgM type 3 (CD40), autoimmune lymphoproliferative disorder (ALPS), TNF-receptor associated periodic fever syndrome (TRAPS) Treatment: IVIG q 2-3 wks / do NOT give live vaccines Brutons X-linked agammaglobulinemia XLR / no functional B-cells (cannot get EBV infection) / low Ig / recurrent bacterial infections beginning at age 6 months / low IG predisposes to chronic  HYPERLINK \l "asepticmeningitis" aseptic meningitis (with secondary dermatomyositis) Duncans Syndrome (X-linked Lymphoproliferative Disease) XLR / impaired response to EBV nuclear antigen (2/3 mortality ) / survivors develop hypogammaglobulinemia and/or  HYPERLINK \l "lymphomab" B-cell lymphomas / decreased NK function and ADCC against EBV-infected cells Defects of B and T Cells Wiskott-Aldrich XLR / mutation of WASP gene / B and T-cells regress / cannot mount IgM response to capsular polysaccharides elevated IgA, normal IgE, low IgM / recurrent pyogenic infections, eczema, thrombocytopenia / increased incidence of lymphoreticular neoplasm Ataxia-Telangiectasia B and T-cell deficiency, with associated IgA deficiency / presents with ataxia, spider angiomas / recurrent infections / can get  HYPERLINK \l "lymphoma" lymphomas / secondary diabetes mellitus? Severe Combined Immunodeficiency Syndrome (SCIDS) no functional B and T cells / defective IL-2 receptors, MHC II, or ADA ( of autosomal forms) Adenosine deaminase deficiency (ADA) excess ATP and dATP provides negative feedback on ribonucleotide reductase,  HYPERLINK "http://www.ubriaco.com/sounds/air-biological.wav" prevents DNA synthesis, lowers lymphocyte count / can produce SCID Defects of Phagocytes [ HYPERLINK "http://content.nejm.org/cgi/content/full/343/23/1703" NEJM] Guideline: these are rare but important diseases, and can be diagnosed by examination of peripheral phagocytes and a few special stains / must catch these early and consider IFN-gamma, g-CSF, broad antibiotics Cyclic Neutropenia Autosomal dominant / ?mutation in neutrophil elastase (ELA2) recurrent neutropenia ( < 200 cells/mL) lasts 3-6 days / cycle usually ~21 days, but in 30% of patients, ranges from 14-42 in 30% During neutropenia: fever, apthous stomatitis, gingivitis, stomatitis,  HYPERLINK \l "cellulitis" cellulitis, cervical LAD Severe congenital neutropenia Autosomal recessive in 90% (unknown mutation) / heterozygous in 10% / Presents during first year of life / cellulitis, perirectal abscess, peritonitis, stomatitis, meningitis (Staph, Burkholderia) / increased risk for myelodysplasia,  HYPERLINK \l "aml" AML Labs: < 500 neutrophils, but increased circulating monocytes, eosinophils Treatments: nearly all improve with exogenous g-CSF Schwachman-Diamond Syndrome Autosomal recessive (rare) / Presents within first yr of life / average life expectancy 35 yrs Exocrine pancreatic insufficiency, skeletal abnormalities, bone marrow dysfunction, recurrent infection / all have neutropenia (cyclic or intermittent), and 10-25% also have pancytopenia / increased risk of marrow aplasia, myelodysplasia, AML Treatments: exogenous g-CSF (not considered a risk factor for malignant transformation) CD18 (leukocyte adhesion deficiency type 1) Autosomal recessive loss of B2 integrin adhesion molecules (from lack of CD18 or B-chain) / neutrophils cannot aggregate or bind endothelial cells / life expectancy is < 10 up to 40 yrs (depends on amount of CD18) Delayed separation of umbilical cord, severe periodontitis (early tooth decay), recurrent infections of all mucosal surfaces, AND delayed wound healing (enlarging borders, dysplastic scars) Leukocyte adhesion deficiency type 2 Growth retardation, dysmorphic features, neurological deficits / lack of sialyl-Lewisx (ligand for selectins) / Treatment with oral fructose has proven helpful Jobs syndrome neutrophils fail to respond to chemotactic stimuli (C3a, 5a, LT-B4) / recurrent cold staph abscesses / dental problems / elevated IgE levels / ?Rac2 (predominant GTPase in neutrophils) Defective INF-gamma/IL-12 Axis Autosomal recessive and autosomal dominant forms / complete loss of ligand-binding chain causes disseminated NTM in infancy or fatal BCG vaccination / partial loss is less severe (NTM develops in early childhood) / defect of IFN-gamma receptor signaling chain resembles complete loss of ligand-binding chain / defect in IL-12 receptor (B1 chain) and IL-12 increases susceptibility to NTM and Salmonella infections Treatment: all respond to exogenous INF-gamma except (complete loss of ligand and receptor signaling) Chronic Granulomatous Disease XLR (gp91phox) make up 70% / presents within first 2 yrs / neutrophils lack hydrogen peroxide burst (myeloperoxidase system) / Autosomal recessive (P47phox) make up 30% / onset may be later Organisms: S. aureus, Burkholderia cepacia, aspergillus, nocardia, serratia, proteus, E. coli Obstructive granulomas of GI/GU tracts,  HYPERLINK \l "pneumonia" pneumonia, skin infections, osteomyelitis,  HYPERLINK \l "liverabscess" liver abscesses, draining adenopathy (at BCG injection site, but mycobacterial disease still rare) Diagnosis: can be delayed by blunted fever, inflammatory symptoms / severe resistant facial acne and painful inflammation of nares, gingivitis, apthous ulcers, NOT periodontal disease Nitroblue tetrazolium test or flow cytometry with dihydrorhodamine dye Treatment: bactrim (one/day) may reduce serious infections from 1/yr to 1 every 4 yrs / IFN gamma reduces bacterial and fungal infections by 70% / stem-cell transplantation and gene therapy protocols under investigation Myeloperoxidase deficiency 50% have complete loss / no chlorine formation in azurophilic (primary) granules / usually asymptomatic except in diabetics who have increased risk of disseminated candidiasis Chediak-Higashi Autosomal recessive mutation in LYST (microtubule and lysosomal defects) Recurrent staph and strep, partial albinism, mental retardation, platelet dysfunction, severe periodontal disease, and in those patients surviving into 20s, striking peripheral nerve defects (nystagmus, neuropathy) Labs: mild neutropenia and normal IG levels Course: 85% have fatal infiltration of CD8+ and macrophages with eventual pancytopenia Neutrophil-Specific Granule Deficiency S. aureus, S. epidermidis, enteric bacteria (skin/lungs) / abnormal migration and atypical nuclear morphology / lack of primary granule defensins, lack of eosinophil-specific granules Feltys Syndrome ( HYPERLINK \l "feltys" see rheumatology) neutropenia, splenomegaly, from long standing RA Complement deficiencies [ HYPERLINK "labs.doc" \l "complement" labs] most are recessive, all occur at similar rates (except C2 may be more common, 1% prevalence) / C3 (severe disease) / C5-8 ( GC meningitis, arthritis Biology of Complement [HYPERLINK "pics/bsl-complement.jpg"activation cascade] Functions: lysis, opsonization, anaphylatoxins (degranulation), chemotaxis Classical: Ag:Ab complex, C1, C4, C2 attachment, activation, amplification, attack Alternative: microbe + P, D, B, C3b Lectin (new): MBP opsonizes foreign carbohydrates C3a, C5a also anaphylatoxins C5a is also a chemotactic factor Deficiency syndromes Clq, C1r, C1s, C4, C2 SLE, some get infectionsC3 Repeated infections, partial lipodystrophy, SLE / C3 or C4 nephritic factor stabilizes convertase of alternate or classical pathway C5-C8 Neisseria infections, arthritis D and properdin (XLR) Recurrent meningococcal meningitis C1 inhibitor (AD) Hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias MBP (3rd pathway)Infections in SLE DAF and CD59 Paroxysmal nocturnal hemoglobinuriaFactors H and I Pyogenic infections, urticaria, glomerulonephritis, secondary C3 deficiency Complement Studies Normal C3 / Normal C4 Normal C3 / Decreased !C4Alterations in vitro (improper specimen handling) Coagulation-associated complement consumption Inborn errors (other than C4 or C3)Immune complex disease Hypergammaglobulinemic states  HYPERLINK \l "cryoglobulinemia" Cryoglobulinemia Hereditary angioedema Inborn C4 deficiency Decreased !C3 / Normal C4Decreased !C3 / Decreased !C4 Acute glomerulonephritis  HYPERLINK \l "mpgn" MPGN Immune complex disease  HYPERLINK \l "sle" Active SLE Inborn C3 deficiencyActive SLE Serum sickness Chronic active hepatitis Subacute bacterial HYPERLINK \l "endocarditis"endocarditis Immune complex disease C1 inhibitor (acquired or AD) hereditary angioedema / may occur in SLE, lymphoproliferative disorders, paraproteinemias recurrent GI attacks of colic are common / no pruritis or urticarial lesions Allergy Anaphylaxis Most common ( B-lactams / S! of cases are idiopathic 5-60 minutes following exposure, but delayed reaction is possible Angioedema with or without urticaria (not true anaphylaxis without life threatening hypotension or laryngeal edema) Presentation: pruritis, flushing, urticaria, angioedema, diaphoresis, sneezing, rhinorrhea, congestion, hoarseness, stridor, laryngeal edema, dyspnea, tachypnea, wheezing, bronchorrhea, cyanosis, tachycardia, bradycardia, hypotension, cardiac arrest, arrhythmias, nausea, vomiting, diarrhea, abdominal cramping, dizziness, weakness, HYPERLINK "ddx.doc" \l "syncope"syncope, sense of impending doom, seizures Treatment: Epinephrine(EpiPen, Adrenaline) IM (anterolateral thigh is fastest absorbed) Benadryl 50 mg PO or IV every 4 hrs H2 blockers (Zantac, Pepcid, etc.) Methylprednisolone (Solu-Medrol, Depo-Medrol) Recumbent position, elevate legs, oxygen (Beta2-adrenergic Agonists: Terbutaline) Volume replacement, pressors as needed Longer Term Treatments Anabolic steroids: Stanozolol (Winstrol) / increases C1 esterase inhibitor and C4 Antigonadotropic agents: Danazol (Danocrine) / increases C4 levels Serine Proteinase Inhibitors (serpins) / C1 inhibitor, human (Cinryze) / IV infusion repeated every few days Ddx:  HYPERLINK \l "erythemamultiforme" EM minor (urticarial or bullous lesions),  HYPERLINK \l "sjs" SJS,  HYPERLINK \l "ten" TEN [these syndromes cause fever, headache, malaise, arthralgia, corneal ulcerations, arrhythmia, pericarditis, electrolyte abnormalities, seizures,  HYPERLINK \l "coma" coma, sepsis] Dilantin hypersensitivity: very common, ranges from minor to life-threatening, mechanism unclear Iodine allergy: not true allergic reaction; hyperosmolar dye causes degranulation of mast cells/basophils Pretreatment protocol: 40 mg prednisone 24 hrs before then 12 hrs, etc / H2 blockers (ranitidine), benadryl / avoid contrast dye with renal insufficiency and  HYPERLINK \l "hbs" sickle cell disease / normal maximum dye load would be 2 CT scans within a 24 hour period (assuming normal renal function) Drug Fever or Drug Rash maculopapular rash, resolve after removal of agent Timecourse: most occur several days after starting treatment, but can happen weeks after initiation of offending agent Labs: elevated eosinophils, CRP, LFTs (e.g. one study found increased LFTs in 20% of cases of maculopapular rash) Note: if you see it on the outside, the same thing can be happening on the inside (such as the liver, etc) Serum Sickness 7-10 days after primary exposure, 2-4 days after secondary exposure Findings: fever, polyarthralgia, urticaria, lymphadenopathy, glomerulonephritis Treatment: removal of agent, antihistamines, NSAIDs Atopy asthma, eczema, and seasonal rhinitis and  HYPERLINK \l "conjunctivitis" conjunctivitis allergic rhinitis: varies with season, treated with antihistamines/topical nasal steroids, itchy vasomotor rhinitis: perennial (no seasonal variation), not itchy Food allergies Most common ( peanuts (soy beans, shellfish, eggs, milk, nuts) / incidence believe about 1 % / breastfeeding may reduce chance of developing in those predisposed / skin testing (radioallergosorbent tests or RAST ) not as good as a simple food diary / reactions usu. in GI and skin but can cause anaphylaxis/respiratory / best treatment is avoidance Dust mite common allergen / grow better in warm, humid environment (so humidifier actually makes worse) / can do skin testing for diagnosis of allergy Insect allergies (e.g. hymenoptera) range from local reactions to anaphylaxis / honeybee (Apis family) is not cross-reactive with Vespid family (e.g. wasps, hornets, yellow jackets) / venom immunotherapy is indicated with history and/or positive skin testing Latex allergy ranges from mild to anaphylaxis / can do scratch test Rheumatology  HYPERLINK \l "bone" Bone  HYPERLINK \l "bonemalformations" Malformations  HYPERLINK \l "fractures" Bone Fractures  HYPERLINK \l "bonecancer" Bone Cancer  HYPERLINK \l "osteomyelitis" Osteomyelitis  HYPERLINK \l "joint" Joint  HYPERLINK \l "ra" Rheumatoid arthritis,  HYPERLINK \l "sle" SLE,  HYPERLINK \l "scleroderma" Scleroderma, HYPERLINK \l "sjogrens"Sjgrens, MCTD,  HYPERLINK \l "jra" JRA,  HYPERLINK \l "sarcoidosis" Sarcoidosis  HYPERLINK \l "oa" Osteoarthritis (OA),  HYPERLINK \l "gout" gout,  HYPERLINK \l "pseudogout" pseudogout  HYPERLINK \l "infectiousarthritis" Infectious arthritis Spondylarthropathies:  HYPERLINK \l "ankylosing" AS, HYPERLINK \l "psoriatic"psoriatic,  HYPERLINK \l "reiters" Reiters and Reactive, IBD  HYPERLINK \l "Fibromyalgia" Fibromyalgia Muscle  HYPERLINK \l "polymyositis" Polymyositis/ HYPERLINK \l "dermatomyositis" Dermatomyositis,  HYPERLINK \l "pmr" PMR,  HYPERLINK \l "rs3pe" RS3PE,  HYPERLINK \l "eosinophilicfasciitis" eosinophilic fasciitis,  HYPERLINK \l "eosinophilicmyositis" eosinophilic myositis,  HYPERLINK "myopathyother" other myopathy  HYPERLINK \l "vasculitides" Vascultides  HYPERLINK \l "giantcell" GCA,  HYPERLINK \l "takayasus" Takayasus,  HYPERLINK \l "kawasakis" Kawasakis,  HYPERLINK \l "pan" PAN,  HYPERLINK \l "wegeners" Wegeners,  HYPERLINK \l "churg" Churg-Strauss,  HYPERLINK \l "buergers" Buergers  HYPERLINK \l "orthopedics" Ortho  HYPERLINK \l "lowbackpain" Low Back Pain,  HYPERLINK \l "knee" Knee Pain,  HYPERLINK \l "cts" carpal tunnel [ HYPERLINK \l "rheumhp" Rheum H&P] [ HYPERLINK \l "hlaassociations" HLA associations] Rheum History and Physical Exam History General: CC/Chronology/demographics/functional impact/FH/ROS Pain Distal (RA), proximal ( HYPERLINK \l "pmr" PMR, fibromyalgia) Gentle activity often improves inflammatory but not pain of OA or fibromyalgia Pain worse as day goes on (OA), wakens from sleep (severe OA, cancer) Stiffness Morning stiffness > 1 hr (RA, PMR) gel phenomenon (worse on initiation/resumption of activity) Swelling Articular (arthritis), periarticular (tenosynovitis, ganglion cyst), entire limb (lymphedema), other (lipoma, tumor) Dependent ( worse as day goes on Weakness muscle vs. neurological Constitutional Fever, inflammation (weight loss) vs. chronic pain (weight gain) Sleep Fibromyalgia and inflammatory disease often poor sleepers (may also have  HYPERLINK \l "osa" sleep apnea, nocturia, narcolepsy) Raynauds Three Stages Ischemic pallor - vasospasm (arteries/arterioles) [HYPERLINK "pics/raynauds.gif"pic] Cyanosis dilation / deoxygenated blood pooling Rubor reactive hyperemia Primary Secondary Collagen vascular disease (SLE, SSc, others) Arterial occlusive disease Pulmonary HTN Neurologic disorders Blood dyscrasias (e.g. Waldenstroms) Trauma Other: thoracic outlet syndrome (decreased blood flow, short rib) Arthritis Ddx by category Acute polyarthritis Infectious: bacterial sepsis, Neisseria, HIV, other virus, Lyme,  HYPERLINK \l "rheumaticfever" rheumatic fever Non-infectious: sarcoid, many CTDs, Spondylarthropathies, juvenile chronic arthritis, gout/ HYPERLINK \l "cppd" CPPD, HSP, HOA, sickle cell, leukemia Intermittent Arthritis Mechanical: loose bodies, partial tears, ligament laxities Crystals: gout, pseudogout, hydroxyapatite Infectious: Lyme,  HYPERLINK \l "whipples" whipples Other: palindromic RA, episodic RA, intermittent hydrarthrosis, FMF, Sarcoid Chronic Arthritis RA, JRA, other CTD, crystals, spondylarthropathies, HOA,  HYPERLINK \l "hypothyroidism" hypothyroid, metabolic/infiltrative bone/joint disease Acute Monoarthritis Note: these can present with only one joint first, of course Trauma, sickle cell, osteonecrosis Crystals, bacteria, spondylarthropathies, RA, palindromic RA, JRA Chronic Monoarthritis Non-inflammatory OA, mechanical, osteonecrosis, neuropathic, reflex sympathetic dystrophy, adjacent bone lesion (tumor/infection) Inflammatory Tb, fungal, lyme, crystals, RA, JRA, spondylarthropathies,  HYPERLINK \l "hemophilia" hemophilia, synovial neoplasm, pigmented villonodular synovitis Low Back Pain Etiologies: Inflammatory: AS, Reiters, Psoriatic, enteropathic (reactive) Infectious: infectious sacroiliitis, osteomyelitis Musculoskeletal: vertebral compression, degenerative facet joint disease, herniated disc, muscular ligamentous injury Neurologic Psychogenic, workers comp Visceral/vascular,  HYPERLINK \l "referredpain" referred pain Primary or metastatic malignancy Congenital Conditions: musculoskeletal lumbar sprain or strain (70%): acute or chronic / young adults degenerative disk disease (10%) spinal stenosis (3%): pain often bilateral lower legs / usu. > 60 yrs / worse w/ extension, relieved by flexion, worse with walking (uphill) intervertebral (herniated disc) disease (4%): worse with sitting (lying may help) spondylosis: defect in pars interarticularis, either congenital or secondary to stress fracture spondylolisthesis: anterior displacement of upper vertebral body on the lower body (can mimic symptoms of spinal stenosis) / condition results from spondylosis or degenerative disk disease in elderly cauda equina syndrome: difficulty in micturation, loss of anal tone, saddle anesthesia, progressive motor weakness, sensory level facet joint syndrome: back pain referred to buttock, worse with extension, relieved by flexion / gradual, chronic / more in older patients / may have paravertebral muscle spasm at level inflammatory: onset < 40, morning stiffness, peripheral joints, iritis, rash, urethral discharge non-mechanical low back pain (1%)  HYPERLINK \l "referredpain" referred or visceral pain (2%) Diagnosis: history and physical usually enough / dont get XR unless suspecting tumor, infection because 60% of asymptomatic patients will have positive findings on XR (which will be useless information) / MRI reserved for severe cases and/or when considering surgery Straight-leg raising (not very sensitive or specific) Patrick maneuver distinguishes pain from sacral-iliac joint (patient externally rotates hip, flexes knee, crosses knee of other leg like a number four while examiner presses down on flexed knee and opposite pelvis) Duration: acute: < 3 months / early: 3 to 6 months / intermediate: 6 to 24 months / late: > 2 yrs Red flags: young or old presentation, previous CA, steroids, drugs, HIV, constant (non-mechanical), thoracic, wt loss, ESR > 25, vertebral collapse on XR Treatment: most cases of acute low back pain resolve in 1-6 weeks w/ analgesics (NSAIDs, other), bed rest NOT recommended, physical therapy NOT necessary (3-5% remain disabled for > 3 months) Pain distribution weaknessReflex affectedScreening testL3-4anterolateral thigh, anteromedial calf to ankleQuadricepskneeSquat and rise (L4)L4-5lateral thigh, anteromedial calf, medial dorsum of foot between 1st and 2nd toesDorsiflexion of footnoneHeel walking (L5)L5-S1gluteal region, posterior thigh, posterolateral calf, lateral dorsum of sole and foot between 4th and 5th toesPlantar flexion of footankleWalk on toes (S1) Referred pain facet joints, intervertebral discs Lumbar ( hip pain localizing to buttock, lateral thigh Cervical ( axilla, shoulder hips ( groin, anterior thigh knee ( heart ( shoulder, jaw, arm (pericarditis ( trapezius ridge) pancreas ( back liver ( shoulder renal (stones, etc) ( flank/groin/ HYPERLINK \l "testes" testicle uterine ( lower back PUD/spleen/pneumonia ( right shoulder throat ( ear (via recurrent laryngeal nerve) Joint Diseases [Synovial Fluid Table] [ HYPERLINK \l "polyarticular" Polyarticular Ddx] Inflammatory Joint Disease  HYPERLINK \l "infectiousarthritis" Infectious arthritis Crystal-induced:  HYPERLINK \l "gout" Gout,  HYPERLINK \l "pseudogout" pseudogout,  HYPERLINK \l "hydroxyapetite" hydroxyapatite,  HYPERLINK \l "caox" calcium oxalate, LLM Trauma: fracture, internal derangement, hemarthrosis  HYPERLINK \l "oa" Osteoarthritis,  HYPERLINK \l "ra" RA and  HYPERLINK \l "jra" JRA  HYPERLINK \l "spondylarthropathies" Spondylarthropathies:  HYPERLINK \l "psoriatic" psoriatic arthritis,  HYPERLINK \l "ankylosing" ankylosing spondylitis,  HYPERLINK \l "reiters" Reiters, reactive arthritis Ischemic (avascular) necrosis: Kasans, alcoholics,  HYPERLINK \l "gauchers" Gauchers Foreign-body synovitis Tumor: mets, osteoid osteoma, pigmented villonodular synovitis (benign, brown-yellow on MRI) GI disease: intestinal bypass,  HYPERLINK \l "whipples" Whipples, reactive arthritis (Shigella, Salmonella, Yersinia, Chlamydia, Campylobacter), IBD ( HYPERLINK \l "crohns" Crohns and  HYPERLINK \l "uc" ulcerative colitis) Viral infections:  HYPERLINK "micro.doc" \l "parvovirus" Parvovirus B19,  HYPERLINK "micro.doc" \l "rubella" rubella, HBV,  HYPERLINK "micro.doc" \l "hcv" HCV Uncommon: mumps,  HYPERLINK "micro.doc" \l "coxsackie" coxsackie, echovirus, adenovirus, VZV, HSV,  HYPERLINK "micro.doc" \l "cmv" CMV Other causes of arthropathy: Relapsing polychondritis Neuropathic joint disease Hypertrophic osteoarthropathy and clubbing  HYPERLINK \l "fibromyalgia" Fibromyalgia Psychogenic rheumatism Reflex sympathetic dystrophy syndrome Costochondritis or Tietzes syndrome (with swelling) Musculoskeletal disorders associated with hyperlipidemia Arthropathy of acromegaly,  HYPERLINK \l "hemochromatosis" hemochromatosis, hemophilia, hemoglobinopathies, Polyarticular Rheum: RA, OA, gout, CPPD, SLE, vasculitis, scleroderma, PM/DM, Stills,  HYPERLINK \l "behcets" Behets, relapsing polychondritis, sarcoidosis, palindromic rheumatism, FMF, malignancy, hyperlipoproteinemia / seronegative: AS, psoriatic, IBD Other: fibromyalgia, multiple bursitis/tendonitis, soft tissue abnormalities, hypothyroidism, neuropathic pain, metabolic bone disease, depression, serum sickness Infectious:  HYPERLINK "micro.doc" \l "lyme" lyme, endocarditis, viral (see above),  HYPERLINK "micro.doc" \l "gonococcus" gonococcal, Tb, other Post-infectious or reactive: Reiters, rheumatic fever, enteric infection HOA and clubbing Primary HOA (pachydermoperiostosis) AD / childhood / remits in 10-20 yrs Secondary HOA Causes: associated with intrathoracic malignancies, suppurative lung disease, congenital heart disease, and more / without clubbing (vascular grafting)  HYPERLINK \l "bronchogenicca" bronchogenic CA (usu. non-small cell) ( RA-like picture (with effusions/arthralgia) can develop even before onset of clubbing Mechanism: megakaryocyte shunting with R to L arteriolar trapping ( release of PDGF ( proliferation [doesnt seem to explain the classic pattern of progressive development of clubbing from feet to hands seen with congenital heart disease] Treatment: after lung tumor resection (or even just radiation of mets) or lung abscess drainage, symptoms and signs of arthropathy often subside rapidly; radiographic changes remit during weeks and months / NSAIDs, ASA, bisphosphonates, even trial of low-dose steroids may relieve bone pain in some pts Diagnosis: clinical? / bone scan will show periosteal deposition [HYPERLINK "http://mdtruth.com/pics/hoa-bonescan.jpg"pic], plain films may reveal changes also Periarticular disorders: bursitis, rotator cuff tendonitis and impingement syndrome, calcific tendonitis, bicipital tendonitis and rupture, adhesive capsulitis, lateral epicondylitis (tennis elbow), medial epicondylitis General Points about OA, RA, gout OA ( affects many vertebrae, RA particularly C1/C2 (because theres a bursa there) RA causes destruction and  HYPERLINK \l "osteoporosis" osteoporosis; gout causes destruction but not osteoporosis Osteoarthritis (OA) most common joint disease Causes: primary (80% of population > 70 yrs) or secondary 5% (previously damaged joints, weight-bearing joints, endocrinopathy, metabolic disease, neuropathy, avascular necrosis, Pagets); 34% of patients presenting with acute knee pain Clinical: age > 50 yrs, morning stiffness < 30 mins, crepitus, bony enlargement or tenderness; no inflammation (no heat), slow progression / normally pain worse with weigh-bearing, motion, but can progress to point where causes pain at rest, at night ACR: osteophytes on XR + at least one of above signs is 90% sensitive, specific for OA Findings: Affected Joints: DIP > PIP > CMC, knee, hip, feet Spared Joints: hands (except DIP/PIP/CMC), wrist, elbow, shoulder, spine Heberdens nodes (DIP) and Bouchards (PIP) seen more in post- HYPERLINK \l "menopause" menopausal women with genetic predisposition [HYPERLINK "pics/oa-dip-pip.jpg"pic] / only wrist joint involved is 1st CMC [HYPERLINK "pics/oahands.jpg"pic] Knees: medial >> lateral involvement / may develop popliteal cysts Radiographic (weight-bearing): osteophytes (77% sensitivity/83% specificity), subchondral sclerosis, subchondral cysts, joint space narrowing (erosions), malalignment, may see soft-tissue swelling Spondylosis is the formation of osteophytes in response to degenerative disc disease / thick and often project laterally (unlike in AS) / spinal stenosis can also occur from hypertrophy of posterior facet joints, spondylolisthesis, synovial cysts,  HYPERLINK \l "pagets" Pagets disease, epidural lipomatosis, and congenitally small spinal canal Schmorls nodes (invasion of disc into vertebral body) are common (often associated with Scheuermanns disease, osteopenia and degenerative disc disease) / bony margin may be visible on roentgenogram Forestiers disease (diffuse hyperostosis) can occur (usu. elderly) and may form flowing ossification (usu. on right side, thoracic vertebrae, but also can occur on ligamentous, tendinous attachments anywhere) Labs: ESR < 40, RF < 1:40, non-inflammatory  HYPERLINK \l "synovialfluid" synovial fluid (< 2000/mm3) Treatment: NSAIDs (some say glucosamine works in patients who cannot tolerate NSAIDs), when its bad enough, only treatment is joint replacement (knee/hip) (~95% 10 yr success rate) / chondroitin sulfate under investigation / multiple, short periods of rest throughout day better than one large period of rest / intraarticular steroids occasionally helpful (esp. in joint lock up) Nodal OA DIP/PIP / runs in families Rheumatoid Arthritis females 4:1 / any age / mildly shortened life span Findings: swollen, painful, warm joints (PIP, MCP, not DIP), ulnar deviation of MCP [HYPERLINK "pics/ra-hands.jpg"pic], radial deviation of wrists, swan-neck fingers [HYPERLINK "pics/swanneck.jpg"pic], Boutonnire or button-hole deformities [ HYPERLINK "pics/boutonniere.jpg" pic][ HYPERLINK "pics/boutonniere1.jpg" pic] Joints: inflamed synovium (pannus) / penetrates to cause erosions, subchondral cysts / fibrin aggregates in joint space (rice bodies) / synovium eventually bridges and ossifies opposing surfaces Skin: 25% have rheumatoid nodules (firm, oval, non-tender, fibrinoid necrosis, inflammation) Vasculitis: rheumatoid vasculitis, ulcers, gangrene, splinter hemorrhages, raynauds Neuro HYPERLINK \l "peripheralneuropathy"peripheral neuropathy (10%; are slowly progressive, distal symmetrical sensory or sensory-motor polyneuropathy) mononeuritis multiplex entrapment neuropathy ( carpal tunnel Renal: early (drug-induced nephropathies), late (amyloid-like renal disease) Lungs (almost always RF positive): [ HYPERLINK "http://content.nejm.org/cgi/content/full/344/13/997?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=rheumatoid+nodules&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=20&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jou" NEJM] pleuritis/pleurisy, effusion  HYPERLINK \l "spn" pulmonary nodules (CT will show them if CXR doesnt) ILD alveolar hemorrhage Heart:  HYPERLINK \l "pericarditis" pericarditis >  HYPERLINK \l "myocarditis" myocarditis, valves / conduction abnormalities Eyes: (1st dry eyes or keratoconjunctivitis sicca (Sjgrens), 2nd episcleritis may be severe, perforate) Heme:  HYPERLINK \l "anemiaofchronicdisease" anemia of chronic disease Diagnosis: r/o TB (also has RF) Criteria: 4 of 7 required morning stiffness > 1 hr swelling of 3 or more joints swelling of hand joints (PIP, MCP, wrist) symmetrical swelling rheumatoid nodules positive RF erosions of hand joints (X-ray) Labs: 80% have RF (IgM to Fc of IgG), ANA / HLA  HYPERLINK \l "dr4" DR4, HLA DR1 anti-CCP (worse prognosis; S! with negative RF will have positive anti-citric citrullinated peptide) Radiography: early X-ray changes in feet (MTPs, very specific for RA), ulnar styloid changes (late becomes piano key sign), C1-2 subluxation (can be very serious and damage spinal cord, but if seen incidentally on lateral flexion c-spine at < 5 mm, can observe) Course: usually insidious course / DMARD-remission achievable (15%) (anti-CCP Abs increase chances of DMARD-free remission) Treatment: aggressive therapy is the rule / immunosuppressive drugs from day one / frequent re-evaluation and willingness to change therapies based on effectiveness (is a trend that has been advancing more and more) / DAS28 scores (sometimes used), TJC (total joint count), ESR (may vary with effective treatment)  HYPERLINK "pharm.doc" \l "steroids" Steroids  HYPERLINK "pharm.doc" \l "mtx" MTX  HYPERLINK "pharm.doc" \l "tnfalpha" TNF-a inhibitors (some believe in switching from one anti-TNF to another may work in treatment failure; or possibly adding newer agents such as the new Abs like  HYPERLINK "pharm.doc" \l "rituximab" rituximab, etc.) Others:  HYPERLINK "pharm.doc" \l "immuran" Immuran Old school:  HYPERLINK "pharm.doc" \l "gold" gold,  HYPERLINK "pharm.doc" \l "penicillamine" penicillamine New school (example of regimens): initial tapered high-dose prednisone + MTX and sulfasalazine or infliximab + MTX Prognosis: more nodules, DR4, anti-CCP, more systemic Sx, are worse indicators Palindromic RA waxing and waning course / usually resolves within 24-48 hrs / joint involvement atypical compared to classic RA Feltys syndrome neutropenia, splenomegaly,  HYPERLINK \l "legulcers" leg ulcers, polyarticular arthritis (RA~) or SLE More: nodules (75%), weight loss (70%), Sjgrens (55%), LAD (35%), leg ulcers (25%), pleuritis (20%), skin pigmentation (15%), neuropathy (15%), episcleritis (10%) caused by autoantibodies and cytokine/T cell suppression of granulocytopoesis / more common in elderly patients with RA (especially if untreated) / may also have vasculitis etc. Large Granular Lymphocytes (LGL) Usually polyclonal, 20% have RA (the rest are considered neoplastic) / usually associated with Feltys / course is variable Juvenile Rheumatoid Arthritis (JRA) (Stills disease) children under 16 Presentation: fever, rash (transient, macular), hepatosplenomegaly, serositis Findings: RF and nodules usually absent (only in older, more severe cases) Complications: pericarditis, myocarditis, pulmonary fibrosis, glomerulonephritis, growth retardation, iridocyclitis (anterior uveitis main systemic symptom in up to 25% of girls with mono/pauciarticular RA, insidious yet may lead to blindness), 40% incidence of myopia / 70% recover, 10% with severe deformities Adult Onset Stills Disease (AOSD) Presents with fever, transient rash, joint inflammation / notable for persistent plaques and linear pigmentation Labs: over 2/3 will have elevated AST/ALT (2-5x) and AST/GGT / (-) RF, ANA / often extremely elevated  HYPERLINK "labs.doc" \l "ferritin" ferritin Cogans syndrome Stills + hearing loss / Treatment: high-dose steroids and pulse Cytoxan Infectious Arthritis Infectious Monoarthritis Neonates: group B strep, H. influenza Children: S.aureus (45%), Strep A (25%), GNR (20%), Gonococcus (5%), Tb (1%) Adults: HYPERLINK "micro.doc" \l "neisseria"Neisseria (50%), S. aureus (35%), Strep A (10%), GNR (5%), Tb (1%) Other causes: Pseudomonas (IV drugs, wounds), Klebsiella/E. Coli (IV users, GU infections), lyme disease, Salmonella in sickle cell patients,  HYPERLINK "micro.doc" \l "syphilis" syphilis (2nd stage and Charcots joints) /  HYPERLINK "micro.doc" \l "HACEK" HACEK organisms Pathology: usually hematogenous spread / polymicrobial from surgical implantation or elderly with peripheral vascular disease / usually monostotic (except newborns and sickle cell pts) Neonates: metaphyses, epiphyses Children: usually metaphyseal only as growth plate prevents spread into joint Adults: growth plate closed, vessels reunite, bacteria can go everywhere Clinical symptoms: early: fever, skin, arthralgias / knee is hot, tender (pain on active AND passive movement; joint movement that is NOT limited by passive motion suggests soft-tissue problem, e.g. bursitis)) Gonococcal: hand and feet lesions (erythematous, +/- pustular) Non-gonococcal: another focus / debilitating illness / other? / pre-existing joint abnormality Synovial fluid from joint aspiration or arthrocentesis of knee [ HYPERLINK "http://content.nejm.org/cgi/video/354/19/e19/" video] WBC is a helpful value: < 200 is normal ( < 25% WBC) 200-2000 is non-inflammatory ( < 25% WBC; PMNs) 2000-100,000 is inflammatory ( > 50% WBC) > 80,000 is purulent/septic ( > 75% WBC) Fungal: 10-40 WBC, 70% neutrophils Syphilis: 10-40 WBC in 2nd glucose: 25% less than fasting blood glucose indicates infection culture and gram stain (60-80% sensitive) wet prep (not always used, many false negatives by non-expert labs) synovial biopsy (may be needed to diagnose Tb or hemochromatosis) XR shows pale bone necrosis (sequestrum) / surrounding deposition of new bone (involucrum) Treatment: empiric antibiotics / joint drainage Tuberculous arthritis (HYPERLINK "micro.doc" \l "tb"see TB) Usually knees / most common is chronic granulomatous monoarthritis / 1% of Tb / 10% of extrapulmonary Tb / onset is months/years / systemic symptoms only in / Synovial fluid: 20 WBC 50% neutrophils, culture positive in 80%, gram stain positive in 1/3 / Potts (spine) / scrofula (TB of neck) Poncets disease reactive arthritis from Tb / bilateral, no organisms found in joints Lyme arthritis ( HYPERLINK "micro.doc" \l "borrelia" see Lyme Disease) large joints, weeks to months duration, periods of remission, permanent deformities in 10% Viral Arthritis (from systemic infection) Parvovirus B19, rubella, HBV, HCV Gout usually not before 30 yrs / many are asymptomatic / asymptomatic intervals get shorter over time (severe cases can mimic RA) Pathology: tophi may occur in joints, ligaments, tendons, soft tissue, earlobes, palms, soles, kidney (uric acid > 8 ( causes gout, > 20 ( causes renal damage (due to very rapid cell turnover) Hyperuricemia (10%) ( > 750 mg/dl) ?HGPRT deficiency Increased turnover: myeloproliferative disorders, hemolytic anemias, lymphoproliferative malignancy,  HYPERLINK \l "psoriasis" psoriasis, glycogen storage diseases Impaired renal excretion of uric acid (90%) ( < 700 mg/dl) polygenic inheritance hypovolemia ( HYPERLINK \l "adrenalinsufficiency" adrenal insufficiency,  HYPERLINK \l "diabetesinsipidus" diabetes insipidus) Toxins: heavy alcohol use / lead toxicity / ASA interferes with tubular secretion / organic acids compete for secretion (ketones, LA) Other drugs: thiazide, radiocontrast agents, allopurinol/probenecid (if given during attack) Presentation: Some classify in stages: I asymptomatic hyperuricemia II acute gouty arthritis more at night, last hours to weeks, 1st attack usually only in one joint / Podagra (90%) 1st MTP (great toe) III intercritical gout most patients have next attack within 1-2 years IV chronic tophaceous gout erosion of underlying bone from chronic inflammation Precipitation: dietary excess, alcohol, acute medical illness, surgical procedures, joint trauma Renal complications: urate crystals in medullary interstitium (pyelonephritis, obstruction) / 20% of chronic gout die of renal failure (typical to have mild albuminuria, not glomerulonephritis) Diagnosis: needle-shaped urate crystals in synovial fluid - yellow, parallel to polarizing light Note:  HYPERLINK \l "infectiousmonoarthritis" dont rule out infection just because you see crystals as infection frequently coexists with hyperuricemia Treatment: Acute attack: HYPERLINK "pharm.doc" \l "colchicine"colchicine (0.6 mg bid or until diarrhea, unless renal impairment) NSAIDs (indocin and tolectin thought to work best) steroids (prednisone 40 mg qd x 2-3d with rapid taper) Prevention: low purine diet / weight loss / avoid alcohol / colchicine (low dose daily)  HYPERLINK "pharm.doc" \l "probenecid" Probenecid: frequent attacks / stones / tophi / do not use with renal insufficiency  HYPERLINK "pharm.doc" \l "allopurinol" Allopurinol: diminishes uric acid production (do not start during acute attack) Pseudogout (CPPD) far less common than gout elderly man/woman (over 85) / calcium pyrophosphate dihydrate in synovial membranes et al / usually asymptomatic rhomboid crystals / familial form chr 8q and chr 5p Labs: mildly elevated ESR / chondrocalcinosis (+ / -) / CPPD crystals - coffin-shaped, weakly (+) positive birefringence (blue when parallel) Presentation: warmth, erythema, tenderness, swelling, may have fever, leukocytosis / self-limited to several days / usually knee (50% of acute attacks) / pseudopodagra is almost impossible Radiography: calcific deposits (chondrocalcinosis present in 26% of asymptomatic adults > 60 yrs) / hook-like osteophytes/subchondral cysts (similar to OA) Associated metabolic conditions: Hyperparathyroidism (primary or secondary) HYPERLINK \l "_hemochromatosis"Hemochromatosis (perform basic Fe studies), maybe Wilsons, A1AT Hypothyroidism Gout Hypomagnesemia (mild hypomagnesemia potentiates PTH action) Hypophosphatemia  HYPERLINK \l "amyloidosis" Amyloidosis Neuropathic joints, aging, trauma/surgery Note: urate gout and rheumatoid arthritis have a strong negative association (10x) Work-up for newly diagnosed CPPD: Ca, Mg, PO4, Alk Phosphate, ferritin, Fe, TIBC, TSH (less Mg and PO4 in over 60 yrs?) Treatment: symptomatic relief from NSAIDs (indomethacin), steroids (injection or PO), joint aspiration, joint immobilization, IV or PO colchicines (only if you can use high doses) / correction of underlying metabolic problem does not always stop progression Pseudogout (Type A) (25% of CPPD) Almost never causes podagra / males / asymptomatic between attacks / usually have radiographic evidence (such as chondrocalcinosis seen in AP pelvis, PA wrists) 20% with hyperuricemia, 5% with urate gout HC associated shows 2nd/3rd MCP enlargement and/or attacks of pseudogout Pseudorheumatoid arthritis (Type B) 10% with low titre RF / joints inflamed out of phase (like gout, not like RA), osteophytes, CPPD, lack of typical erosion patterns on X-ray can mimic sepsis in elderly patients (fever, WBCs, mental status, polyarthritis) Hydroxyapatite (HA) secondary to many systemic disease states (apparently, mostly with elevated Ca2+) / crystals so small, a special stain is required to detect / anti-inflammatory treatment may shorten duration of attacks, long-term changes cannot be undone? Calcium oxalate (CaOx) strong positive (+) birefringence Primary: rare genetic disorder, death < 20 yrs Secondary: renal failure or vitamin C abuse Fibromyalgia usu. middle-aged women / hypersensitivity to physical stimulation causing pain, fatigue, poor sleep(mechanism poorly understood) Diagnosis: diagnosis by exclusion of other disorders and demonstrating e" 11 of 18 trigger points Labs: no specific lab abnormalities Treatment: no good treatment, but  HYPERLINK "pharm.doc" \l "tca" TCAs might provide some relief Relapsing polychondritis Inflammation of cartilage (breakdown of chondroitin sulfate) Findings: saddle-nose deformity, scleral thinning (scleromalacia), floppy ear, aneurysms, valvular insufficiency (AR, MR, TR), tracheal narrowing (steeple sign) Liquid lipid microspherules? Other Bone Disorders Scoliosis adolescent females > males / 20% with positive family history slipped capital femoral epiphyses 20% with referred knee pain (can be misleading) / occurs in pubescent males, happens gradually, can be bilateral / Treatment: surgical with pinning Villonodular synovitis (benign neoplasms) aggregates of polyhedral cells, hemosiderin, foam cells, giant cells, zones of sclerosis Treatment: surgery if possible, usually difficult to excise pigmented villonodular synovitis (PVNS) single or multiple, diffuse involvement, red-brown projections giant cell tumor of tendon sheath (localized tenosynovitis) small, discrete nodule Bone Cancer mets most common form: BLT2KP  HYPERLINK \l "lungca" lung > HYPERLINK \l "breastca"breast (lytic) >  HYPERLINK \l "prostateca" prostate (blastic) > testes, kidney primary malignant: OS, malignant fibrous histiocytoma, adamantinoma, chordoma Osteochondroma most common primary bone lesion / young males / sessile or stalked / cartilage cap / usually stops growing as bones mature Chondroma single or multiple (Oliers Disease, Maffuccis syndrome) / short bones of hands, feet / radiolucent [ HYPERLINK "pics/chondroma-hand.jpg" XR] / lobulated, hypercellular, disorganized / focal calcification w/in lesion / self-limited disease Chondrosarcoma - good prognosis proliferation of malignant cartilage / older males / axial skeleton / surgery only useful option Osteoid osteoma very common / young males / < 2 cm growth / appendicular skeleton / produces pain at night (relieved by aspirin) / radiolucent lesion surround by reactive bone formation / surgical removal / 25% relapse due to poor nidus locating by surgeon Osteosarcoma (OS) - poor prognosis pre-op and post-op chemotherapy / arm, leg bones / produces bone, cartilage, spindle cells usually have mets / cortical destruction w/ extension in soft tissues (Codmans triangle) Parosteal osteosarcoma (POS) - excellent prognosis young, early middle age, women / long bones / radiolucent string sign along cortex / spindle cells produce well-formed bone Ewings sarcoma (variable prognosis) small cell neoplasia / unknown histiogenesis / very young, males, lower extremities / XR: moth-eaten intramedullary pattern, onion skin periosteal reactive bone / diaphysis to metaphysis / PAS+ cytoplasm / therapy evolving Fibrous cortical defect very common / young, males, long bones / XR: metaphysis, sub-cortical, soap bubbles, sclerosis at interface spindle cells, foamy macrophages, hemosiderin, chronic infiltrate / self-limiting at skeletal maturity Fibrous dysplasia very common / single, multiple / young, localization random / XR: radiopaque, shepherds crook of proximal femur / spindle, cells, woven bone, lack of osteoblastic rimming, Chinese character appearance / no treatment unless symptomatic / excellent prognosis Malignant fibrous histiocytoma (poor prognosis) similar demographics to OS / XR: metaphysis, destructive, radiolucent / anaplastic spindle cells, storiform pattern / treatment same and prognosis slightly worse than OS Giant cell tumor of bone benign but aggressive local tumor / young, wide distribution / hemorrhage / surgery when possible / extended curettage (experimental) or resection / prosthesis / 98% monostotic / radiation contraindicated (secondary sarcomas) Adamantinoma (good prognosis) primary malignant bone tumor / young males, tibia/fibula / XR: may be multifocal (observe carefully) / epithelial or endothelial proliferation / complete surgical extirpation Chordoma malignant bone tumor arising from notochord / 40s to 60s / males / physaliferous cells in acid mucoid background / surgery and post-op  HYPERLINK \l "irradiation" radiation survival: sacral 60% (fair) 5 yr, cervical (horrible) 50% 5 yr 0% 8 yr Myositis ossificans athletic adolescents, history of trauma (50%) / central fibroblast proliferation, intermediate zone of osteoid formation, peripheral shell of organized bone / Treatment: usually cured by excision Connective Tissue Diseases Rheumatoid arthritis ( HYPERLINK \l "ra" see bone) Systemic Lupus Erythematosis (SLE) 1 in 300 black women / HLA-DR3 / HLA-DR2 Differential: psoriasis (i.e. avoid UV light therapy), lyme disease, drug reactions,  HYPERLINK "micro.doc" \l "tinea" tinea Diagnosis: must meet 4 of 11 criteria (malar rash, discoid rash, photosensitivity, mucosal ulcers, arthritis, serositis, renal, neurologic, hematologic, positive ANA, positive LE or anti-ds or anti-Sm) Complications: General: fatigue, weight loss, fever Skin: malar rash (fixed erythema, flat or raised over malar area, tends to spare nasolabial folds), discoid rash (erythematous raised patches with adherent keratotic scaling and follicular plugging), photosensitivity, periungual telangiectasia, HYPERLINK "ddx.doc" \l "alopecia"alopecia Renal: many forms possible / note: 80-90% of SLE becomes dormant when ESRD occurs mesangial (earliest: may remit or transition to other forms) focal proliferative (50%) membranous (50%) diffuse proliferative (20%, worst) Cardiovascular: endocarditis (Libman-Sacks/caused by  HYPERLINK \l "apa" APA syndrome) pericarditis hypercoagulability Raynauds (20-30%) purpuric lesions (see hematologic) Hematologic: hypercoagulable state (in addition, there is arterial-specific hypercoagulability in SLE patients due to variant mannose-binding lectin genes) leukopenia (<4000/mm3), lymphopenia (<1500/mm3), thrombocytopenia (<100,000/mm3), hemolytic anemia Pulmonary: More common ( pleuritis (LE cells are very specific, WBCs with pushed aside nucleus, very characteristic appearance, but make sure pathologist looks for them),  HYPERLINK \l "pleuraleffusion" pleural effusion (mildly exudative, unilateral or bilateral) Less common ( ILD (including pneumonitis) PE (from APA) pulmonary HTN diffuse alveolar hemorrhage (rare): 90% will have concurrent nephritis, abrupt onset, young women, association with pneumonia) malignancy: ! risk of  HYPERLINK \l "lungcancer" lung cancer > lymphoma other: BOOP, shrinking-lung syndrome, lymphadenopathy, infections GI: painless oral or vaginal ulcers, non-specific abdominal complaints / GI vasculitis (less common, serious) Musculoskeletal: arthralgias (symmetric/peripheral, two or more joints, swelling, effusion, tenderness but NOT erosive; only small percentage actually get joint deforming arthritis as in RA) CNS: diffuse psychosis, depression or focal neurological deficits (including seizures) [ HYPERLINK "pics/cnslesion-lupus-ddx.jpg" Ddx] / 50% experience some degree of neuropsychiatric problems / may see cystoid bodies in fundus Other: hepatosplenomegaly (functional hyposplenism), LAD Labs: decreased C3/C4 (can be marker of active disease, either can be depressed first depending on if classical or alternate pathway is activated, can also be decreased from poor synthesis such as in liver disease) thrombocytopenia, anemia  HYPERLINK \l "schistocytes" schistocytes generally not seen without active vasculitis or major  HYPERLINK \l "htn" HTN anticardiolipin Ab (30-50% have it, fewer actually have APA syndrome) false positive VDRL anti-nuclear antibodies (ANA) ( HYPERLINK "labs.doc" \l "ana" labs) 98% sensitivity, often high titre (1:80 happens in many people is non-specific) / 10% of SLE in whites may be ANA only (no other positive Abs), this is rare in non-whites Specific Patterns Peripheral ( active disease, renal involvement Diffuse ( SLE, RA, discoid lupus, normal elderly (rare) / can mask speckled or peripheral pattern Speckled ( RA, SLE, MCTD, chronic discoid lupus, chronic lung disease, scleroderma, normal elderly (rare) Nucleolar pattern ( scleroderma (occasionally SLE, RA, Sjogrens) anti-ds DNA specific for SLE, can fluctuate with treatment RPGN, rash, pneumonitis anti-Sm very specific anti-Ro (SSA) Sjogrens, SLE, myositis, etc. anti-La (SSB) cannot have La without Ro anti-U1-RNP/nRNP SLE, PSS, myositis / cytoplasmic Ab, thus can be negative ANA / very strong correlation with blacks + Raynauds and/or myositis and primary pulmonary HTN (uncommon) anti-ribosomal P specific for SLE, can be sole antibody with ANA negative SLE ANA to histone (diffuse pattern) suggests drug-induced (90% sensitive, but not so specific in that 20-30% of idiopathic SLE will have anti-histone Abs) Note: each patient has there own idiosyncratic pattern of lab markers to follow (compliment, platelets, WBC?, Anti-DS) Drug-induced SLE SLE-like syndrome / (+) ANA to histone / (+) genetic predisposition, ANA may remain positive for years Course: usually much less severe, resolves within 6 months of stopping drug Drugs: procainamide, INH, hydralazine, chlorpromazine, methyldopa Cutaneous lupus erythematosus Pathology: interface dermatitis and granular deposition of IgG along the dermal-epidermal junction Chronic Discoid Lupus Chilblains Lupus rare violaceous digital plaques, nodules develop after cold exposure / anti-Ro (SSA), Raynauds, changes in nail-fold capillaries / lesions contain papillary and deep dermal T-cells Pregnancy and SLE antibodies DO cross placenta and affect infant up to 6 months after birth / can cause irreversible congenital heart block (anti-Ro/SSA) (often before mother is diagnosed) Treatment: education! If disease is controlled (and < 10 mg prednisone), then it is okay to proceed with pregnancy Sjgrens syndrome (Keratoconjunctivitis Sicca) [ HYPERLINK "http://content.nejm.org/cgi/content/full/344/22/1701?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1701&journalcode=nejm" NEJM] females (usu. peri-menopause) / HLA-DR3 / can have primary or secondary (with SLE/RA) Mechanism: lymphocytic infiltration and destruction of lacrimal and salivary glands Presentation: dry eyes, dry mouth, dry skin, enlarged parotid, enlarged lacrimal gland / patient avoids sour foods Findings: dry skin, GI, GU, arthritis (more synovitis), bronchitis Complications: Peripheral neuropathies (50-60%) / usu. pure sensory, asymmetric chronic neuropathy (may precede other symptoms by many years)  HYPERLINK \l "gerd" GERD increased risk of B-cell lymphoma (1-5%) association with decreased  HYPERLINK \l "pfts" PFTs (lung disease) Diagnosis: eye exam (Schirmer test), lip biopsy (salivary gland) in uncertain cases, SSA (anti-Ro), SSB (anti-La) occur in only 3% of cases [note, one does not have anti-SSB without anti-SSA], often have elevated RF, ESR Treatment: symptomatic (fake tears, benzodiazepines for anxiety, etc.), pro-cholinergic agents, steroids for severe systemic complications Polymyositis/Dermatomyositis Antibodies Many with (-) Abs, but if (+) ( very specific for autoimmune myositis anti-Jo1 (his-tRNA synthetase) moderate prognosis 30% of PM, 20% of DM arthritis, interstitial lung disease, fever, Raynauds, mechanics hands all patients with Jo-1 are DR52, whites may also have DR3 or DR6 anti-SRP (signal recognition particle) poor prognosis cardiac (with palpitations), myalgias, mostly blacks / DR5 Anti-Mi-2 good prognosis 8% PM/DM, 20% of DM classic DM picture / 7, DRW53 Polymyositis Onset usually > 50 yrs Genetics: HLA-DR3, DQA1*0501 (whites and blacks), 0401 (blacks) Mechanism: CD8 T-cell mediated destruction Muscle: inflammatory myopathy Lungs: pulmonary inflammation / mostly CD8, some CD4 Heart: can get  HYPERLINK \l "cardiomyopathy" cardiomyopathy (even heart block) Diagnosis: clinical, EMG, biopsy Presentation: proximal muscle weakness, up to 30% with esophageal dysphagia, Raynauds (30%); eyes are spared; unlike myasthenia gravis; up to 50% will have additional connective tissue disease at same time Diagnosis: electromyography, biopsy (not always conclusive) / often confused with other forms of myopathy Labs: elevated plasma CK ESR may be elevated (but a super-high ESR may hint that something else instead or along with myositis is happening) Antibodies Anti-Jo-1 associated ILD responds more to steroids than other ILD (scleroderma, RA) Anti-Ku ( SCL/PM overlap (mostly in Japanese) / association with Graves, pulmonary HTN, and RNAP-II Course: less prolonged than muscular dystrophies / mortality usually from aspiration (pharyngeal weakness) Malignancy: risk ~2.0 x (no particular types, usually occur after PM diagnosis) Treatment: high-dose steroids (up to ~100 mg/day IV then PO) / improvement should occur with first few weeks with continued improvement over 3 to 6 months / continue initial dose until strength and CK normalizes for 4-8 weeks / CK can remain elevated due to leaky membranes and strength can remain low with normal CK due to steroid myopathy (i.e. steroid myopathy does not cause elevated CK) / reduce steroids by 10 mg/month, then qod dosing / 90% will improve at least partially / 50-75% will enter remission / can try MTX, azathioprine or even both together after 6 weeks of non-response to steroids / Plaquenil can help with skin manifestations of DM / others like cyclosporin and Cytoxan have been used / IVIG is useful for DM, and is being tried for  HYPERLINK \l "ibm" IBM Dermatomyositis bimodal age peaks [15-20] and [45-55] Mechanism: CD4 T-cell and B-cell mediated destruction / humoral response more important Skin changes without muscle involvement occurs in ~10% of cases Skin/Joints: heliotrope rash on face (Shawl sign) [HYPERLINK "pics/dm-shawl.jpg"pic], V-sign, mechanics hands, cuticle Changes (capillary engorgement, capillary dropout), periungual telangiectasia [HYPERLINK "pics/dm-telangiectasia.jpg"pic], calcinosis [HYPERLINK "pics/dm-calcinosis-elbow.jpg"pic] [ HYPERLINK "http://dermis.net/dermisroot/en/37886/diagnose.htm" dermis], Gotrons papules over finger joints, knuckles, elbows, patella Lungs: can have bad lung disease (usu. w/ anti-Jo1) Vasculitis of the gastrointestinal tract, kidneys, lungs, and eyes can complicate dermatomyositis (but not polymyositis), particularly in children Malignancy: relative risk 6.2 (about 20%, no particular type) / DM often diagnosed after or at same time as cancer, then risk decreases to 1.6 after 5 yrs Biopsy: classically different pattern than PM / ?can it look like SLE Treatment: similar to PM (with exception that IVIG can be particularly useful) / newly diagnosed patients should have basic workup for malignancy Juvenile Dermatomyositis (JDM) ANA negative / disease usually lasts about 2 years / diagnosis often suggested by calcinosis on plain films [HYPERLINK "pics/dm-calcinosis-elbow.jpg"pic] Scleroderma more in females Presentation: CREST (60-98%), raynauds (20%) [HYPERLINK "pics/raynauds-scars.jpg"pic], diffuse systemic sclerosis (10%) / cardiovascular, skin, kidney, GI, lungs / fibrosis, infarction may develop rapidly progressing renal disease / malignant hypertension in 1-2 weeks Diffuse type: rapid, early visceral involvement, diffuse skin involvement [ HYPERLINK "http://dermis.net/dermisroot/en/33886/diagnose.htm" dermis] (morphea) ~50% mortality rate at 5 years Lungs: pulmonary fibrosis or primary pulmonary HTN Diagnostic criteria: major - proximal skin thickening / minor sclerodactyly, digital pitting (ischemia), pulmonary fibrosis (CXR) Early signs: look for drop out capillaries in nail folds Genetics: anti-Scl 70 or anti-topoisomerase I CrEST type: calcinosis, Raynauds, esophageal dismotility (loss of smooth muscle may occur anywhere in GI tract), sclerodactyly, telangiectasia (mat and periungual) Labs: schistocytes on peripheral blood smear, ANA (20-30%), RF (20%) SCl-70 (DNA topoisomerase I) ( 70-80% of diffuse scleroderma Anti-centromere ( 70-80% CrEST, 25% Raynauds Nucleolar antigens ( 4-8% of scleroderma PM-Scl ( polymyositis, scleroderma overlap Anti U1-RNP/nRNP Anti-Ku (see PM) Ddx: eosinophilic fasciitis,  HYPERLINK \l "porphyriacutaneatarda" porphyria cutanea tarda, papular mucinosis (i.e., scleromyxedema), lichen sclerosis et atrophicus, melorheostosis, chronic GVHD, eosinophilia-myalgia syndrome Treatment: ACE inhibitors, Ca blockers (Raynauds), metoclopramide, sucralfate, omeprazole (GI problems), cisapride (from Mexico) Prognosis: may survive up to 20 years before succumbing to pulmonary hypertension Sarcoidosis more common in women, African-Americans Presentation: various protean manifestations / adults: CNS, lungs > heart >> renal Lungs: restrictive lung disease, pleurisy (with effusion) / actually does not produce rales (too much fibrosis) Liver: hepatomegaly (20-30%) Skin: both acute and chronic changes / lupus pernio (violaceous indurated lesions with a predilection for the nose, ears, lips, and face), skin plaques [ HYPERLINK "http://dermis.net/dermisroot/en/17039/diagnose.htm" dermis], maculopapular/papules (red-brown, waxy), subcutaneous nodules, and  HYPERLINK \l "erythemanodosum" erythema nodosum,  HYPERLINK \l "vitiligo" vitiligo (hypo or hyperpigmented), alopecia, old cars Ddx (for skin changes): Tb, berylliosis, leprosy, leischmaniasis, syphilis, deep fungal infection / other panniculitis (Behets, superficial thrombophlebitis, cutaneous vasculitides) CNS (5%): can present with only CNS problems (peripheral neuropathy, aseptic meningitis) or focal (cranial nerves; usu. bilateral VII, hypothalamus, pituitary) Ddx (for CNS): cancer with mets, fungal or Tb, lymphoma, HYPERLINK \l "langerhans"Langerhans histiocytosis, other Joints: knees, ankles, elbows, wrists, small joints of the hands / swollen, warm, tender, painful Complications: Lungs: hilar lymphadenopathy, pleural effusion Eye: variety of conditions / uveitis / others (20% incidence) ENT: parotitis / nasal involvement CNS: Bells palsy, diabetes insipidus (posterior pituitary > anterior), cranial nerves, basal meninges, hypothalamus, seizures, etc. / elevated ACE in CSF (66%), mononuclear pleocytosis / leptomeningeal enhancement [HYPERLINK "pics/neurosarcoidmri1.jpg"MRI] Heart: restrictive cardiomyopathy Liver: very common, but usually no symptoms, can be good biopsy site Renal: very uncommon Diagnosis: can be diagnosis of exclusion when biopsies inconclusive, often first recognized from CXR in asymptomatic patients (60-70% will have some abnormality on chest CT) Biopsy (of involved lesions): widespread non-caseating granulomas with Schaumann and asteroid bodies / may look like Tb / any one of following has 50-80% sensitivity (all three combined have 99% sensitivity) / note: granulomas in scalene, liver nodes are not (by themselves) sufficient for diagnosis (because granulomas are so frequent in these nodes) Transbronchial biopsy (TBLB) Transbronchial needle aspiration (TBNA) BAL showing lymphocyte predominance ( > 12%), high CD4:CD8 ratio (should not have high neutrophils or eosinophils at same time; ratio > 3.5 has 90% specificity, 50% sensitivity) Labs: Hypercalcemia (10%) (elevated 1-hydroxylase produces 1,25-OH D3) (hypercalciuria in 33%) serum ACE elevated in 66% (many false positives including Mycobacteria and malignancy) lysozyme elevated d-dimer (correlates with disease activity) Course: often asymptomatic and self-limiting Children under 5: skin rash, eyes (uveitis), arthritis (worse prognosis) Older children: lungs (usu. bilateral, hilar lymphadenopathy), lymph nodes, eyes Treatment: for stage I (asymptomatic), observation only, may regress / for stage II-III or with any serious organ involvement, corticosteroids (40 mg/day), other  HYPERLINK "pharm.doc" \l "dmards" DMARDs Prognosis: earlier onset tends to mean better prognosis Lofgrens syndrome acute sarcoidosis / usually with symmetric, periarticular ankle inflammation / may have  HYPERLINK \l "erythemanodosum" erythema nodosum Systemic vasculitides Complement levels all have normal complement levels except variable in PAN, leukocytoclastic, connective tissue disease, endocarditis / decreased in urticarial vasculitis Vasculitis Associations  HYPERLINK \l "pan" PAN and  HYPERLINK \l "hairycellleukemia" hairy cell leukemia  HYPERLINK \l "wegeners" Wegeners and  HYPERLINK \l "hodgkins" Hodgkins disease Granulomatous angiitis of CNS and lymphoma  HYPERLINK \l "gca" GCA and lymphoma  HYPERLINK \l "hsp" HSP and lymphoma grouped by vessel-size Large  HYPERLINK \l "gca" giant-cell arteritis  HYPERLINK \l "takayasus" Takayasus arteritis primary CNS vasculitis Medium (with or w/out involvement of small)  HYPERLINK \l "pan" PAN  HYPERLINK \l "kawasakis" Kawasakis  HYPERLINK \l "churg" Churg-Strauss  HYPERLINK \l "wegeners" Wegeners  HYPERLINK \l "buergers" Buergers? Small leukocytoclastic ( HYPERLINK \l "hsp" HSP,  HYPERLINK \l "cryoglobulinemia" cryoglobulinemia, infectious) connective tissue diseases  HYPERLINK \l "paraneoplastic" paraneoplastic microscopic PAN urticarial vasculitis Any size (pseudovasculitis) APAS endocarditis (bacterial/marantic) other embolic cholesterol embolism drugs (amphetamines and rarely  HYPERLINK "pharm.doc" \l "cocaine" cocaine) Infectious Vasculitis Ddx Bacterial agents Acute septic meningitis agents Mycobacteria Spirochetes Treponema, Borrelia sp., Leptospira Other agents Brucella species Bartonella henselae  HYPERLINK "micro.doc" \l "rickettsia" Rickettsiae Mycoplasma Viral agents HSV, VZV, CMV, EBV, B19, HBV, HCV, HIV,  HYPERLINK "micro.doc" \l "htlv" HTLV More: hantavirus, California encephalitis virus, EEE encephalitis virus, influenza, rubella Fungus Aspergillus, Coccidoides, Candida Mucormycetes Parasites Cysticercosis CNS vasculitis Ddx: reversible cerebral vasoconstriction syndromes ( HYPERLINK \l "rcvs" RCVS) PAN classic, microscopic/HBV, HIV Wegeners Takayasus hypersensitivity angiitis drug-induced, HSP neoplasia (many) infection ( HYPERLINK \l "vasculitisinfection" see below) CTD: SLE, RA, GCA primary angiitis of CNS (PACNS) CNS angiography, brain biopsy Diagnosis: start with MRI, then CNS angiography ( vessel wall irregularities, focal dilations, supraclinoid internal carotid artery narrowing, and distal branch occlusions [ HYPERLINK "pics/primarycnsvasculitismri1.jpg" MRI][ HYPERLINK "pics/primarycnsvasculitismri2.jpg" MRI][HYPERLINK "pics/primarycnsvasculitismri3.jpg"MRI][ HYPERLINK "pics/primarycnsvasculitismri4.jpg" MRI] Infectious Causes of Vasculitis Bacterial agents Acute septic meningitis agents Mycobacteria (5%) Spirochetes Treponema, Borrelia sp., HYPERLINK "micro.doc" \l "Leptospirosis"Leptospira (Weil syndrome) Brucella species Bartonella henselae Rickettsiae Mycoplasma Viral agents HSV, VZV, CMV, HBV, HCV, HIV, HTLV Fungus Aspergillus, Coccidoides, Candida Mucormycetes Parasites Cysticercosis BACTERIAL AGENTS Neonate (<1 month) Streptococcus agalactiae (44%) Escherichia coli (26%) Gram-negative bacilli (10%-22%) Listeria species (5%-10%) Children (1 mo to 15 yrs) Neisseria meningitidis (25%-40%) Streptococcus pneumoniae (10%-20%) Haemophilus influenzae (8%-12%) Adults (>15 years) Streptococcus pneumoniae (30%-50%) Neisseria meningitidis (10-25%) Staphylococci (1%-15%) Gram-negative bacilli (1%-10%) Listeria species (5%) Streptococci (5%) Head trauma, surgery Staphylococci Gram-negative bacilli Immunocompromise Listeria monocytogenes Respirator support Proteus species Pseudomonas Serratia Flavobacterium Ruptured brain abscess Gram-negative bacilli Anaerobes  Neonates get arteritis/thrombophlebitis (larger, +/- hemorrhagic infarcts, +/- secondary abscess formation) / venous thrombosis and hemorrhagic necrosis (associated with Pseudomonas, Proteus, Enterobacter, and Serratia) Septic venous sinus thrombosis/thrombophlebitis (up to 5%, usu. < 1 or 2 weeks) Note: sinus, middle ear, skull infection can beget cerebral vasculitis without detectable meningitis / also, basilar infection can causes vasculitis of ascending arteries Peripheral Nervous System Lyme disease ( multifocal axonal radiculoneuropathy HIV-1 ( multiple mononeuropathies CMV HCV ( cryoglobulinemia HSV, VZV ( sensory ganglia, radicular syndrome Giant Cell Arteritis (GCA) (temporal arteritis) Not uncommon (1 in 5000) / usually > 50 yrs / women > men (2:1) / whites, Scandinavians / HLA-DRB1*04 and DRB1*01 Presentation: gradual > abrupt / 15% fever / headache (66%, unilateral >> bilateral, dull and boring, superimposed sharp pain), jaw claudication (50%), temporary blindness, fever, weight loss, myalgias/arthralgia, malaise, cough/hoarseness (10%), neuropathies (10%), TIA,  HYPERLINK \l "pmr" polymyalgia rheumatica (50%) Complications: blindness (can occur early on, retinal changes like edema of optic disk, cotton-wool patches, small hemorrhages, usu. occur after blindness, usu. from nerve ischemia), eye exam can be helpful / thoracic aortic aneurysm (17x) normal incidence Associations: lymphoma (vasculitis may precede lymphoma) / Pathology: mainly external carotids and vertebral / can hit central retinal artery (but intracranial arteries are NOT involved) Diagnosis: biopsy temporal artery, try to get affected site (if cannot localize on exam, then get larger piece, 3-5 cm), can do bilateral biopsy to increase yield, yield of biopsy decreases with each day of steroids but can still be positive even at 1-2 wks post-steroid (lymphocytes, plasma cells, giant cells) / high ESR (over 50, often > 100, can be expected to decrease within days of treatment, ~20% have normal ESR) / CRP is more sensitive / NOTE: careful exam may reveal findings prior to onset of symptoms Treatment: prednisone (1 mg/kg qd 1-2 months then taper by 5-10% q 1-2 wks) / usually see improvement within days (if not, question diagnosis) / can use 100 mg qd for optic nerve involvement / can begin cyclophosphamide (maybe other DMARDS) if necessary / can begin to think about tapering after 1-2 months (10-20% every 2 weeks), but must continue to treat for a long time (1-4 yrs to reduce recurrence) / qod therapy thought to be less effective but open question of whether some patients can start at lower doses (20-30 mg qd) / of patients have serious complication of extended steroid use ASA also thought to decrease risk of occlusions Recurrence: 30-50% have spontaneous exacerbations independent of steroid regimen / most often, recurrence involves PMR Sx and can be treated by increasing steroids by 2 to 5 mg/qd Takayasus Arteritis Granulomatous inflammation of large arteries / young women (>Asian) / complications may develop over months to years / affects aorta and branches (subclavian), pulmonary arteries (up to 50%), renal artery Presentation: weak pulse in upper extremities (arm claudication), ocular disturbances, HTN (renal artery) / Raynauds / systemic: fever, weight loss Diagnosis: CT may reveal circumferential thickening / MRI may show enhancement on T1 Labs: increased ESR Kawasakis Mostly children (4-5/years) / medium-sized arteries 5 diagnostic criteria: more than 5 days of fever, bilateral conjunctival injections, oral mucosa and pharynx (infected and dry fissured lips, strawberry tongue), peripheral extremities (edema, erythema, desquamation rash, primarily truncal), cervical adenopathy Complications: hydrops of gallbladder, more - Treatment: restrict activity 3-4 wks Anti-inflammatory Immunoglobulin 2 gm/kg single / 400 mg/kg/day x 4 days MMR should be delayed 6 months Aspirin 80-100 mg/kg/day QID until afebrile Anti-platelet agents Treat for 3 months, but indefinitely and add more agents? if coronary involvement ANCA Associated Vasculitides (AAV) Polyarteritis Nodosum (PAN) rare / occlusion (infarct) of medium to small arteries (NOT capillaries) /  HYPERLINK \l "typethree" type III hypersensitivity Presentation: usually present with constitutional symptoms Associations: HBV, hairy cell leukemia Findings: cotton-wool patches, pericarditis, myocarditis, palpable purpura aneurysm (hemorrhage) Diagnosis: 3 or more of 10 criteria (sensitivity 80%, specificity 85%) Weight loss > 4 kg HYPERLINK \l "livedo" livedo reticularistesticular paintesticular biopsy useful if involvedmyalgias/arthritisCK usually normalmono/polyneuropathy50-80% (only 15% in MPA) good chance of recovery within 1 yrdiastolic ( > 90) elevated BUN/CrRenal vasculitis (not RPGN) Renal failure may occur laterHBV positiveNot in MPAGI aneurysms by MRAGI pain in 30% (risk of perforation)positive biopsy Labs: elevated ESR (~85), CRP, WBC, eosinophils, normochromic anemia, HBsAg found in 10-30%, HCV rarely associated, 20% have positive  HYPERLINK "labs.doc" \l "panca" p-ANCA to myeloperoxidase (MPO), RF (+) in 20% Treatment: steroids, cyclophosphamide, plasma exchange (2nd line) HBV-PAN More HTN than classic PAN Remember to treat both HBV and PAN Treatment: plasmapheresis and lamivudine Microscopic Polyangiitis (MPA) May have capillary involvement in addition to small/medium arteries (unlike classic PAN) Glomerulonephritis (usu. RPGN) common (not in PAN), alveolar hemorrhage (not in PAN) Presentation: can have arthralgias,  HYPERLINK "ddx.doc" \l "hemoptysis" hemoptysis et al for months/yrs!!! before explosive onset (longer prodrome than with PAN) / most with constitutional symptoms before diagnosis Labs: almost always have p-ANCA (+) and MPO (+) / rarely c-ANCA will be (+) / other P-ANCA (but not MPO):  HYPERLINK \l "feltys" Feltys,  HYPERLINK \l "uc" UC (directed against different proteins) Course: relapse in MPA (35%) > HBV-PAN and c-PAN (10%) Treatment: ?similar to classic PAN Wegeners Granulomatosis medium to small arteries /  HYPERLINK \l "typefour" type IV DTH Presentation: chronic sinusitis, epistaxis, mucosal ulcers, cough (45%), HYPERLINK "ddx.doc" \l "hemoptysis"hemoptysis (30%), fever, night sweats, arthritis, myalgia, skin nodules, renal failure, cranial nerve palsies (II, VI, VII), pachymengitis / mean interval from symptoms to diagnosis 15 months Affected: nose, throat, bronchi, kidneys Complications: renal failure (HYPERLINK \l "hematuria"hematuria, RBC casts,  HYPERLINK \l "rpgn" RPGN) / saddle-nose deformities, sepsis, hemorrhage, DIC / usu. does not lead to respiratory failure Associations: Hodgkins lymphoma Diagnosis: cANCA (confirm with anti-proteinase 3) (90% sensitivity, few false positives) / ~10% with p-ANCA / ~10% with anti-GBM biopsy of ENT likely to show only necrosis, biopsy of kidney likely to show only non-specific RPGN, you cant stain for IF (thats why its called pauci-immune!!!), biopsy of lung most likely to confirm diagnosis Chest CT [HYPERLINK "pics/wegeners-chestCT1.jpg"CT] [ HYPERLINK "pics/wegeners-chestCT2.jpg" CT] [ HYPERLINK "pics/wegeners-chestCT3.jpg" CT] pulmonary infiltrates or nodules (up to 85%) / not pleural effusions Labs: elevated ESR, thrombocytosis Prognosis: higher ESR, older age gives worse prognosis / ENT involvement gives better prognosis Treatment: cyclophosphamide (1st), steroids (2nd or 1st for  HYPERLINK \l "dah" pulmonary hemorrhage) / bactrim is sometimes helpful (prevention of infection may avoid a potential trigger) / not MTX Hypertrophic pachymeningitis (HP) pANCA positive CNS disease, which some think of as Wegeners limited to CNS/cranial nerves / treat as Wegeners Buergers (Thromboangiitis Obliterans) [ HYPERLINK "http://content.nejm.org/cgi/content/full/343/12/864?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=buerger&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nej" NEJM] male, smokers / medium to small arteries AND veins Presentation: hypercoagulability, claudication, pain, Raynauds, gangrene Exam: Allens test Treatment: perhaps ca-blockers, stopping smoking will hopefully stop progression of disease Churg-Straus Angiitis [ HYPERLINK "http://content.nejm.org/cgi/content/full/343/13/953?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=churg&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nejm" NEJM] 3 stages (order can vary) / asthma, eosinophilia, vasculitis Asthma may occur up to 30 yrs (mean 3) before vasculitis, onset with vasculitis in 10%, after in 2%) / sinusitis, allergic rhinitis, nasal polyps Eosinophilia can mimic chronic HYPERLINK \l "eosinophilicpneumonia"eosinophilic pneumonia Vasculitis mononeuritis multiplex (72%), weight loss (>50%), fever, myalgia, skin lesions (60%) > GI (50%) > spleen > heart (myocarditis, infarction) > kidneys (FSGN) Diagnosis: angiitis and extravascular necrotizing granulomas with eosinophils Labs: P-ANCA (50%, usu. anti-MPO), RF, elevated ESR (80% of cases), eosinophilia (over 10% in 90% of cases) Often seen in asthma patients being tapered from PO or inhaled steroids (may be associated with leukotriene antagonists) Treatment: Hypersensitivity Angiitis adverse drug reaction HSP (Henoch Schnlein Purpura) ( HYPERLINK \l "hsp" see renal) small vessel vasculitis Behets Disease (Behcets) [ HYPERLINK "http://content.nejm.org/cgi/content/full/341/17/1284?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=%22oral+ulcers%22&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jour" NEJM] mostly in people of Middle East, Japanese descent / onset in 20 to 30s Course: chronic, relapsing acute attacks / manifestations (except uveitis) usually self-limited Presentation: Mouth: aphthous oral [HYPERLINK "pics/behcets.jpg"pic] / genital ulcers [HYPERLINK "pics/behcets.gif"pic] Eye: uveitis,  HYPERLINK \l "retinitis" retinitis (can cause blindness),  HYPERLINK \l "hypopyon" hypopyon Skin: superficial migratory thrombophlebitis, erythema nodosum (including pseudofolliculitis and acneiform nodules / pathergy Joints: mono/polyarthritis (50%, knees > wrist, elbows, ankles) (non-deforming) Coagulopathy: vasculitis/ hypercoagulability (major concern is retino-occlusive disease), venous 7 times more than arterial (however, can get aneurysms, stenoses), 25% will have at least superficial venous thromboembolism Less common: GI, CNS (early onset males 10-20%), large vessels / may have Diagnosis: oral ulcers + 2 other criteria / can look for HLA-B51 (not in S. American, N. American), elevated IgD levels CSF: elevated IgG (not oligoclonal), pleocytosis MRI: multiple high-intensity focal lesions in brain stem, basal ganglia, and cerebral white matter are typical on T2-weighted MRI Ddx: chronic oral aphthosis, Sweets, HSV, AS / GI (IBD), CNS (MS), pathergy (Sweets, pyoderma gangrenosum), retinitis (sarcoid, viral retinitis) Treatment: Skin: topical steroids, thalidomide, colchicines, oral steroids Ocular, GI, CNS: oral steroids / other immunosuppressives (Cytoxan, Immuran, others) / note: cyclosporin may worsen CNS symptoms (its not a first line agent) / IFN-a, IVIG under investigation Arthritis: steroids, NSAIDS, colchicines, sulfasalazine, IFN-a (highly effective) Vasculitis: steroids / be careful with anticoagulation for venous thrombosis (can get big time hemoptysis with arteritis) / treatment of vascular complications is very tricky in this disease since mechanisms are multiple and unclear / CV surgery for complications HLA Associations [HYPERLINK "pics/bsl-hla1.jpg"HLA genetics diagram] Disease HLA alleleRelative risk factor DR5Hashimotos thyroiditis 3DR4Rheumatoid arthritis6DR3Dermatitis herpetiformis SLE (esp. subacute cutaneous, neonatal) Sjogrens PM56DR2Goodpastures  HYPERLINK \l "ms" Multiple sclerosis13 5B27 Ankylosing spondylitis Reiters Postgonococcal arthritis87 37 14C6 Psoriasis vulgaris13B8Myasthenia gravis4B51 Behets Reversible cerebral vasoconstriction syndromes (RCVS) (or Call-Fleming Syndrome or Migraine Angiitis [ HYPERLINK "http://www.annals.org/cgi/content/full/146/1/34" AIM] must be distinguished from classical cerebral angiitis (using CNS imaging) Associated conditions (many) [HYPERLINK "pics/rcvs.jpg"table] / unlike migraine, no aura, presentation is hyperacute Causes: vasoactive drugs, diet pills, stimulants, some antidepressants, decongestants, illicit drugs (amphetamines, cocaine, ecstasy) Treatment: calcium channel blockers, steroids (mechanisms and treatments being worked out 1/07) Spondylarthropathies  HYPERLINK \l "ankylosing" AS,  HYPERLINK \l "psoriasis" psoriasis,  HYPERLINK \l "reiters" Reiters and Reactive, IBD spondylitis sacroiliitis enthesopathy asymmetric oligoarthritis Other: inflammatory eye disease, urethritis, and mucocutaneous lesions Labs: all have negative RF Ankylosing spondylitis (AS) (Marie-Stumpell Disease) inflammation and ossification of the joints and ligaments of the spine and of the sacroiliac joints Epidemiology: young people (~24 yrs) / males=females / HLA B27 (90%) / may occur in association with  HYPERLINK \l "ibd" IBD Pathology: chronic, progressive (insidious) inflammatory disease of axial joints (hips, shoulders, sacroiliac) / asymmetrical, oligoarticular (1-4 joints) / inflammation at site of insertion / autoantibodies to joint elements following infection Complications: kyphosis and eventually complete fusion or bamboo spine /  HYPERLINK \l "ai" aortic insufficiency / peripheral joint involvement / pulmonary fibrosis / uveitis (25%) (can lead to glaucoma and blindness) Diagnosis: do sacral XR 1st reveals squaring, syndesmophytes, Presentation: morning stiffness (gel) / pace floor at night / improves with exercise / pain may move from one joint to another Treatment: therapeutic goal is to maximize the likelihood that fusion will occur in a straight line physical therapy / avoid smoking (pulmonary compromise) NSAIDS (for symptomatic relief) Anti-TNF-alpha (now in use 2008) methotrexate and sulfasalazine (were tried before TNF-alpha available) surgical procedures to correct some spine and hip deformities may be used in select cases Course: only 6% die from actual disease; most commonly (cervical fracture, heart block, amyloidosis), and more rarely from the restrictive lung disease Psoriatic arthritis ( HYPERLINK \l "psoriasis" see skin psoriasis) hereditary, 20 to 40 yrs / 7-40% of psoriasis patients get arthritis (may precede skin findings) / also has sporadic form presenting later on in life 4 major forms of arthritis most have peripheral, asymmetric oligoarticular arthritis DIP with nail disease 25% have symmetric polyarthritis similar to RA spondylitis/sacroiliitis less common Findings: DIP swelling, sausage digits [HYPERLINK "pics/psoriaticarthritishands.jpg"pic] / nail problems (onychodystrophy, onycholysis, nail pitting, and subungual keratosis, onychauxis) [HYPERLINK "pics/psoriasishands.jpg"pic] / psoriatic lesions on extensor surfaces Diagnosis: must have skin or nail changes for definitive diagnosis Labs: mildly elevated ESR / hyperuricemia in severe cases Synovial fluid: 2 to 15 WBCs / Radiography: distal interphalangeal erosions or telescoping joints, asymmetric sacroiliitis, isolated axial syndesmophytes Treatment: TNF-alpha blockers slow progression of arthritis and skin complications  HYPERLINK "pharm.doc" \l "nsaids" NSAIDs (indomethacin) and intra-articular steroids (avoid injections through psoriatic plaques) for symptomatic relief / 2nd line:  HYPERLINK "pharm.doc" \l "mtx" MTX,  HYPERLINK "pharm.doc" \l "penicillamine" penicillamine,  HYPERLINK "pharm.doc" \l "gold" gold,  HYPERLINK "pharm.doc" \l "hydroxychloroquine" hydroxychloroquine Reiters syndrome (see reactive arthritis) HLA B27 / males, 20-30s / HIV patients Presentation: asymmetric oligoarthritis, (non G-C) urethritis, conjunctivitis, uveitis, characteristic skin and mucous membrane lesions low back pain Onset: 2-4 weeks after inciting GI or GU infection( Chlamydia) Common complications: lower extremities: ankles, knees, feet, heels (enthesitis of Achilles tendon) oligoarticular sausage digits (dactylitis) Other complications: transient conjunctivitis (40%) / may need urgent opthalmological referral (topical or systemic steroids) for (3-5%) disabling iritis, uveitis (can be difficult to treat), corneal ulceration oral ulcers and glans penis (circinate balanitis; 25-40%; painless, red rash) keratoderma blennorrhagicum (mollusk shell skin lesions on palms and soles, may have severe desquamation; similar appearing to papular psoriasis nail changes myocarditis: heart block (<5%), aortic insufficiency Note: many people have single reactive arthritis symptoms without multiple findings Causative organisms: chlamydia trachomatis (decreasing), Neisseria (culture-negative), GI: Shigella, Salmonella, Campylobacter jejuni, Yersinia enterocolitica Labs: elevated ESR and leukocytosis / 0.5 to 75 WBCs in synovial fluid / bacterial antigens present in joints (chlamydia is dormant) / ANA and RF usu. negative Radiography: asymmetric syndesmophytes along spine (ankylosing spondylitis has symmetric and contiguous) Course: most recover (one to several months), 50% recurrence (varying degrees of disability) Prevention: must take antibiotics (doxycycline) prior to travel / even with HLA B27 20% risk of reactive arthritis with proper infection Treatment: symptomatic relief with NSAIDs (2nd line sulfasalazine) and intra-articular steroids / topical steroids for skin complications / prolonged doxycycline may be useful in cases with chlamydia infection Reactive arthritis may follow GI infection (Shigella flexneri, Salmonella species, or Yersinia enterocolitica infections / same joint problems as Reiters / extra-articular symptoms tend to be mild / treatment will be similar to Reiters (doxy?) HLA B27 Ankylosing Spondylitis (90%) Reiters Syndrome (75%) Psoriatic arthritis (20%) / with sacroiliitis/spondylitis (50%) Enteropathic arthritis (IBD) (8%) / with sacroiliitis/spondylitis (50%) Arthritis of inflammatory bowel disease Crohns or UC (10-20%) / similar to that of AS spondylitis, sacroiliitis, and peripheral arthritis ( > knee / ankle) peripheral arthritis may correlate with colitis activity (spinal disease does not) antibiotics not effective, but still must rule out septic joints Treatment: NSAIDS (not salicylates) / GI intolerance more likely in these patients,  HYPERLINK "pharm.doc" \l "misoprostol" misoprostol may cause unacceptable diarrhea / sulfasalazine may also be effective / local steroid injection / PT Myopathy Drugs causing myositis (by mechanism) Inflammatory L-dopa, procainamide, cimetidine, D-penicillamine, L-tryptophan, Non-inflammatory necrotizing or vacuolar cholesterol-lowering agents, chloroquine, colchicine, emetine, aminocaproic acid, labetalol, cyclosporine and tacrolimus, isoretinoic acid (vitamin A analog), vincristine, alcohol  HYPERLINK \l "rhabdomyolysis" Rhabdomyolysis and myoglobinuria cholesterol-lowering drugs, alcohol, heroin, amphetamine, toluene, cocaine, aminocaproic acid, pentazocine, phencyclidine  HYPERLINK \l "malignanthyperthermia" Malignant hyperthermia halothane,  HYPERLINK \l "ethyleneglycol" ethylene, diethyl ether, methoxyflurane, ethyl chloride, trichloroethylene, gallamine, succinylcholine Mitochondrial Zidovudine (AZT) Myotonia 2,4- d-chlorophenoxyacetic acid, anthracene-9-carboxycyclic acid, cholesterol-lowering drugs, chloroquine, cyclosporine Myosin loss non-depolarizing neuromuscular blocking agents, IV steroids Drugs causing myopathy (painful vs. painless) Painless Alcohol (chronic), steroids Myoglobinuria CNS depressants, CNS stimulants, CO,  HYPERLINK \l "cyanide" cyanide,  HYPERLINK \l "arsenic" arsenic, snake venom Hypokalemia Diuretics, laxatives, licorice, carbenoxolone, ampho B, toluene, alcohol Painful Inflammatory Procainamide, phenytoin, levodopa, interferon alpha, cimetidine, leuprolide, PTU, penicillamine Mitochondrial AZT, germanium Drugs of abuse Alcohol, cocaine, heroin, PCP, volatile chemicals Focal myopathy IM injections, IVDA, cephalothin, lidocaine, diazepam, pethidine, pentazocine, meperidine, antibiotics in children Other Alcohol (acute), NMJ blockers (vecuronium, pancuronium), lovastatin < simvastatin, clofibrate, gemfibrozil, aminocaproic acid, excess vitamin E, etritinate, ipecac, emetine (overuse), organophosphates (acute poisoning), toxic oil syndrome, eosinophilia myalgias syndrome, snake venom (peak at 24-48 hrs) Chronic Alcohol Myopathy Painless, progressive proximal muscle weakness / of alcoholics / damage is cumulative, but strength often restored after cessation Histology: type 2b fiber atrophy, no necrosis Acute Alcohol Myopathy Weak, painful, swollen muscles and cramps / may be limited to only one limb or muscle in most cases, cramps resolve in 1-2 days, pain and swelling takes 1-2 weeks, strength normal in 10-14 days / can develop rhabdomyolysis / lag time between alcohol consumption and elevated CK (several indirect mechanisms proposed) Labs: CK, LDH, myoglobin elevated Histology: necrosis and myofibrillar disorganization (inflammation is debatable) Hypokalemia Severe, painless proximal muscle weakness (no cramps, no swelling) / develops over hours/days / serum K between 1.4 2.5 / can cause rhabdomyolysis / complete reversal with K replacement Labs: CK, AST, aldolase elevated Histology: vacuolar changes, macrophages, +/- necrosis, regeneration Steroids (esp. dexamethasone, triamcinolone) Symmetrical, proximal muscle weakness / lower > upper / occasionally myalgias / may have generalized weakness, atrophy (severe cases) / very unlikely with < 10 mg/day or alternate day dosing Chronic Steroids Usually > 3 weeks / usually with other stigmata of steroids use Labs: CK usually normal / EMG shows normal rest activity, short-duration, low-amplitude motor units / Histology: type II atrophy, increased glycogen in type II fibers, lipid droplets in Type I fibers / EM shows sarcolemmal projections, vesicular bodies High-dose steroids Can occur 1-2 days after treatment / often seen when treating severe asthma / may be generalized / may involve respiratory muscles / additional risk factors such as NMJ blockers, sepsis / near total recovery in weeks Histology: changes in both fiber types, vacuolar changes, regenerating fibers / normal EMG Licorice, carbenoxolone Pseudo-hyperaldosteronism / Na retention, edema, hypokalemia Chloroquine Usually starts in legs / takes 6 months to occur / may also have neuropathy EMG shows fibrillations, positive waves, occasionally myotonic discharges Histology: degeneration and acid phosphatase positive vacuoles in up to 50% of fibers / type I fibers predominantly affected / EM shows myeloid bodies and curvilinear bodies similar to neuronal ceroid lipofuscinosis Hydroxychloroquine (Plaquenil) is supposed to be safer, but I suspect the findings are similar  HYPERLINK "pharm.doc" \l "amiodarone" Amiodarone may occur as early as 1 month / also get peripheral neuropathy, tremor, ataxia Perhexilene Anti-anginal agent / myopathy usually with long-term use only (reported as soon as 2 weeks, associated with rash, resolved with discontinuation Other side effects include weight loss, hypoglycemia, hepatic dysfunction, peripheral neuropathy Colchicines Note: sometimes misdiagnosed for polymyositis Sensory or motor nerve conduction is low-amplitude or absent EMG shows fibrillations, positive waves, myopathic motor units Histology: vacuolar myopathy Vincristine Histology: segmental necrosis, phagocytosis, spheromembranous degeneration / probably can have myopathy without neuropathy Zidovudine (AZT) Mechanism: ?false substrate for mitochondrial DNA polymerase Dose-related proximal muscle weakness and myalgias with pronounced wasting / elevated CK / usually improves with discontinuation Histology: ragged RED fibers / rod-body formation, necrosis, microvacuolization / EM has various changes Cannot always distinguish from HIV myositis Lovastatin Rapidly progressive, necrotizing myopathy / weakness, myalgias, CK 8000-30,000 / can lead to rhabdomyolysis / incidence of 0.5% (compare to incidence of elevated LFT of 2%) / risk increased with combination of lovastatin, gemfibrozil,  HYPERLINK \l "niacin" niacin, immunosuppressive agents Histology: necrosis Much less common with Simvastatin Aminocaproic acid usu. > 4 wks, can occur as early as several days Etritinate (dermatology drug) mild-transient myalgias occur in 15%, do not require discontinuation / occasionally, can be more severe Synovial fluid analysis Characteristics RAGout/PseudogoutReiters/PsoriaticSepticOA/TraumacoloryellowclaritycloudypusviscositypoorMucin clotpoorWBC3-50 K> 50 K% poly> 70glucose10-25% less than serumprotein> 3.0 g/dlcomplementlowmicroscopicRA cellsculturenegative WBC (% Poly)glucoseotherearly RAchronic/subsiding crystalosteonecrosisSLESclerodermaVasculitissickle cellamyloidosisHypothyroidOsteochondritis dessicansGroup IIRAReitersPsoriasisIBDASAcute crystalViralARFJRABehetsInfectionGroup IIIBacterial FungalMycobacterialAcute crystalGroup MTraumaNeuropathyBleeding Disorders (hemophilia,  HYPERLINK \l "vwf" vWF, anticoagulation, scurvy, TCP, thrombocytosis)Tumor, VNS, hemangiomaProsthesis, post-op aneurysmSickle cell Cardiovascular [ HYPERLINK "cardiology.html" a bunch of images]  HYPERLINK \l "circulatory" General Circulatory  HYPERLINK \l "htn" HTN,  HYPERLINK \l "edema" Edema,  HYPERLINK \l "thrombosis" Thrombosis,  HYPERLINK \l "pe" PE,  HYPERLINK \l "dic" DIC,  HYPERLINK \l "shock" Shock,  HYPERLINK \l "chf" CHF,  HYPERLINK \l "corpulmonale" Cor Pulmonale General Metabolic  HYPERLINK \l "hyperlipidemia" hyperlipidemia,  HYPERLINK \l "atherosclerosis" atherosclerosis ( HYPERLINK \l "pvd" PVD)  HYPERLINK \l "cad" Ischemic   HYPERLINK \l "angina" ANGINA,  HYPERLINK \l "mi" MI  HYPERLINK \l "mi" (myocardial infarction)  HYPERLINK \l "cardiomyopathy" Cardiomyopathies dilated,  HYPERLINK \l "restrictivecardiomyopathy" restrictive,  HYPERLINK \l "hocm" HOCM  HYPERLINK \l "Arrhythmias" Arrhythmias  HYPERLINK \l "bradycardia" bradycardia,  HYPERLINK \l "heartblock" heart block,  HYPERLINK \l "afib" atrial fibrillation,  HYPERLINK \l "atrialflutter" atrial flutter,  HYPERLINK \l "svt" SVT  HYPERLINK \l "mat" MAT,  HYPERLINK \l "vt" VT,  HYPERLINK \l "qt" prolonged QT,  HYPERLINK \l "torsades" torsades de pointes  HYPERLINK \l "valvular" Valvular  HYPERLINK \l "as" AS, HYPERLINK \l "mitralstenosis"MS,  HYPERLINK \l "ar" AR,  HYPERLINK \l "mr" MR,  HYPERLINK \l "tr" TR,  HYPERLINK \l "rheumaticfever" Rheumatic Fever  HYPERLINK \l "antibioticprophylaxis" antibiotic prophylaxis  HYPERLINK \l "aaa" Aortic Aneurysm  HYPERLINK \l "aorticdissection" Aortic Dissection  HYPERLINK \l "endocarditis" Endocarditis  HYPERLINK \l "myocarditis" Myocarditis  HYPERLINK \l "pericarditis" Pericardial Disease   HYPERLINK \l "pericardialeffusion" pericardial effusions,  HYPERLINK \l "acutepericarditis" acute pericarditis,  HYPERLINK \l "InfectiousPericarditis" infectious pericarditis,  HYPERLINK \l "dresslers" Dresslers,  HYPERLINK \l "uremicpericarditis" uremic,  HYPERLINK \l "restrictivepericarditis" restrictive pericarditis,  HYPERLINK \l "cardiactamponade" cardiac tamponade HYPERLINK \l "cardiactumors"Cardiac Tumors, HYPERLINK \l "pedheart"Cardiac Malformations [ HYPERLINK \l "cardiacpreop" cardiac pre-op][ HYPERLINK \l "cardiacphysiology" cardiac physiology][HYPERLINK \l "cardiacphysical"cardiac physical exam][ HYPERLINK \l "ekg" EKG reading] [ HYPERLINK \l "milabs" cardiac labs] Cardiac Physiology Single Cardiac Cycle [HYPERLINK "pics/cardiaccycle.jpg"see diagram] Jugular Venous Pulses [HYPERLINK "pics/jvp.jpg"see diagram] Swan-Ganz catheter [ HYPERLINK \l "swanganz" interpretation of values]  HYPERLINK "http://home.mdconsult.com/das/book/view/882?sid=21483771" Radiology of the Heart in Cecils at MDconsult (great pictures) Fick equation CO = (O2 consumption) / (AO2% - VO2%)(Hg)(1.36)(10) Cardiac Physical Exam Systolic murmurs [HYPERLINK "pics/systolicmurmurs.jpg"see diagram] Diastolic murmurs [HYPERLINK "pics/diastolicmurmurs.jpg"see diagram] Low-Pitched Sounds ( Bell ( S3, S4, MS, AR (Austin-Flint) High-Pitched Sounds ( Diaphragm ( everything else Sound Best Heard S2 2nd/3rd LICS S3 3rd/4th LPS and apex / increased with inspirationS4 3rd/4th LPS and apexPDA 1st/2nd LICS mid-clavicularMRARMSASMSMR can radiate to various places ARASASD pulmonic area of the chest / may radiate to back as with pulmonary stenosisVSD S1 increased (!) LVH (muscle), MS S1 decreased (!) LVH (collagen), LV dilatation/dysfunction, some MR, AR, prolonged PR, LBBB Note: mechanisms can be way too complex and youll make yourself crazy; just refer to this S2 (normally S2 splitting increases with inspiration due to increase venous return and RVEF; it follows that inspiration will increase most right-sided murmurs/gallops) abnormally increased split S2 Delayed RV (electrical): incomplete RBB, pacemaker,  HYPERLINK \l "pvc" PVC Delayed RV (mechanical): VSD (if L(R flow), pulmonic stenosis, severe pulmonary edema (! impedance) Shortened LV ejection time:, MR fixed split S2 ASD ( HYPERLINK "http://www.uni-duesseldorf.de/WWW/MedFak/Herz-Kreislauf-Physiologie/lehre/sounds/html/asd.html" explanation; why not variable? RV already ~max overloaded; and L/R atrial pressures equalized so no net  in LV/RV output with inspiration unlike VSD) mild pulmonary HTN RVF paradoxically split S2 (decreases with expiration) usually from delayed A2 due to electrical (complete LBB (1st), RV PVC) or mechanical (AS, HOCM, acute ischemia, myocarditis, CHF) S3 AR, TR, MR / dont confuse with tumor plop S4 stiff ventricle (various causes) / it cant happen during  HYPERLINK \l "afib" Afib Jugular Venous Pulsations (JVP) [HYPERLINK "pics/jvp.jpg"diagram] dip and plateau or square root sign (  HYPERLINK \l "constrictivepericarditis" constrictive pericarditis Kussmauls sign ( constrictive pericarditis Prominent y descent ( constrictive pericarditis Large V wave ( TR Canon a wave ( AV dissociation Pericardial effusion r/o tamponade (pulsus paradoxus, undulating pulses) elevated venous pressure Borderline expiration/inspiration 105/94 Electrical alternans or alternating voltage big pericardial effusions from TB and tumor [< 5 mm leads 1-aVF] / can also be from AV fistula in lungs/coronary vessels Treatment: pericardial window / can also obliterate pericardial space with nitrogen mustards, talc, tetracycline to prevent recurrence Pulsus paradoxus > 10 mmHg fall in SBP during inspiration / occurs in 95% of cardiac tamponade (as well as disorders involving intrathoracic pressure changes, such as COPD) / 4 mechanisms septal shift/pressure, RV enlargement (prevents filling of LV) tensing of pericardium (impairs cardiac output) increased capacitance of pulmonary capillary bed (decreases LV filling) decreased afterload (negative intrathoracic pressure, this is normal) Tilt Table Testing Decreased preload stimulates Bezal Jarisch reflex / catecholamines can be used to enhance this reflex / hold vasoactive drugs for 5 half-lives before / endpoint is pre- HYPERLINK "ddx.doc" \l "syncope" syncope w/ hypotension or bradycardia Reading EKGs [HYPERLINK "pics/limbleads.jpg"Vectorial diagram of Limb Leads] EKGs of the Major Arrhythmias [HYPERLINK "more/ekg.html"tutorial with pictures] Method for EKG reading:  HYPERLINK \l "heartrate" heart rate /  HYPERLINK \l "heartrhythm" heart rhythm /  HYPERLINK \l "intervals" intervals /  HYPERLINK \l "axisdeviation" axis deviation /  HYPERLINK \l "hypertrophy" hypertrophy EKG reading in  HYPERLINK \l "ekgischemia" myocardial ischemia For ECG changes associated with electrolyte disturbances ( HYPERLINK \l "lytes" see lytes) [HYPERLINK "pics/ecgpotassium.gif"potassium ECG] Definitions: If the QRS complex begins with a negative deflection, it is called a Q wave 1st positive deflection is R wave a negative deflection following an R wave is an S wave T waves are positive because the ventricles repolarize from epicardium to endocardium (opposite of contraction) Heart Rate Each small box is 0.1 mV and 0.04 seconds / one large square is 0.2 seconds (5 small boxes of 0.04) HR is 300/# of large boxes in RR interval [ex., 4 large boxes between R waves ( 300/4 or 75 bpm or just count # of large squares from 1,2,3,4,5,6 corresponds to 300, 150, 100, 75, 60, 50 Heart Rhythm Regular? Are P waves present? In sinus rhythm, P waves should be upright in lead II (unless reversal of leads or dextracardia) Are P waves related to QRS? [sinus arrhythmia v. multifocal atrial tachycardia v. atrial fibrillation v. ventricular arrhythmias etc.] Intervals PR interval [0.12 to 0.21] becomes shorter as HR increases QRS Axis Extreme left axis (-90 to -180) Right-axis deviation in presence of LBBB (+90 to +180) QRS interval [0.04 to 0.1] LBBB: >160 msec RBBB: >140 msec QRS Morphology QT interval normal is less than RR interval with HR < 100 Prolonged QT interval QTc corrected for heart rate / women > men / can be a sign of ischemia (lack of ATP and reduced inward K current) / can cause  HYPERLINK \l "torsades" torsades de pointes Prolonged QT: HYPERLINK "pharm.doc" \l "classi"class Ia and  HYPERLINK "pharm.doc" \l "classiii" III agents, sotalol, amiodarone,  HYPERLINK "pharm.doc" \l "tca" TCAs, phenothiazines, ketoconazole, quinolones, erythromycin, clarithromycin, antiemetics, antipsychotics, pentamidine, hypomagnesemia, hypokalemia, hypocalcemia, hyperthyroid, hypothyroid, intracranial bleeds, congenital long QT Shortened QT: hypercalcemia,  HYPERLINK "pharm.doc" \l "digitalis" digitalis (scooping) Tip: regarding intracellular electrolytes (K, Ca, Mg) ! Elevations ( shorten ! QT interval ! Depressions ( prolong ! QT interval Voltage low voltage is any 3 limb leads < 15 mm or any one precordial lead < 10 mm Causes: pericardial effusion/tamponade, emphysema, obesity Axis [HYPERLINK "pics/limbleads.jpg"vectorial diagram of limb leads] Calculate Axis If lead I and II /aVF are both positive ( 0 to 90 and normal axis (down and to the left) If lead I is positive and II/aVF is negative ( LAD If lead I is negative and II/aVF is positive ( RAD Note: axis can also be determined by finding the isoelectric deflection (i.e., shortest QRS) (axis is perpendicular to that vector) Frontal planes: axis deviation (I, II/AVF) Horizontal planes: axis rotation (V1-6) LAD ( LVH, LBBB, LAFB RAD ( RVH, RBBB, LPFB, RV strain (pulmonary HTN, PE), emphysema / may be normal in children, young adults Note: mean QRS tends to point away from infarct, toward hypertrophy Hypertrophy LVH sum of deepest S in V1 or V2 and tallest R in V5 or V6 is > 35 mm (in patients > 35 yrs) R in aVL > 12 mm (strain pattern) R in V6 > 25-35 mm Note: may see asymmetrical or inverted T in V5 or V6 (strain pattern ~ ST ! with upward hump in middle) Criteria for LVH (sensitivity/specificity) RaVL + SV3 > 28 mm (men) (40/95) or RaVL + SV3 > 20 mm (women) SV1 + RV5 or RV6 > 35 mm (30/95) RV5 or RV6 >/= 25 mm (20/95) RaVL > 11 mm (20/95) RVH right atrial enlargement, right axis deviation, incomplete RBBB, low voltage, tall R wave in V1, persistent precordial S waves, right ventricular strain Criteria for RVH (sensitivity/specificity) Limb lead criteria R in I 1 (30/100) R wave height in V1 > 0.7 mV (30/100) S wave depth in V1 < 0.2 mV (20/100) R/S ratio in V5 or V6 < 1.0 (10/100) QR in V1 (-/100) QRS axis > + 90 degrees (15/100) P wave amplitude > 0.25 mV in II, III, aVF, V1 , or V2 (20/100) LAE (P-mitrale) broad, notched (M-shaped) P waves in mitral leads (I, II, aVL) or deep terminal negative component to P in lead V1 (biphasic V1 is the most specific criterion) / causes include MS, HTN RAE (P-pulmonale) P waves are prominent V1 or > 2.5 mm in any limb lead (tall, peaked in II) EKG segments [HYPERLINK "pics/fn-heartvesselsanterior.jpg"anterior heart] [HYPERLINK "pics/fn-heartvesselsposterior.jpg"posterior heart] Q waves Septal depolarization normally moves from R to L causing small downward deflection in V6 Significant Q waves > 1 mm wide or > S! QRS amplitude (measured from top to bottom) / can start early in MI or in ensuing weeks Small, insignificant Q waves normal is < 0.04 seconds in I, aVL and V1-6 / < 0.025 in II and < 0.030 in aVF small septal Qs commonly seen in lateral leads (I, aVL, V4, V5, or V6) mid-septal depolarization (from LBB) moving L to R medium to large Q waves may be normal in aVR if not lead placement Q in V2 could be lead placement, LVH, LBB, pulmonary disease downgoing delta waves in II, III, aVF can mimic Q waves large (deep, broad) Qs in I and III may occur in HOCM R waves R in V1, V2 with posterior MI (see below) Intrinsicoid deflection > 50 mm with some LVH Delta wave with  HYPERLINK \l "wpw" WPW, large R in I with LBBB and LAFB, large R in inferior leads with LPFB R wave progression transition should occur between V2 and V4; LVH may change vector of conduction such that R wave progression seems poor (yet not ischemic); poor R wave progression is c/w prior anteroseptal infarct; early R wave progression can be sign of prior inferior infarct S waves V6 with RBBB Large S in inferior leads with LAFB Large S in lateral leads with LPFB T wave changes [HYPERLINK "pics/twavechanges.jpg"diagram]  cannot definitively localize MI s subepicardial ischemia (inverted, symmetric), subendocardial ischemia (peaked) hyperacute MI (tall, peaked, may have associated ST ! and/or Q s) RBBB, LVH, RVH (septal leads), LBBB (lateral leads) hyperkalemia (peaked, also with widened QRS, prolonged PR, sine wave) [HYPERLINK "pics/ecgpotassium.gif"ECG] hypokalemia (may have flat, inverted T) pericarditis (inverted), intracranial hemorrhage (ICH) Note: can be normal in limb leads, but usually pathological in V2 to V6 Wellens T waves deep, symmetric TWI (usu. early precordial leads) may occur in significant left main or proximal LAD ST segment changes [HYPERLINK "pics/stchanges.jpg"diagram] shape more important than size of changes / J point is the beginning of the ST segment / ST segment changes tell you where the injury is because the injured tissue remains depolarized when surrounding tissue is repolarized / diffuse ST elevations with chest pain [ HYPERLINK "pics/stelevationsandchestpain.jpg" table] ventricular aneurysm: can produce baseline ST elevations pericarditis: ST elevations are flat or concave (often entire QT segment) ST elevation Diffuse: pericarditis, myocarditis, cerebral hemorrhage, others Localized: transmural ischemia, MI, wall motion disorder (e.g. aneurysm), others ST depressions  cannot definitively localize MI s subendocardial ischemia (e.g. angina) ST ! V1, V2 with posterior MI (flip and invert EKG to see posterior ST " s) reciprocal changes with ST elevation MIs (note:) LVH, LV strain with repolarization (inverted Ts)  HYPERLINK \l "hypokalemiaecg" hypokalemia  HYPERLINK "pharm.doc" \l "digoxin" digoxin toxicity U waves (+) > 1 mm / caused by  HYPERLINK "pharm.doc" \l "classi" class Ia drugs,  HYPERLINK \l "hypokalemiaecg" hypokalemia [HYPERLINK "pics/ekg-potassium.gif"pic], hypomagnesemia, CNS disease (TU fusion waves) [ HYPERLINK "pics/ekg-tuwave-cnsdisease.gif" pic], LQTS (+/-) [ HYPERLINK "pics/ekg-lqts.gif" pic] / predisposes to  HYPERLINK \l "torsades" torsades de pointes (-) HTN, AV valvular disease, RVH, major ischemia, 60% of anterior MI, 30% of inferior MI, 30% of angina ECG changes suggestive of MI ST changes: convex suggests infarction (concave could be pericarditis, other) ST ! > 2 mm in 2 contiguous (by grouping) precordial leads ST ! > 1 mm in 2 contiguous (by grouping) limb leads > 1 mm ! in at least 2 contiguous leads suggests ongoing ischemia (subendothelial infarct, positive  HYPERLINK \l "stresstest" stress test) or  HYPERLINK "pharm.doc" \l "digoxin" digoxin effect In presence of LBBB: cannot exclude MI but MI very likely if: ST ! > 1 mm concordant with QRS (in same direction as QRS) ST ! > 5 mm discordant (not in same direction as QRS) ST ! > 1 mm in V1, V2 or V3 Indication for  HYPERLINK \l "thrombolysis" thrombolysis: > 2 mm ST elevation in 2 limb leads, new onset LBBB Contraindications include SBP > 180 (at any time, despite what happens after BP meds) Reciprocal changes suggest ischemia (where to look) Inferior ST depression, T inversion ( anterior leads Anterior ST depression, T inversion ( inferior lateral Lateral ST depression, T inversion ( inferior, anterior Localization of infarct Which artery is/was occluded I, aVL (high lateral) L circumflex V1- V4 (anteroseptal) LAD ( HYPERLINK \l "lad" see below) V5- V6 (lateral) L circumflex II, III, aVF (inferior) RCA (85%), L circumflex (15%) Note: minimal ST changes and inverted T waves in II, III, aVF ( common with circumflex a. occlusion S! of inferior MI involve right ventricle / get right sided ECG if inferior leads involved, because right ventricular MI requires much different treatment! (see treatment of MI and avoid nitrates) Anterior Vs. Posterior MI V2 is most reliable for determining anterior vs. posterior (it lies in the A-P vectorial plane through LV) Dont confuse anterior sub-endocardial MI with posterior MI acute posterior MI (would be mirror of anterior MI) ( V1-V2 w/ large R wave, ST depression LAD occlusion Scenario A (wrap-around LAD) V3 V4 ST ( II, III, AVF ST ( Scenario B V1V2 ST ( II, III, AVF may be normal 2o to cancellation of vectorial forces I, AVL, ST ( if affecting high diagonal Scenario C ST ( I, AVL, V1-6 ST ( II, II, AVF Swan-Ganz Catheter Interpretation of Values Complications: dysrhythmias (75%), thrombosis (3%), sepsis (2%), pulmonary infarction (2%), pulmonary valve perforation (1%) RAP [0 to 8 mm Hg] PAP [systolic: 15-30, diastolic 5-12, mean 10-20 mm Hg] PCWP [5 to 12 mm Hg] normally LVEDP = PCWP PCWP > LVEDP in MS, LA myxoma, pulmonary venous obstruction, patient on PEEP PCWP < LVEDP with stiff left ventricle ( > 25 mm Hg) Cardiac output [3.5 to 7 L/min] Cardiac index [2.4 to 4 L/m2] SVR [900-1300 dynes/sec/cm-5] PVR [155-255 dynes/sec/cm-5] Echocardiography Normal EF roughly 55% McConnells sign: reduced RV function with apical sparing (suggestive of PE) Detect intracardiac shunt with agitated saline bubbles General Circulatory Disturbances  HYPERLINK \l "edema" Edema  HYPERLINK \l "hypothermia" Hypothermia  HYPERLINK \l "Hypovolemia" Hypovolemia  HYPERLINK \l "shock" Shock  HYPERLINK \l "chf" CHF  HYPERLINK \l "htn" Hypertension   HYPERLINK \l "corpulmonale" Cor Pulmonale ACLS Edema Ddx: CHF, renal disease, inflammation, various drugs, hypothyroid, exogenous estrogen, thiamine (B1) deficiency Effects: hypovolemia, hydrocephalus, pulmonary edema anasarca (severe edema) / chronic passive congestion of lungs (hemosiderin, brown induration) / chronic passive congestion of liver (nutmeg liver) and spleen (splenomegaly) Hypovolemia Free Water Deficit: 0.6* weight (kg) | current Na ----------- - 1 140 *0.5 if female Shock stage I compensated stage II tissue hypoperfusion / dilated arterioles, fall in urinary output, DIC ? stage III cell and organ injury / decreased CO from hypoxia or pancreatic myocardial depressant factor / ATN (kidney) / ischemic encephalopathy / hemorrhage, necrosis in heart (zonal lesions, bands) / Phases 1) brain and CVS changes 2) renal dysfunction (2-6 days) 3) diuretic phase (renal tubules recover fxn) hypovolemic replace with saline/ringers cardiogenic this is due to left ventricular failure (MI, cardiomyopathy, etc) consider Swann-Ganz catheter to maintain wedge of ? 17 Consider ongoing occlusion: coronary reperfusion with PTCA Pressors: dopamine, dobutamine, levafed With LV failure: consider intraaortic balloon pump placement to increase coronary flow (increased diastolic pressure) and decrease afterload / can also use left-ventricular assist device (LVAD) (risk of infection, thrombosis, mechanical pump failure) Septic shock decreased SVR / goal is to maintain preload of ?>higher than normal consider Swann-Ganz catheter IVF: saline or lactated ringers to maintain wedge Pressors: dopamine, dobutamine, levafed Course: Capillary leak combined with a catabolic state will decrease albumin and cause 3rd spacing of fluid / pre-renal state will occur as renal arteries constrict as the body diverts blood to brain and other organs / after recovery, there will be a diuresis as fluid re-enters circulation and renal tubules are somewhat leaky may be associated with  HYPERLINK \l "dic" DIC Congestive Heart Failure (CHF) [ HYPERLINK "http://content.nejm.org/cgi/content/full/348/3/243" NEJM] Systolic dysfunction (pump failure) ( all systolic also has some diastolic failure  HYPERLINK \l "diastolic" Diastolic dysfunction (impaired filling) ( can have isolated diastolic failure Note: RHF usually from LHF or cor pulmonale (RHF alone can actually cause pulmonary edema from pleural venous drainage) Causes: myocardial injury (see  HYPERLINK \l "cm" cardiomyopathies), chronic overload (AS, HTN), chronic volume overload (MR, other), infiltrative (amyloid, HC, other) Systolic dysfunction Framingham Criteria Clinical diagnosis of CHF can be made with at least one major and two minor Major: PND, neck vein distension, JVP, rales, cardiomegaly, acute pulmonary edema, S3 gallop, positive hepatojugular reflex, weight loss > 4.5 kg with 5 days treatment Minor: peripheral edema, night cough, DOE, hepatomegaly, pleural effusion, reduced VC (! S!) NYHA Functional Classification I  no limitation during ordinary physical activity II  slight limitation of physical activity. Develops fatigue or dyspnea with moderate exertion. III marked limitation of physical activity. Even light activity produces symptoms. IV symptoms at rest. Any activity causes worsening. Exam Findings Elevated  HYPERLINK \l "jvp" JVP Pulmonary edema ( HYPERLINK \l "pulmonaryedema" see other) Orthopnea LV failure or inflow obstruction causes raised PCWP and dyspnea Paroxysmal nocturnal dyspnea (PND) similar phenomenon that occurs after several hours of recumbency (similar findings with pulmonary disease) Leg Swelling Pulsus alternans S3 Lab findings (biomarkers in heart failure) pro-inflammatory CRP FAS TNF, IL1,6,18 oxidative stress MPO, others neurohormones Renin, ATII, aldosterone, endothelin, others myocyte injury HYPERLINK \l "cardiacenzymes"troponins, light chain kinases, CKMB, others myocyte stress  HYPERLINK "labs.doc" \l "bnp" BNP, NTProBNP, others Treatment of CHF (stages I-IV): I  HYPERLINK "pharm.doc" \l "acei" ACE inhibitors II ACE inhibitors + salt restriction + diuretics +/- B-blockers (metoprolol, carvedilol) III add inotropic agents and vasodilators IV add aortic balloon pump or  HYPERLINK \l "cardiactransplant" cardiac transplantation Note: if cannot tolerate ACEI, isosorbide dinitrate + hydralazine has proven mortality benefit over placebo (Imdur alone has not been proven as of 3/07) Plus: Anticoagulants with atrial fibrillation or other risk factors for thrombus formation (such as very low EF with severe hypokinesis)welling Anti-arrhythmia agents vs. AICD Some patients may need anti-arrhythmia agents for chronic atrial fibrillation (B-blockers are safest and might be useful) Some studies favor AICDs (+/- sotalol) over anti-arrhythmia agents alone for severe CHF with high-risk of ventricular tachycardia Cardiac resynchronization therapy (CRT) or biventricular pacing may decrease mortality by decreasing sympathetic activation; consider for moderate to severe HF The intra-aortic balloon pump (IABP) is positioned in the aorta with its tip distal to the left subclavian artery. Balloon inflation is synchronous with the cardiac cycle and occurs during diastole. The hemodynamic consequences of balloon counterpulsation are decreased myocardial oxygen demand and improved coronary blood flow. Additionally, significant preload and afterload reduction occurs, resulting in improved cardiac output. Severe aorto-iliac atherosclerosis and aortic valve insufficiency are relative contraindications to intra-aortic balloon pump placement. Ventricular assist devices (VADs) require surgical implantation and are indicated for patients with severe HF after cardiac surgery, in patients who have intractable cardiogenic shock after  HYPERLINK \l "mi" acute MI, and in patients who deteriorate while awaiting cardiac transplantation. Currently available devices vary with regard to degree of mechanical hemolysis, intensity of anticoagulation required, and the difficulty of implantation. Therefore, the decision to institute VAD circulatory support must be made in consultation with a cardiac surgeon experienced in this procedure. Prognosis: 75% five-year survival with transplant peak oxygen uptake of 20 mL/min/kg is associated with a good 1-year prognosis Physiology of CHF Vasoconstriction / Salt-retention Left ventricle, carotid sinus, aortic arch, renal afferent ( increased ADH, renin Brain-derived natriuretic peptide (BNP) promotes diuresis Sympathetic System B1 and B2 are uncoupled (B1 ! HR, B2 ! TPR) NE causes myocyte hypertrophy, direct myocyte toxicity / NE (over 4.7 nmol/L) carries poor prognosis Treatment: B-blockers may ! survival by counteracting NE affects (may also have anti-oxidant properties), ! diastolic filling time (via slowing HR) / biventricular pacing Renin-angiotensin system No escape from renal sodium retention / combination of NE and ATII stimulation increases Na transport in proximal tubule and decreases delivery to distal tubule (which helps explain lack of escape phenomenon in CHF, unlike  HYPERLINK \l "conns" Conns syndrome) / resistance to atrial natriuretic peptide may result from decreased distal delivery of Na ACE inhibitors and ATII blockers also reduce mitogenic effect on cardiac muscle (which would crowd capillaries and decrease blood delivery) / they may actually reverse LVH ATII receptors may stimulate thirst despite hyponatremia Treatment: ACE inhibitors and spironolactone both reduce mortality ADH (AVP) System ADH V2 receptors in collecting duct principal cells ( AC ( aquaporin-2 translocation and production ADH V1 receptors constrict vascular smooth muscle Baroreceptors override atrial receptors (Henry-Gauer atrial reflex) Endothelial hormones Endothelin Prostacyclin and PGE2 counteracts (afferent?) renal vasoconstriction ( NSAIDS can precipitate acute renal failure in severe CHF Endothelin receptor antagonist BQ-123 (in development) may also counteract vasoconstriction Diastolic Dysfunction Inadequate filling during diastole / can be due to variety of causes Treatment depends on cause control heart rate and increase relaxation with B-blockers (1st), Ca channel blockers (2nd) normalize any arrhythmias (i.e. atrial fibrillation, atrial flutter) Cor Pulmonale Hypotension Cardiovascular Orthostatic hypotension ( HYPERLINK "ddx.doc" \l "orthostatichypotension" see Ddx) Postural orthostatic tachycardia syndrome (POTS) Young females, light-headed, palpitations, weakness, tremulousness upon standing / fatigue, sleep disturbance / heat and exercise worsens / S! with abnormalities of autonomic function testing Pulmonary HTN and RV dysfunction vasoconstriction (ex. CF) primary idiopathic part of autoimmune disease (scleroderma) chronic pulmonary embolism parenchymal (sarcoidosis, ILD) obesity hypoventilation syndrome ECG: peaked P waves in II, III, aVF (RA enlargement), deep S in V6 with ST changes (RVH), R-axis deviation, RBBB occurs in 15% of patients CXR: edema (if pleural effusion, think more of LV failure instead) Treatment: treat pulmonary HTN ( HYPERLINK \l "pulmonaryhypertension" see other) Hypertension [see pulmonary hypertension] Definitions > 140/90 (stage I) >160/100 (stage II) essential HT 90% of HTN / genetics, environment / older age, except blacks malignant HT (5%) 50% essential, 50% secondary (10% renal, 40% endocrine, vascular, neurogenic (rare)) Secondary causes Renal parenchymal (chronic pyelonephritis, glomerulonephritis,  HYPERLINK \l "apkd" APKD) Tubular interstitial (reflux and analgesic) Endocrine:  HYPERLINK \l "hyperthyroidism" hyperthyroidism, HYPERLINK \l "primaryhyperaldosteronism"primary aldosteronism,  HYPERLINK \l "cushings" Cushings syndrome,  HYPERLINK \l "pheochromocytoma" pheochromocytoma,  HYPERLINK \l "acromegaly" acromegaly, oral contraceptives Other: pain!, hypervolemia (posttransfusion, renal failure), hypercalcemia, drugs (steroids, TCAs, sympathomimetics, NSAIDs, cocaine), coarctation of aorta, vasculitis, renovascular hypertension (RAS), fibromuscular dysplasia Clues to renovascular HTN: epigastric or flank bruits, accelerated or malignant HTN, < 35 or > 55, sudden development or worsening, concomitant poor renal function, refractory to anti-HTN meds, extensive occlusive disease in peripheral circulation (including CAD/CVA) Complications cardiac hypertrophy ( heart failure, MI vascular ( aortic dissection ( hyaline arteriolosclerosis: retinal, renal disease ( arteriolosclerosis: MI, CVA, renal failure ( fibroelastic hyperplasia ( retinal changes grade III retinal changes (hemorrhages, cotton wool spots, hard exudates) grade IV retinal changes (papilledema) Other ( 2x risk of  HYPERLINK \l "rcc" renal cell carcinoma Initial work-up: CBC, chemistries (K, Ca, PO4, BUN/Cr), UA (protein, blood, glucose, micro), consider TSH / lipid profile / fasting glucose / EKG / consider CXR, head CT, echo Secondary: captopril-enhanced radionuclide renal scan, MRA, spiral CT / pheo labs / Treatment: Goal is to reduce BP by 10-15% or diastolic 110 Organ dysfunction usually at > 130 diastolic Outpatient Treatment: Clinical Trials HOT showed 51% reduction in cardiovascular events with diastolic < 80 (not 90) UKPD suggested systolic should be < 120 HOPE ( ramipril ! MI (22%), ! CVA (33%), ! mortality (24%) LIFER ( losartan decreased mortality more than atenolol for DM with LVH ACE inhibitors B-blockers Ca blocker Diuretics (HCTZ) Avoid B-blockers with asthma, CHF (depends), peripheral vascular disease, theoretical risk of increasing sugars with DM or hyperlipidemia (nobody really worries about that) Avoid diuretics with gout (impairs urate excretion) With pregnancy, ACE contraindicated (fetal kidney agenesis) and diuretics risky; use aldomet or hydralazine HTN emergency must lower BP in < 1 hr Causes: malignant HTN, associated with MI, flash pulmonary edema, ARF, intracranial events, post-operative bleeding, eclampsia, pheochromocytoma) ( SZ, coma, death MRI: posterior leukoencephalopathy (parietooccipital regions) can be missed on CT Cerebral blood flow autoregulation ( maintains MAP 60-120 (curve shifts to right in chronic HTN; which is why BP must not be lowered > 25% over ~1 hr, especially in presence of neurological effects) HTN urgency must lower BP in < 24 hrs Causes: accelerated HTN, associated with CHF, stable angina, TIA, peri-operative Pre-eclampsia and Eclampsia (Toxemia of Pregnancy) Presentation: headache, epigastric pain, visual disturbances, swelling Criteria: hypertension (systolic > 140 or +30, diastolic > 90 or +15),  HYPERLINK \l "proteinuria" proteinuria, edema Complications: placental ischemia, hypertension, DIC, seizures (true eclampsia) 6% of pregnancies / often last trimester (20 wks to 6 wks post-partum) / Risk factors: hydatidiform moles, age extremes Mechanism: angiotensin hypersensitivity may result from decreased PGE synthesis Treatment: IV MgSO4 or BZ for seizures Screening: neurokinin B test under development / maternal serum inhibin A concentration is elevated in established preeclampsia (early indicator of risk?) Treatment for HTN emergency/urgency Hypertensive encephalopathy Labetalol, nicardipine, fenoldopam, nicardipine Avoid: b-blockers, clonidine, methyldopaSubarachnoid HemorrhageNimodipine, nitroprusside, fenoldopam, labetalol Avoid: beta-Blockers, clonidine, methyldopa, diazoxideIntracerebral HemorrhageNo treatment, nitroprusside, fenoldopam, labetalol Avoid: beta-Blockers, clonidine, methyldopa, diazoxideIschemic StrokeNitroprusside, labetalol, fenoldopam Avoid: beta-Blockers, clonidine, methyldopa, diazoxideAcute MI/unstable angina b-blocker + nitroglycerin Avoid: diltiazem, hydralazine, diazoxideAcute LV failureNitroprusside, IV nitroglycerin Avoid: diltiazem, b-lockers, labetalolAcute pulmonary edema 1st line Nitroprusside or fenoldopam + Lasix 2nd line nitroglycerin (up to 200 mug/min)Acute aortic dissection(B-blocker then nitroprusside) or labetalol or trimethaphan Avoid: Hydralazine, diazoxideAcute renal failure Fenoldopam, nitroprusside, nicardipine, labetalol Avoid: beta-blockers, trimethaphanSympathetic Crisis (pheochromocytoma)Phentolamine, labetalol, nitroprusside, clonidine (for clonidine withdrawal only) Note: block a then b to avoid problemsMicroangiopathic hemolytic anemia EclampsiaMagnesium sulfate, hydralazine, labetalol, calcium antagonists Avoid: ACE inhibitors, diuretics, trimethaphanPostoperative crisisLabetalol, fenoldopam, nitroglycerin, nicardipine, nitroprusside Avoid: trimethaphan Arteriosclerosis Pathological Types Senile sclerosis insidious / aging Monckebergs medial calcification / wear and tear lesion? Atherosclerosis  HYPERLINK \l "Atherosclerosis" see below Arteriolosclerosis hyaline benign HT, DM / slow, stenosis / plasma proteins, thick BM hyperplastic malignant HT / flea-bitten kidney transplant accelerated 2 to 5-10 yrs Atherosclerosis abdominal aorta > coronary > popliteal > carotid Pathology: diffuse intimal thickening (normal aging) / gelatinous lesions (focal edema) / microthrombi / fatty streaks (normal aging) Causes: by hyperlipidemia (diet,  HYPERLINK \l "dm" DM, gout), chronic HTN, smoking, Fabrys, elevated homocysteine Markers: CRP is associated with increased risk / other markers are associated but not useful for screening: homocysteine, lipoprotein A, plasminogen activator factor 1 / C. pneumoniae and CMV also implicated Coronary Artery Disease ( HYPERLINK \l "cad" see other) Peripheral Vascular Disease [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/12/1241" NEJM] Presentation: < 20% report typical symptoms of intermittent claudication / leg fatigue, difficulty walking, other atypical leg pain Exam findings: cyanosis (with dependent rubor), decreased temperature, atrophic changes (shiny skin, thick nails, absence of hair), decreased pulses / ulceration usu. toes, heels, anterior shin and extended over malleoli Risk factors: smoking, diabetes, HTN, hyperhomocysteinemia, hyperlipidemia Diagnosis: [ HYPERLINK "pics/pad-imaging.jpg" table] ankle-brachial index (ABI) > 1.0 normal / 0.41 to 0.9 intermediate / < 0.40 critical ultrasound limited compression of calcified vessels, operator dependent MRA/CTA usual considerations angiography good because could also do stenting at same time Ddx [ HYPERLINK "pics/pad-ddx.jpg" table]:  HYPERLINK \l "buergerdisease" Buergers disease,  HYPERLINK \l "fibromusculardysplasia" fibromuscular dysplasia,  HYPERLINK \l "takayasus" Takayasus, acute arterial occlusion, compartment syndrome, venous congestion, spinal stenosis Treatment: reduce contributing factors (smoking, DM, etc) ( smoking cessation reduces related/CAD mortality 50% / exercise (as tolerated re: possible CAD) actually helps Medical therapy  HYPERLINK "pharm.doc" \l "cilostazol" cilostazol phosphodiesterase type 3 inhibitor ( vasodilation + mild anti-platelet activity / shown to increase walking distance 50% pentoxifylline (Trental) ( immunomodulator ( people doubt efficacy ASA or plavix ( more to prevent MI and CVA Note: other vasodilators (CA blockers, a-blockers, hydralazine) may worsen symptoms by decreasing perfusion to affected area Surgery: critical leg ischemia, persistent foot pain at rest, non-healing ulcers, disabling claudication PTA (PCI) versus bypass / must take several factors into decision [ HYPERLINK "pics/pad-surgeryorstent.jpg" table] Leriche syndrome claudication in buttock, buttock atrophy and impotence in men due to aortoiliac occlusive disease / treat with bypass Acute arterial occlusion embolic or in situ / consider source / consider HIT Ab Treatment: heparin (to prevent propagation), limb placed below horizontal plane without pressure, urgent vascular consult Hyperlipidemia diagnose based on FH, blood tests (cholesterol not changed by fasting, TG are decreased) Friedwald formula:  HYPERLINK "labs.doc" \l "ldl" LDL chol = total - ( HYPERLINK "labs.doc" \l "hdl" HDL chol + TG/5) / 100 - 139 (mild) / >139 (severe) Note: very severe hyperlipidemia can affect platelets causing elevated ESR CARE trial ( no benefit shown for lowering LDL < 125 mg/dL in post-MI patients HPS trials ( simvastatin reduced coronary or vascular events by 33% (regardless of lipid levels) SSSS trial ( simvastatin reduced MI (55%), mortality (43%) VA-HDLIT ( 24% reduction in stroke/MI with gemfibrozil and LDL > 140 and HDL < 40 Combination of  HYPERLINK "pharm.doc" \l "statins" statin and fibrate is promising; fibrate alone probably not as good as statin alone Current trend is treat CHD or CHD equivalents (DM, stroke, PVD) with goal of LDL < 100 Primary hyperlipidemias FH AD / chol Familial HTG AD / TG combined AD / chol, TG broad beta (rare disorder) (85%) polygenic chol sporadic TG Secondary hyperlipidemia elevated cholesterol elevated TG (DM, other) Hypolipoproteinemia AR disorders Diabetes Mellitus ( HYPERLINK \l "dm" see endocrine) Drug-Induced: certain b-blockers, protease inhibitors Coronary Artery Disease [ HYPERLINK \l "chestpain" chest pain Ddx] [ HYPERLINK \l "angina" angina] [ HYPERLINK \l "mi" MI] 1st COD in US / 90% of cardiac deaths PDA to AV node 90% L circumflex / 10% RCA Risk Factors: DM ( extremely important risk factor [ HYPERLINK "http://www.annals.org/cgi/content/full/139/10/824" annals] Family history (MI < 40 yrs) Smoking HIV Male, post-menopausal Age Hypercholesterolemia (LDL > 100 / HDL < 50 / TG > 170) Cocaine (vasospasm, promotes blood clotting) Obesity (BMI > 27) OCP/estrogens HTN LVH Stress Hyperthyroid Initial testing guidelines: Pts over 50 yrs old: LDL, smoking, fasting glucose ankle-brachial index can be checked in patients over 55-60 yrs old Second line tests (not part of any initial work-up) low serum  HYPERLINK \l "folate" folate (required for homocysteine ( methionine) elevated CRP, homocysteine, ApoA, ApoB Physical Exam Retinal changes AV nicking and/or copper-wire changes (HTN) S4 (HTN) Peripheral bruits Absent/decreased peripheral pulses HYPERLINK \l "xanthomas"Xanthomas (hyperlipidemia) Common causes of chest pain ( HYPERLINK "ddx.doc" \l "chestpain" see Ddx) Cardiac:  HYPERLINK \l "aorticdissection" aortic dissection, myocarditis, pericarditis, valvular heart disease (MVP, AS, HOCM, MS) Lungs:  HYPERLINK \l "pe" pulmonary embolism, pleurisy, pneumonia, pneumothorax, pulmonary HTN GI: cholelithiasis, cholecystitis,  HYPERLINK \l "gerd" GERD, HYPERLINK \l "sdes"esophageal spasm, PUD,  HYPERLINK \l "pancreatitis" pancreatitis Musculoskeletal: costochondritis, chest wall trauma, cervical arthritis with radiculopathy, muscle strain, myositis Other: Herpes zoster Diagnosis of CAD (sensitivity/specificity of various criteria) Exercise electrocardiography >1 mm ST depression (70/75) >2 mm ST depression (33/97) >3 mm ST depression (20/99) Perfusion scintigraphy Planar (83/88) SPECT (87/65) Echocardiography Exercise (85/76) Pharmacologic stress (86-96/66-95) Stress Test adenosine / sestamibi (MIBI) / dobutamine (less bronchoconstriction, better for COPD) Pt unable to exercise: can use persantine (vasodilates normal but not diseased vessels, inducing ischemia) Contraindications: severe AS, HOCM, unstable angina, severe arrhythmias, EKG suggesting ischemia, severe COPD, active CHF, endocarditis, severe AV block, aortic dissection, severe HTN, recent cerebral hemorrhage Bruce (fast) vs. Naughton (slower) Note: females tend to have less reliable results on graded stress tests (use of thallium/nuclear imaging improves specificity) Angina pectoris (see  HYPERLINK \l "chestpain" chest pain Ddx)  HYPERLINK \l "stableangina" Stable /  HYPERLINK \l "unstableangina" Unstable /  HYPERLINK \l "prinzmetals" Variant /  HYPERLINK \l "syndromex" Syndrome X /  HYPERLINK \l "stresstest" Stress Test Stable angina Presentation: substernal or epigastric, usually radiates (usually left side, can be right) to shoulder, neck, jaw/teeth, and arm (ulnar distribution4th/5th digit) / can be from exertion, emotional upsets, cold, eating Note: noncardiac disorders often trigger angina from real CAD Symptomatic with occlusion of 50% diameter or 75% cross-sectional area EKG: may show ST depression, T wave flattening or inversion Diagnosis: stress test or other Treatment: ASA and other newer anti-platelets to limit aggregation Nitroglycerin SL or spray should work in 5-7 mins (if not, could be MI or other) coronary artery dilation improves blood flow to sub-endocardium venodilation reduces preload and wall tension Isosorbide dinitrate / mononitrate (Imdur) is taken during daytime / can use patch to protect against night time MI Note: tolerance develops to nitrates Side effects: hypotension, light-headedness, HA B-blockers reduce myocardial oxygen demands (try to avoid worsening CHF) Calcium channel blockers (Verapamil, Diltiazem) Coronary vasodilation, variable peripheral vasodilation can be used instead of B-blocker to reduce HR, BP and vasodilate [except in heart block, bradycardia, severe CHF (due to negative ionotrope/chronotrope activity] Unstable angina pre-MI (80%) / thrombus persists 15-20 mins (> 20 mins is MI) / chest discomfort at rest / decreased O2 delivery because plaque ruptures, thrombus formation / Biological factors: thromboxane, 5HT, ADP, platelet activating factor, tissue factor (endothelium/macrophage), endothelin (potent vasoconstrictor), free radicals vasospasm, vasoconstriction mitogen residual fibroproliferation - elevated troponin I or CRP is a poor prognostic sign Treatment: B-blockers and nitrates +/- Ca blockers (not Ca blockers as single agent) Variant or Prinzmetals Angina coronary artery spasm (causes similar EKG changes as STEMI) / majority of cases do have CAD and spasm occurs within 1 cm from lesion / RCA most common location / usu. younger age, do not have preceding stable angina and usu. risk factors Presentation: similar to ACS, often occurs in early morning (4-11am) / sudden cardiac death (30% of heart attacks, most common COD post-MI, V-fib) Diagnosis: may see spasm if active in catheterization / can provoke using hyperventilation ergonovine, acetylcholine, other agents Treatment: nitrates, calcium antagonists (nifedipine, verapamil, diltiazem) / do not give B-blocker (may increase frequency); ASA also thought to worsen spasm / viral, sheer stress, smoking, catecholamines excess Microvascular Angina (Syndrome X) Defect in coronary microcirculation / normal angiogram, abnormal stress test / excellent prognosis Anxiety induced chest pain neurocirculatory asthenia, Da Costa syndrome, soldiers heart, cardiac neurosis / often after exertion, fleeting or prolonged, associated with hyperventilation syndrome Inappropriate myocardial lactate production rare, usually woman / typical angina +/- abnormal resting/stress ECGs (but normal arteriograms) Chronic ischemic heart disease (CIHD) calcification, lipofuscin, scarring, nodular stenosis of valves Sympathetic Crisis Withdrawal of short-acting anti-hypertensives ( HYPERLINK "pharm.doc" \l "clonidine" clonidine or propranolol), cocaine, amphetamines, phencyclidine, MAO + tyramine foods, pheochromocytoma, and ANS dysfunction ( HYPERLINK \l "gbs" Guillain-Barr) Treatment: anti-hypertensive medication / labetalol can cause paradoxical worsening Alternatives: phentolamine and nitroprusside Cocaine Cocaine-associated chest pain ( 25% ischemia, 75% be musculoskeletal or psychological Cocaine use may reduce the sensitivity and specificity of CK-MB and myoglobin (80(50%) for infarction Thrombosis (increased platelet action) Vasospasm (acute) Peripheral vasoconstriction (with prolonged adrenergic sensitization) Increased heart rate (with prolonged adrenergic sensitization) Accelerated atherosclerosis Complications: endocarditis, hemorrhagic and ischemic stroke, aortic dissection, accelerated CAD, MI, sudden cardiac death Treatment: debate ( is it better to give metoprolol or labetalol for cocaine-assoc. chest pain? Myocardial Infarction [ HYPERLINK \l "milabs" lab markers] [ HYPERLINK \l "mitreatment" treatment][ HYPERLINK \l "micomplications" complications][ HYPERLINK \l "miprognosis" prognosis][ HYPERLINK \l "mifollowup" follow-up] [ HYPERLINK \l "othercausesofmi" non-CAD causes] Presentation: intense pain / may radiate or present as chest, jaw/teeth, left arm (4th 5th digit), epigastrum / Lavines sign ( clenched fist over midchest / diabetics 20% or more have decreased sensation of pain from peripheral neuropathy / post-cardiac transplant patients also have a decreased sensation of pain Ddx for MI Pericarditis ( ST elevations / echo Myocarditis ( ST elevations, Q waves / echo Aortic dissection ( ST elevation/depression, non-specific ST/T waves / TEE, chest CT, MRI, aortography Pneumothorax ( new, poor R-wave progression in V1-V6, acute QRS axis shift / CXR PE ( inferior ST elevation, ST shifts V1-V3 Cholecystitis ( inferior ST elevation / U/S, radioisotope scan Subendocardial (non-Q wave) not occlusive (successful fibrinolysis occurs) / ST depression, flat T-wave Transmural (Q wave) 90% occlusive / moves from inner wall, vertically outward / ST elevation, inverted T-wave, wide Q wave is pathognomonic for MI only ischemic condition requiring  HYPERLINK \l "thrombolysis" thrombolytic therapy Location of Infarction Anterior vs. Septal vs. Posterior vs. Right Ventricle (determined by ECG) Note: pre-existing BBB clouds evaluation of ischemia Early R wave progression (V1/V2) suggests posterior MI Lab markers for MI Note: cardiac markers may also be elevated with myocardial strain (e.g. PE), CHF, myocarditis CK (CPK) [ HYPERLINK "labs.doc" \l "ck" more] not selective / rises at 4-8 hrs, peaks at 16-24 hrs, normal by 2-5 days Note: if CK goes up in 7-15 hrs, could be early washout (reperfusion)CK-MB [HYPERLINK "labs.doc" \l "ckmb"more] very selective / rises at 8 hrs, peaks at 16-24 hrs, normal by 3 days / cannot rule out MI when taken 24-48 hrs later CKMB [0-10] / CK-MB to CK fraction [0-2.5] increase within 3 hrs peaks 10-12 hrs (reperfused infarct later peak if you dont reperfuse) descend [MM (skeletal > heart), BB (brain), MB (heart >)] Troponin C up in 3-5 hrs, normal by 10 days / 20 mins rapid test Troponin I [< 0.3] more specific 6-8 hrs after infarction remains elevated 7-10 days Note: troponins can also be elevated (mildly) in renal failure Note: peak troponin levels 6 hrs after onset of chest pain in unstable angina and non Q MI can predict subsequent more severe MI within 30 days Troponin T [< 0.1] more specific 6-8 hrs after infarction remains elevated 10-14 days myoglobin fast and sensitive (also from skeletal muscle damage) / leaks out within 1 hr / 4-6 hr peak normal by 24 hrs / used to monitor thrombolysis / urine myoglobin underestimates level LD1 [30-80] not specific, but sensitive / up at 24 hrs / peak at 3 days / normal by 1-2 wks LD isozymes LD1 > LD2 / LD flip is more selective Other labs: high WBC 12-24 hrs to 2 wks AST up at 12 h, peak at day 2, normal by day 5 (over 200 means liver damage) CRP mediator/marker of inflammation cardiac myosin light chains under investigation Management of LV Infarct ASA, Plavix, GP IIb/IIIa inhibitors (see below) Heparin (UFH or LMWH) to prevent clot propagation / risk of major bleed is 2% ( with subsequent CABG will bleed, but this can be controlled with transfusions) Trends: AIM 10/6 current thinking is LMWH better than UFH for reducing risk of reinfarction (has not been shown yet to reduce mortality) at cost of slightly increased risk of bleed GP IIb/IIIa inhibitors give with ASA and heparin in pts in whom cath is planned; some cardiologist are more aggressive about giving IIb/IIIa agents (i.e. even if cath not necessarily planned, even if only NSTEMI, still not ruled in, etc) Nitroglycerin coronary artery dilation improves blood flow to sub-endocardium venodilation reduces preload and wall tension Morphine Pain, anxiety, decreased work for heart ACE inhibitors benefits are seen with early initiation (< 24 hrs) for afterload reduction and to limit ventricular remodeling B-blockers shown to decrease mortality (but be careful to make sure patient is hemodynamically stable; overly aggressive b-blockade can worsen acute heart failure) Statins may have early benefit on vasodilatory tone (so give in early with ACS) Other Pacing: transvenous pacemaker for complete heart block from acute MI Ca channel blockers are in general ?frowned upon for CAD patients (but I havent read the studies) Avoid: steroids, NSAIDs which impede healing, increase risk of myocardial rupture, increase size of resulting scar / isoproterenol (increases cardiac demand, ischemia) Reperfusion Thrombolysis (HYPERLINK "pharm.doc" \l "thrombolysis"see thrombolytics/contraindications) benefit declines as one moves to 30-60 mins, 1-3 hours, and 3-6 hours after pain [by 12 hrs, risk of bleed outweighs benefit of thrombolysis] (RPA + Reapro) slightly better outcome than (RPA alone) tPA or rPA (increased half-life, action / studies ongoing) expect idioventricular reperfusion rhythm (accelerated idioventricular rhythm) ( dont be alarmed if rate drops to 45~ (often 60-110 bpm; wide-complex escape rhythm) reperfusion is almost assured with resolution of chest pain / 5% get acute re-occlusion Prognosis: 30 day mortality only 2% with 60% post-thrombolysis reduction in ST segment elevation (7% otherwise) / mortality also better with flip T at 2 hrs post-MI PCA (with stenting) (cardiac cath) Indications for cath: recurrent ischemia at rest, elevated troponins, new ST depressions, recurrent angina w/ CHF Sx, high-positive stress test, decreased LV systolic fxn (EF < 40%), hemodynamic instability, sustained VT, PCI w/in last 6 months, prior CABG Indications for CABG: three vessel disease, significant left main disease, two vessel and diabetes (BARI trial), patients with CAD already needed other intracardiac surgery Issues: pretreatment with Mucomyst for renal insufficiency, adequate pre-post hydration, stop metformin 48 hrs before, watch for dye allergy, how long to run IIb/IIIa inhibitors after procedure, which sealing method reduces risk of hematoma Plavix: CURE ( add plavix along with ASA in pts w/ UA/NSTEMI in whom PTCA planned (duration from 19 months) PCI-CURE ( start plavix x 1 mo s/o PTCA Note: hold plavix 5-7 d prior to surgery in planned CABG SIRIUS study showing dramatic reduction in restenosis rates using drug-eluting stents (especially for DM patients) General outcomes for elective stenting: 1% mortality, 2-5% incidence of nonfatal MI, 1-3% need for emergency CABG / clinical restenosis rate of 10-20% in discrete lesions low-risk ( ASA before, heparin during mod-risk ( ? high-risk ( 2b3a inhibitors before, during, after TIMI risk score (0 to 14) one point each for: ( 3 CAD risk factors; prior angiographic evidence; ST changes; ( 2 anginal events last 24 hrs; use of ASA in last 7 days; increased troponins, time to reperfusion therapy > 4 hrs two points: age > 65, HR > 100, Killip class II to IV three points: SBP < 100 mm Hg, age > 75 yrs Risk of event increases linearly for TIMI 0/1 to 6/7 (4 to 41%) 30-day mortality (1 to 36%) / 1 yr mortality (those surviving 1st 30 days) (1 to 17%) Implications: TACTICS-TIMI 18 ( TIMI ( 3 benefited from early invasive PRISM-PLUS ( TIMI ( 4 benefited from 2b3a in addition to heparin TIMI 11B, ESSENCE ( benefit of Lovenox over heparin for ( 4 and ( 5 respectively Treatment of Right Ventricle Infarct key is not to lose LV preload give IVF as needed avoid NTG, morphine (use with caution) still give antiplatelet and anticoagulation agents Complications of MI Arrhythmias (1st COD post-MI; most often < 1 hr post-MI; must monitor closely first 24 hrs) Atrial arrhythmias: sinus tachycardia, AF, paroxysmal SVT, junctional (inferior) Ventricular arrhythmias (NSVT, sustained VT (> 30s requires treatment), VF) Note: females with MI more likely to develop cardiac arrest or shock (males ( VT) Bradycardia/heart block 1st degree AV block every P followed by QRS 2nd degree AV block Mobitz I (inferior MI) Mobitz II (large anterior MI, needs pacer) 3rd degree AV block (needs pacer) Indications for temporary AV pacing Asystole, 3rd degree block, Mobitz II AV block, sinus brady or Mobitz II w/ hypotension and refractory to atropine, new trifascicular block, alternating BBB, 3rd degree block w/ inferior MI complicated by RV infarction, incessant VT CHF w/ pulmonary edema Killip classification (pulmonary associations with MI) I - no rales; clear 90% survival II - bibasilar rales 80% survival III - rales, low BP 60% IV - rales, low BP, poor perfusion 20% (cardiogenic shock) Shock Acute pericarditis (3-5 days) vs.  HYPERLINK \l "dresslers" Dresslers autoimmune pericarditis (weeks to months) Mural thrombosis  HYPERLINK \l "papillaryrupture" Rupture of papillary muscle (1%; 2-7 days)  HYPERLINK \l "vsd" VSD (1 to 4%; 3-7 days)  HYPERLINK \l "cardiactamponade" Cardiac tamponade  HYPERLINK \l "ventricularaneurysm" Ventricular aneurysm (rupture of infarct) (5-10 days) Other treatment concerns Tight glucose control ( HYPERLINK \l "digiami" see DIGI-AMI) Prognosis Increased Risk of subsequent MI post-MI angina, non-Q wave MI, CHF, EF < 40%, failed stress test by ECG or scintigraphy, ventricular ectopy (> 10 PVCs/min) Note: females have higher mortality in 30 days after MI (various theories) Follow-up Care measure left ventricle EF / submaximal stress test before discharge (> 2 days post MI) / maximal stress test 4-6 wks later return to work and resume sexual activity from 6-8 wks cardiac rehab improves functional status, exercise/activity tolerance / aerobic activity 20-30 mins 3 x week at 60-80% peak capacity or rate of perceived exertion of 13-15 on Borg Scale (can gradually build up if pt cannot start at this level) Other Causes of MI (besides coronary artery disease) Coronary emboli aortic or mitral valve lesions, left atrial or ventricular thrombi, prosthetic valves, fat emboli, intracardiac neoplasms, infective endocarditis, and paradoxical emboli Thrombotic coronary artery disease oral contraceptive use, sickle cell anemia and other hemoglobinopathies, polycythemia vera,  HYPERLINK \l "thrombocytosis" thrombocytosis, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, antithrombin III deficiency and other hypercoagulable states, macroglobulinemia and other hyperviscosity states,  HYPERLINK \l "mm" multiple myeloma, leukemia, malaria, and fibrinolytic system shutdown secondary to impaired plasminogen activation or excessive inhibition Coronary vasculitis Takayasus disease, Kawasakis disease, polyarteritis nodosa, lupus erythematosus, scleroderma, rheumatoid arthritis, and immune-mediated vascular degeneration in cardiac allografts Coronary vasospasm May be associated with variant angina, nitrate withdrawal, cocaine or amphetamine abuse, and angina with "normal" coronary arteries Infiltrative and degenerative coronary vascular disease amyloidosis, connective tissue disorders (such as pseudoxanthoma elasticum), lipid storage disorders and mucopolysaccharidoses, homocystinuria, diabetes mellitus, collagen vascular disease, muscular dystrophies, and Friedreichs ataxia Coronary ostial occlusion aortic dissection, luetic aortitis, aortic stenosis, and ankylosing spondylitis syndromes Congenital coronary anomalies Bland-White-Garland syndrome of anomalous origin of the left coronary artery from the pulmonary artery, left coronary artery origin from the anterior sinus of Valsalva, coronary arteriovenous fistula or aneurysms, and myocardial bridging with secondary vascular degeneration Trauma coronary dissection, laceration, or thrombosis (with endothelial cell injury secondary to trauma such as angioplasty); radiation; and cardiac contusion Augmented myocardial oxygen requirements exceeding oxygen delivery aortic stenosis, aortic insufficiency, hypertension with severe left ventricular hypertrophy, pheochromocytoma, thyrotoxicosis,  HYPERLINK \l "methemoglobinemia" methemoglobinemia, carbon monoxide poisoning, shock, and hyperviscosity syndromes Valvular Disease [HYPERLINK "http://content.nejm.org/cgi/content/full/337/1/32"NEJM] Note: prophylactic antibiotics not needed for orthopedic procedures (board question) exceptions? AORTIC STENOSISMITRAL STENOSISMITRAL REGURGITATIONAORTIC REGURGITATIONIdiopathic calcification of a bicuspid or tricuspid valve Congenital RheumaticRheumatic fever Annular calcificationMVP Ruptured chordae Endocarditis Ischemic papillary muscle dysfunction or rupture CTD LV myocardial diseasesAnnuloaortic ectasia Hypertension Endocarditis Marfan syndrome Ankylosing spondylitis Aortic dissection Syphilis CTDMechanismPressure overload upon the LV with compensation by LV hypertrophy. As disease advances, reduced coronary flow reserve causes angina. Hypertrophy and afterload excess lead to both systolic and diastolic LV dysfunction.Obstruction to LV inflow increases left atrial pressure and limits cardiac output mimicking LV failure. Mitral valve obstruction increases the pressure work of the right ventricle. Right ventricular pressure overload is augmented further when pulmonary hypertension develops.Places volume overload on the LV. Ventricle responds with eccentric hypertrophy and dilatation, which allow for increased ventricular stroke volume. Eventually, however, LV dysfunction develops if volume overload is uncorrected.Chronic increased SV ( hyperdynamic circulation, systolic HTN (pressure and volume overload) Compensation (concentric and eccentric hypertrophy) Acute Because cardiac dilation has not developed, hyperdynamic findings are absent. High diastolic LV pressure causes mitral valve preclosure and potentiates LV ischemia and failure.Symptoms Angina Syncope Heart failureDyspnea Orthopnea PND Hemoptysis Hoarseness Edema Ascites Dyspnea Orthopnea PNDDyspnea Orthopnea PND Angina SyncopeFindingsSystolic ejection murmur radiating to neck Delayed carotid upstroke S4 , soft or paradoxic S2Diastolic rumble following an opening snap Loud S1 RV lift Loud P2Holosystolic apical murmur radiates to axilla, S3 Displaced PMIChronic Diastolic blowing Hyperdynamic circulation Displaced PMI Quincke et al Acute Short diastolic blowing Soft S1ECGLAA LVHLAA RVHLAA LVHLAA LVHCXRBoot-shaped heart Aortic valve calcification on lateral viewStraightening of left heart border Double density at right heart border Kerley B lines Enlarged pulmonary arteriesCardiac enlargementChronic Cardiac enlargement Uncoiling of the aorta Acute Pulmonary congestion with normal heart size Echo Concentric LVH Reduced aortic valve cusp separation Doppler shows mean gradient > 50 mm Hg in most severe casesRestricted mitral leaflet motion Valve area  INCLUDEPICTURE "http://home.mdconsult.com/images/isochar/le.gif" \* MERGEFORMATINET 1.0 cm2 in most severe cases Tricuspid Doppler may reveal pulmonary hypertensionLV and left atrial enlargement in chronic severe disease Doppler: large regurgitant jetChronic LV enlargement Large Doppler jet PHT < 400 msec Acute Small LV, mitral valve preclosureCath Increased LVEDP Transaortic gradient 50 mm Hg AVA < 0.7 in most severe casesElevated pulmonary capillary wedge pressure Transmitral gradient usually >10 mm Hg in severe cases MVA < 1.0 cm2Elevated pulmonary capillary wedge pressure Ventriculography shows regurgitation of dye into left ventricleWide pulse pressure Aortography shows regurgitation of dye into LV Usually unnecessaryMedical TreatmentAvoid vasodilators Digitalis, diuretics, and nitroglycerin in inoperable casesDiuretics for mild symptoms Anticoagulation in atrial fibrillation Digitalis, beta-blockers, verapamil or diltiazem for rate controlVasodilators in acute disease No proven therapy in chronic disease (but vasodilators commonly used)Chronic Vasodilators in chronic asymptomatic disease with normal left ventricular function Acute VasodilatorsIndications for SurgeryAppearance of symptoms in patients with severe disease (see text)Appearance of more than mild symptoms Development of pulmonary hypertension Appearance of persistent atrial fibrillationAppearance of symptoms EF < 0.60 ESD > 45 minChronic Appearance of symptoms EF < 0.55 ESD > 55 min Acute Even mild heart failure Mitral valve preclosure Cardiac Maneuvers valsalva: decreases preload / ! HCM, ! AS sustained handgrip: increases afterload (but may enlarge LV cavity) / variable effect on HCM, AS / ! AR, MR, MS squatting: increases venous return and afterload / ! HCM / ! most murmurs inspiration: increases flow through right side of heart / ! TR leg raise (decreases HCM, increases AS) Aortic Stenosis Etiology: congenital AS (pediatrics/young adults) senile calcific AS (50s and older)  most common cause of AS in Western world  HYPERLINK \l "bicuspidaorticvalve" bicuspid AS (30-40s) rheumatic AS (always associated with mitral valve disease) / 20% w/ mitral injury also Pathology: concentric LVH, large pressure gradient (LV to aortic outflow) / > 50 mm Hg / AVA < 1.0 cm2 / < 0.75 cm2 is critical (can still have a soft murmur that is hard to hear) Clinical symptoms: (up to 80% of patients with symptomatic AS are male) Angina occurs in 35-50% / die within 5 years without valve replacement / LVH impairs cardiac blood flow  HYPERLINK "ddx.doc" \l "syncope" Syncope: due to decreased TPR in exercise / due to A/V arrhythmias or heart block (conduction system calcification) / survival is 2-3 years without valve replacement Heart failure: 1-2 year survival without correction Physical signs: Delayed carotid upstroke: most reliable for gauging severity of disease (except under 7?) Systolic ejection murmur: harsh, late-peaking (crescendo, decrescendo) / heard in aortic area, transmitted to carotids / murmur decreases with valsalva / may be reflected in mitral area, producing false impression of mitral regurge (Gallavardins phenomenon) Soft, single S2: aortic component is absent S4 results from reduced LV compliance Sustained, forceful apex beat (not displaced until heart failure occurs) Labs: ECG shows LVH / fluoroscopy (absence of calcium indicates less severe AS) / echocardiography can rule out severe AS if valve motion is normal, but doppler more precisely measures pressure gradient / cardiac catheterization can be used Treatment: Note: DO NOT give too much afterload reducers at one, which can create a severe pressure gradient (serious hypotension) as the cardiac output cannot compensate for afterload reduction Palliative: Medical therapy useful but temporary improvement of heart failure / statins may actually slow progression of valve leaflet calcification Balloon valvuloplasty only moderate, temporary improvement (used in children) Aortic valve replacement: May or may not be able to correct any resultant heart failure Homograft: no anticoagulation required / donors hard to get Heterograft (porcine): only lasts about 10 yrs Mechanical: more durable, coagulation therapy required Bicuspid Aortic Valve 1-5% overall incidence Present with AR in 30-40s or AS in 50-70s / ejection click Mitral Stenosis Etiology: almost always due to rheumatic heart disease (mostly in women; over T!), thrombus, myxoma [similar to endocarditis with fever, chills, embolisms, but negative cultures] Pathology: elevated LAP leads to pulmonary congestion / 3-5 fold elevated pulmonary arterial pressure leads to RH failure / jet lesions Symptoms: Left heart failure: due to mitral stenosis itself, dyspnea on exertion, orthopnea, paroxysmal nocturnal dyspnea Right heart failure: edema,  HYPERLINK \l "ascites" ascites,  HYPERLINK \l "anorexia" anorexia, fatigue High risk of pulmonary hypertension during pregnancy Hemoptysis: rupture of small bronchial veins Hoarseness: enlarged left atrium impinges on left recurrent laryngeal nerve [HYPERLINK "pics/fn-esophagus1.jpg"pic] Physical signs: Atrial fibrillation usually irregularly irregular (may be present) Carotid pulse is brisk but diminished Pulmonary rales due to pulmonary hypertension Increased S1: may become reduced late due to incomplete closure Increased P2 component of S2: due to pulmonary hypertension Opening snap follows S2: shorter interval from S2 ( < 0.1 sec) means higher LAP and more severe MS [very calcified MS may not have opening snap] Diastolic rumble: low-pitched apical rumble begins after opening snap (pre-systolic accentuation occurs with atrial contraction when in NSR) Sternal lift (enlargement of RV due to pulmonary hypertension) Neck vein distension, edema, hepatic enlargement, ascites (if right heart failure occurs) Data: ECG shows atrial fibrillation, left atrial enlargement, RVH CXR: straightened left heart border, double density of right heart border / Kerley B lines / loss of retrosternal space when RVH is present Echocardiography: reduced excursion, thickened valve leaflets / can measure residual orifice, left atrial enlargement always present Cardiac catheterization: used frequently for coronary arteriography in susceptible patients Treatment: < 1.0 cm2 is severe diuretics to control pulmonary congestion (but be careful because MS patients can be very preload dependent and hypovolemia can lead to cardiac collapse) B-blockers to decrease rate and increase LV filling if atrial fibrillation present, can use digitalis to control ventricular rate and anticoagulation (warfarin) to prevent systemic embolism Balloon valvuloplasty: may be as effective as surgery for mild cases Surgical: should be performed prior to pulmonary hypertension (usually regresses if surgery is successful) Mitral commissurotomy: young patients without significant calcification or MR Mitral valve replacement: Aortic Regurge Acute: infective endocarditis ( HYPERLINK \l "endocarditis" see causes) aortic dissections (retrograde), aneurysm congenital bicuspid valve Sub-Acute: Idiopathic aortic root dilatation: frequently associated with hypertension and correlates with increasing age Rheumatic heart disease: most severe manifestation Secondary Syphilis Collagen vascular diseases such as SLE, ankylosing spondylitis, relapsing polychondritis Myxomatous degeneration / weight loss Congenital: Marfan syndrome (proximal root dilatation or aortic root dissection), Ehlers-Danlos, osteogenesis imperfecta, elastica? something AS: things that cause AS can also cause AR (e.g. bicuspid aortic valve) Course: eccentric dilatation (ESV 40-50, normal 10-15), LVH, decreased ejection fraction, systemic blood pressure !! Symptoms: Left ventricular failure: Syncope: Angina: Physical signs: Left ventricular impulse displaced left and downward Diastolic murmur (high pitched, blowing) (increased with squatting and handgrip) S3 due to rapid filling  okay in young people / suggests surgical correction in older pts Austin flint murmur heard best with bell over PMI Increased total stroke volume and pulse pressure (may be absent in acute AR) Corrigans pulse Hills sign Pistol-shot femoral pulse Duroziers sign De Mussets sign Quinckes pulse Labs: ECG CXR enlarged LV (pic?) Echocardiography Cardiac catheterization Treatment: afterload reduction if LV dilatation is present: ACE inhibitors / nifedipine periodic echo to evaluate LV function mildly elevated BP may be due to widened pulse pressure (may not need specific therapy) antibiotics as needed to prevent endocarditis valvuloplasty or valve replacement surgery Mitral Regurge Etiology: CAD - myocardial infarction of LAD (see  HYPERLINK \l "papillarymuscle" ruptured papillary muscle) Dilated cardiomyopathy  HYPERLINK \l "mvp" MVP click-murmur syndrome Rheumatic heart disease Ruptured chordae tendinae spontaneous (Marfans) Endocarditis myxomatous degeneration (including MVP) Mechanism: LV initially remodels and enlarges eccentrically to compensate, but eventually muscle gives out Physical signs: Murmur: holosystolic, apical, radiates to axilla, frequently has a thrill / increased with squatting (increase venous return and afterload) / high pitch, blowing SEM / murmur may be absent with severe MR / mid-systolic click with MVP / can have diastolic rumble from blood flowing? Shorter duration? S3 from rapid filling of LV by large volume of blood in LA PMI displaced down and to left, carotid upstroke brisk but diminished Diagnosis: ECG w/ LVH/LAE, CXR w/ cardiac enlargement, cath w/ large V wave (full LA) Treatment: afterload reduction (ACE, nitroprusside) digoxin for EF and Afib diuretics for volume overload anticoagulants for Afib and very low EF Surgery: valve replacement best if done before EF too low (symptomatic or EF <60% or end-systolic cavity dimension > 45 mm; once EF < 30%, results less favorable); valve repair is better if possible (if chordal continuity can be preserved) Rupture of (posterior) papillary muscle (must have high index of suspicion) [HYPERLINK "http://content.nejm.org/cgi/content/full/355/19/2022"NEJM] new murmur after MI (acute MR is result of ischemia of posteromedial papillary muscle in 80% of cases; likely from PDA infarct) murmur peaks in mid-late systole, but usually not holosystolic or short ejection Treatment: aortic balloon pump; nitroprusside; urgent surgical valve replacement / avoid dobutamine (often makes worse) Mitral valve prolapse (MVP) and click-murmur syndrome (Barlows Syndrome) redundant valve leaflets prolapse into left atrium during systole / most common cause of isolated severe MR in U.S. / females (14-30 yrs) / familial inheritance (could be AD) Pathology: can be from connective tissue disorders such as OI, ED, Marfans) / redundant leaflets (post>ant) and chordae tendinae, calcifications and annular dilation can cause MR Others: rheumatic valve disease, cardiomyopathy, CAD, 20% of ostium secundum ASD pts Presentation: variable chest pain (substernal, prolonged, atypical), palpitations / ?personality changes Physical Exam: can have click w/ or w/o murmur or murmur w/ or w/o click increasing LV size (squatting, B-blockers) delays click-murmur, decreasing LV size (valsalva, hand-grip), advances murmur (and also increases intensity of late systolic component) EKG: usu. normal but can have biphasic or inverted T in II, III and aVF Treatment: reassurance +/- B-blockers (empirical relief of CP), abx (for  HYPERLINK \l "endocarditisprophylaxis" endocarditis prevention), anti-arrhythmics (if this is an issue) Arrhythmias: VT, PVC and PSVT / can get ventricular arrhythmias from regional defects from papillary stress / very rarely causes sudden death Endocarditis: may need abx prophylaxis if very thickened valves or MR present on echo TIA: can occur in some pts as a result of endothelial defects (?) / treat accordingly Tricuspid/Pulmonic associated w/ other valve disease / drug use and infections of valve Tricuspid Regurge Infective endocarditis, RV failure, rheumatic heart disease, RV infarction Presentation: similar as RV failure Physical exam: RV lift, holosystolic murmur at LSB (increases with inspiration), large V wave in JVP [HYPERLINK "pics/jvp.jpg"diagram], pulsatile liver Acute Rheumatic Fever (ARF) Epidemiology: overcrowded, undernourished areas / occurs 3-4 weeks after Strep A pharyngitis in a small percentage of untreated cases 3 yrs and up (average age ~8 yrs) / 20% of patients have 1st attack in adulthood (50% of 1st attack involves heart) Etiology: Strep (A-T) / Strep A has 80 types of M protein (determines if it causes ARF or PSGN) Mechanism: molecular mimicry (autoimmune reaction) / familial predisposition: alloantigen on b cell (75% vs. 16% controls) Note: impetigo causing strep do not cause rheumatic fever, but can cause renal disease Valvular Involvement: (mitral >> aortic > tricuspid) / mitral only (65-70%) / mitral + aortic (25%) / mitral regurge then stenosis later / aortic regurge but no stenosis Presentation: Arthritis: transient migratory polyarthritis / large joints, hot, red, tender, limitation of movement no residual deformity / symmetric Chorea (Sydehams): purposeless, involuntary, rapid, emotional lability / can happen 6 months later (as isolated symptom) and is usually transient Skin Lesions erythema marginatum: pea-sized, extensor surfaces, pink with clear centers, serpiginous margins change from morning to evening trunk and proximal extremities (never on face) subcutaneous nodules: firm, painless, freely moving, extensor surfaces of elbows, knees, spine, occiput Acute Rheumatic Carditis (treat with steroids), focal interstitial, diffuse interstitial, direct injury / migratory polyarthritis, erythema marginatum Aschoff nodule: exudative, granulomatous with Aschoff (multinuclear) and caterpillar/owl-eye cells, (mononuclear), fibrous scar Verrucae vegetations along lines of closure MacCallums plaques sub-endocardial lesions, usually in left atrium Prolapse: myxoid replacement of leaflets, chordae tendinae may rupture ( severe MR, apical systolic murmur MR, apical mid-diastolic murmur (?Corey-Coombs), basal diastolic murmur aortic regurge, change in previous murmur Diagnosis: must have documented Strep A infection / must have 2 major / 1 major, 2 minor Major criteria: carditis, arthritis, chorea, erythema marginatum, subcutaneous nodules Minor criteria: arthralgia, fever, elevated acute phase reactants, ESR, prolonged PR, erythema nodosum other findings: malaise, anemia, epistaxis, precordial pain Labs: high ESR, leukocytosis, prolonged PR interval, acute phase reactants / ASO positive in 80% (95% by 2 levels) / > 250 for adults / > 333 for children / positive throat culture (may give false positives due to colonization) Treatment: Initial: rest until afebrile (up to 2-3 months) Heart failure: repair/replace valve once activity level impaired from MS; also put patients on coumadin because they are likely to have paroxysmal atrial fibrillation Chorea: protect from injury / haldol (1st), chlorpromazine, diazepam, barbiturates Antibiotics: prophylaxis for 5 years (after 5 yrs secondary prevention on individual basis; indication for ongoing prevention are recurrence, rheumatic heart disease, occupation exposure) / benzathine penicillin G 1.2 IM every 3-4 weeks or penicillin V 250 mg bid / others: sulfadiazine, erythromycin, amoxicillin, cephalosporin, clindamycin Suppression therapy: aspirin 100 mg/kg/day QID (taper down with no heart symptoms) prednisone 2 mg/kg/day for 2 weeks (taper for 2 weeks), then switch to aspirin with good response (changes clinical course, but not long-term outcome) Aortic Aneurysm Causes (same list of causes for aortic dissection): HTN, hereditary fibrillinopathies (Marfans, Ehlers Danlos), hereditary vascular (bicuspid, coarctation), vascular inflammation (GCA, Takayasus, RA, Behets, Reiters, psoriasis, ankylosing spondylitis, syphilis, Tb, mycotic, Ormonds), trauma (MVA, fall), iatrogenic (catheterization, aortic surgery) Cystic medial necrosis: degeneration of collagen and elastic fibers in tunica media and medial layer of aorta / occurs in congenital syndromes (above) / also occurs in pregnant women, HTN, patients with valvular heart disease / predisposes to aortic dissection Aortic Dissection Presentation (based on location of dissection): sharp or tearing pain (often confused for MI), may radiate to back, may persist for long period of time may have unequal pulses in extremities: involves brachiocephalic artery AR: involves aortic root and/or pericardial tamponade: neurological deficits from cerebral compromise (type A ( CVA) or acute peripheral neuropathies (type B ( peripheral ischemia) hypotension from pericardial tamponade or exsanguination MI from coronary occlusion, bowel ischemia (SMA/IMA), ARF (renal arteries)  HYPERLINK \l "horners" Horners syndrome: compression of superior cervical ganglion  HYPERLINK \l "svc" SVC syndrome: compression of SVC Findings: wide pulse pressure (aortic regurge, also seen with sepsis) Mechanism: may occlude brachiocephalic trunk (right!), common carotid or subclavian (left!), renal arteries, celiac, SMA, IMA, etc [HYPERLINK "pics/esophagus1.jpg"pic] Classification: Debaky I (both), II (only ascending), III (descending +/- ascending) / Sanford A (involves ascending), B (does not involve ascending) Radiography: CXR: widened aorta (mediastinum) CT chest with contrast (85% are true medial and are visualized by CT) MRI TTE or TEE very important when type A suspected (15% are intimal (non-communicating) and are best diagnosed by TEE Treatment: must reduce flow velocity as well as BP ( 100-120 systolic or as tolerated (must avoid a reflex ! HR and flow increase) B-blocker then vasodilator (NP or even Ca blocker) Labetalol (as single agent) Trimethaphan camsylate (can be used without B-blocker ( bad for COPD, bradycardia, CHF) Ascending aorta ( emergent surgical repair (90% mortality without surgery) Descending aorta ( observe, control BP (75% survival with medical then surgical management; some conditions like the congenital and inflammatory cases may be more likely to require surgical correction and more aggressive observation; also, if major artery branch occluded or impending occlusion such as spinal or renal arteries) Ventricular aneurysm Diskinetics ( persistent ST elevation (indefinitely) Heart failure Clot ( 10-40% of anterior MI develop clot (risk of embolism) Sustained VT/VF True aneurysm: rupture not the problem False aneurysm: partial rupture of heart, lined by pericardium / echo, LV angiogram, MRI show narrow discrete communication Abdominal Aortic Aneurysm (AAA) major cause of death / present in 1.5-3% of adults (5-10% of higher risk pts) Presentation: abdominal pain, hemodynamic instability from rupture/bleed Diagnosis: abdominal ultrasound, CT, MRI Treatment: watch (scan at 3-12 mo intervals) if < 5.5 cm; if > 5.5 cm (or expanding > 0.5 cm/year), can do endovascular or surgical repair (risk of rupture is 5-10%/year > 6 cm but only 1-2% <5 cm) Prognosis: mortality for elective repair 1-2% / emergent repair 50% Screening: TNT and IDEAL suggest screening with abdominal all men between 65+ who have ever smoked (even briefly) or others considered at high risk (HTN, CAD/PVD, smoking) Non -Bacterial Thrombotic Endocarditis (NBTE) usually secondary to cancer, DIC, renal failure, sepsis / fibrin deposition, nidus / marantic Infective Endocarditis [HYPERLINK "http://content.nejm.org/cgi/content/full/348/9/834"NEJM] [HYPERLINK "http://content.nejm.org/cgi/content/full/345/18/1318"NEJM] Incidence: 1 in 1000 hospital admissions / leading overall ( S. aureus ( of all cases are health-care related now 9/06) Organisms: Sub-acute: S. viridans (66%, indolent), HYPERLINK "micro.doc" \l "hacek"HACEK (GNRs, 5% in children), Candida non-albicans,  HYPERLINK "micro.doc" \l "coxiella" Coxiella (Q fever), Brucella, Bartonella Acute: S. aureus (20%),  HYPERLINK "micro.doc" \l "Enterococcus" Enterococcus (15%),  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus (1-3%) Post-surgical: S. epidermidis, S. aureus, pseudomonas, Candida (5-10%) Neonates:  HYPERLINK "micro.doc" \l "groupbstrep" Group B Strep Elderly: Streptococcus bovis (5-10%) (clue to underlying GI disease, malignancy), Enterococcus (GU disease or instrumentation) Immunocompromised, IV drug users (usually involves tricuspid): GNRs Others:  HYPERLINK "micro.doc" \l "rhusiopathae" E. rhusiopathae, Legionella, aspergillus, T. whippelii Culture-negative endocarditis [ HYPERLINK "pics/endocarditis-culturenegative.jpg" table] Mechanism: time from seeding to endocarditis < 2 wks in 80% of cases Presentation: fever (90%), new or changing murmur (85%), chest pain, dyspnea, arthralgia, myalgia, headache, malaise Other Findings: may have hematuria or TIA / commonly presents with acute renal failure from immune complex deposition / Osler nodes (vasculitis in fingers, toe pads) [ HYPERLINK "pics/oslersnodes.jpg" pic][HYPERLINK "pics/oslersnodes1.jpg"pic][HYPERLINK "pics/oslersnodes2.jpg"pic][HYPERLINK "pics/oslersnodes3.jpg"pic], Roths spots (flame shaped with white center, seen in retina [ HYPERLINK "pics/endocarditis-rothspots.jpg" pic]; not directly in blood vessel), Janeway lesions (erythema of palms, soles), splinter hemorrhages, petechiae [ HYPERLINK "pics/endocarditis-petechiae.jpg" pic], splenomegaly (sequestration) and hepatomegaly (congestion) after 2-3 weeks of infection / erythema nodosum is painful (different from rheumatic fever) Complications: seeding of various organs (e.g., brain, kidney, eyes), vascular occlusion (e.g. myocardial infarction, CVA) Presentation in children: fever (1st), Osler and Janeway are rare in children Diagnosis: [ HYPERLINK "pics/dukescriteria.jpg" table] Dukes major criteria: endocardial involvement: new murmur (not change in murmur) / positive echo isolation of typical organisms from 2 separate cultures or persistently positive Dukes minor criteria: these are just some predisposing valvular lesion or IVDA fever vascular or immune-mediated phenomenon (see above) positive blood cultures (not meeting major criteria) Echocardiography: TTE (50% sensitivity, but aorta often not seen well by TTE (you should always speak with the cardiologist who actually read the echo) TEE (95% sensitivity) (must not have ongoing upper GI problems, bleeding) Large vegetations suggests Staph or fungus Note: please consider TEE (as 1st test) with high-suspicion of IE with fulminant-type organisms / also TEE can r/o abscesses Blood cultures (3 in 24 hrs is 95% sensitive; best if each culture is > 2-3 hrs apart; but in interest of getting antibiotics started after cultures, can take 3 cultures over four hours) Note: 50% of fungal cultures will be negative; lysis centrifugation blood tubes will increase yield with HACEK (usu. grow within 5 days), nutritionally deficient Strep, Histoplasma, Fusobacterium (Candida does not need the help), Bartonella and Proprionibacterium are very slow growing Labs: elevated ESR, hematuria and anemia are most often seen Elevated WBC with left shift may or may not be present CBC, ESR, UA, 4 blood cultures over 48 hrs Tends to cause false positive RPR, SLE and immune reactants in general Treatment: always use high-dose antibiotics given IV (see below) Duration: 4-6 weeks (6 if prolonged illness, relapse, prosthetic valve, other) Long-term prophylaxis: PO amoxicillin or IV ampicillin/gentamicin Procedural prophylaxis: PO amoxicillin or IV ampicillin/gentamicin or vanc/gent Indications for surgery: severe heart failure (failed valve), abscess, fungus, multiple embolic phenomenon, uncontrolled infection (>7 days), prosthetic valve Note: anticoagulation shown to increase mortality due to hemorrhagic stroke) / use only if necessary for PE/mechanical valve Note: serial echos not helpful because vegetations organize and persists for months/years without late embolization Empiric RxDefinitive RxCommunityStrep viridans Enterococcus S. aureus S. pneumonia (1-3%)amp nafcillin nafcillin/AG Penicillin/ceftriaxone ampicillin/gentamicin nafcillin + 5 days gentamicinIVDAS. aureus (95%) S. non-aureus (5%) Pseudomonasnafcillin/AG nafcillin/AG? nafcillin/AG +/- ceftazidimeProsthetic valve (early) S. epidermidis (50%) S. aureus (50%) Pseudomonas (10%) Fungal (5%)vancomycin + ceftazidime or anti-pseudomonal AGProsthetic valve (late)S. aureus or MRSA Enterococcus S. epidermidis GNRvancomycin + gentamicinCrohnsS. milleriColon CancerS. bovis Austrian syndrome ( pneumococcal pneumonia, meningitis, endocarditis (rapidly progressive) Antibiotic prophylaxis for endocarditis (also see HYPERLINK \l "antibioticprophylaxisbonesurgery"  bone surgery) Give prophylaxis for the following conditions (all are high-risk unless otherwise stated) all prosthetic cardiac valves previous endocarditis surgical systemic pulmonary shunts most congenital heart defects (including ductus arteriosis, coarctation, Marfans, others; complex defects are at high risk; except isolated secundum ASD and many of those which have been well surgically corrected) acquired valve dysfunction (moderate risk) hypertrophic cardiomyopathy (HCM) (moderate risk) mitral valve prolapse with regurgitation or thickened leaflets (moderate risk) Low-risk: ASD, post-CABG, AICD or pacemakers, MVP without MR, (surgically repaired ASD, VSD, PDA) Any procedure with high chance of transient bacteremia GI surgeries, biliary tract, ERCP, esophageal sclerotherapy or dilatation surgery involving respiratory mucosa or rigid bronchoscopy prostate surgery or cystoscopy any dental procedure likely to cause bleeding (e.g. dental extraction) tonsillectomy & adenoidectomy Dental and upper respiratory tract: amoxicillin 2 g PO or cephalexin 2 g PO or clindamycin 600 mg PO or clarithromycin 500 mg PO 1 hour prior to procedure or ampicillin 2 g IV or clindamycin 600 mg IV (make sure infusion ends 30 minutes prior to procedure) GI/GU: moderate risk ( amoxicillin or ampicillin as above / vancomycin 1 g IV if PCN allergic high risk ( give ampicillin 2 g IV +  HYPERLINK "pharm.doc" \l "gentamicin" gentamicin 1.5 mg/kg (up to 120 mg) 30 minutes prior to procedure, followed in 6 hours by ampicillin 2 g IV or amoxicillin 2 g PO / if PCN allergic, give vancomycin 1 g IV + gentamicin 1.5 mg/kg (up to 120 mg) Other Causes of Cardiac Damage Tertiary Syphilis tree barking vessels, aneurysms / valves SLE pericarditis, endocarditis / resembles rheumatoid type / Libman-Sachs RA valves, granulomas Ankylosing Spondylitis fibrotic lesions of aorta Carcinoid Heart Disease caused by carcinoid tumors / endocardial thickening impairs tricuspid/pulmonic valves Calcification of Mitral Ring common over 70 yrs / may cause insufficiency Cardiomyopathy [Dilated / Restrictive] Dilated Cardiomyopathy Alcohol (most common, reversible) Coxsackie B Cocaine (irreversible) Doxorubicin (irreversible, perhaps glutathione might prevent) CHF from garden-variety CAD Post-partum cardiomyopathy ( HYPERLINK \l "postpartumcardiomyopathy" more) Exposure: cobalt, mercury, lead Endocrine: thyrotoxicosis, hypothyroid, acromegaly (usually reversible) Metabolic: Fabrys (hemi), hypophosphatemia, hypocalcemia, thiamine deficiency (wet Beri-beri), Hemoglobinopathies: sickle cell,  HYPERLINK \l "thalassemia" thalassemia CXR: cardiothoracic ratio ( > 0.6 is abnormal) / heart looks wider on expiration (largest effect) and diastole (max 2 cm change) Obliterative Cardiomyopathy calcification, thrombi, macrophages Restrictive Cardiomyopathy [see restrictive pericarditis] sarcoidosis, amyloidosis, hemochromatosis, carcinoid, idiopathic eosinophilia, endocardial fibroelastosis, endomyocardial fibrosis (Loefflers) / also obliterative agents Hypertrophic Obstructive (HOCM) AD defect in contractile proteins leads to concentric hypertrophy of septum Presentation: sudden death, dyspnea on exertion, syncope (usually occurs after exercise when venous return due to leg muscle contraction abates in the face of continued low TPR leading to woefully inadequate cardiac output) Findings: bisferiens pulse, systolic ejection murmur Maneuvers: conditions that shrink the size of the ventricle (valsalva) increase intensity of murmur; handgrip increases afterload and may increase LV volume which has variable effect (usu. decreases intensity of murmur) Diagnosis: echo Treatment: -blocker, Ca-blocker (to relax ventricle, slow HR and allow more filling) avoid afterload reducers (similar to  HYPERLINK \l "as" AS) indications for AICD (multiple trials looked at this and decision is not really based on EP study) check all 1st degree relatives with echo Post-partum cardiomyopathy may occur during last trimester or within 6 months of delivery (most often in 1 month before or after) / African-American, age > 30 / 50% will recovery completely (10-20% mortality) Treatment: same as other cardiomyopathies (except avoid ACE in pregnancy) / avoid future pregnancy due to increased risk of recurrence Cardiac tumors Most are mets 10:1 from lung, breast, lymphoma, melanoma Myxoma ball valve obstruction of left atrium (tumor plop sound) / most common adult cardiac tumor / can mimic PAN / can cause syncope Rhabdomyoma hamartoma / vacuolated myocytes / spider cells / most common childhood Sarcoma malignant / very poor prognosis Arrhythmias  HYPERLINK \l "bradycardia" Bradycardia  HYPERLINK \l "heartblock" Heart block  HYPERLINK \l "lbbb" LBBB,  HYPERLINK \l "rbbb" RBBB,  HYPERLINK \l "hemiblocks" Hemiblocks  HYPERLINK \l "atrial" Atrial  HYPERLINK \l "afib" atrial fibrillation,  HYPERLINK \l "atrialflutter" atrial flutter,  HYPERLINK \l "svt" SVT,  HYPERLINK \l "mat" MAT  HYPERLINK \l "ventricular" Ventricular  HYPERLINK \l "vt" VT,  HYPERLINK \l "qt" prolonged QT,  HYPERLINK \l "torsades" torsades de pointes Bradycardia Sinoatrial node dysfunction or SA nodal dysfunction Intrinsic Idiopathic degeneration (most common) Infarction/ischemia Infiltrative sarcoid, amyloid, hemochromatosis Connective tissue diseases SLE, RA, scleroderma Surgical, trauma Infectious/infiltrative Chagas, endocarditis Extrinsic Autonomic syndromes neurocardiogenic, carotid sinus hypersensitivity, situational disturbances Acute HTN Drugs: B-blockers, ca-blockers, clonidine, digoxin, anti-arrhythmics Hypothyroidism Hypothermia (look for J-point elevation or Osborn waves) Hypercapnia Acidemia Electrolyte disturbances Advanced liver disease Infectious/bradycariogenic brucellosis, typhoid fever Heart Block Causes (most common) [ HYPERLINK \l "avconductiondelay" Ddx]: drugs, CAD, degenerative process / congenital (in children) / others: increased vagal tone, surgery, electrolyte disturbances, myoendocarditis, tumors, rheumatoid nodules, calcific aortic stenosis, myxedema, polymyositis, infiltrative processes (such as amyloid, sarcoid, scleroderma), Chagas disease, lyme disease, many others Note: there is type I and II for each of the 3 degrees of heart block type I above His / more likely to be inferior MI, transient, edema of AVN type II His and below / more likely to be anterior MI, permanent, QRS > 0.10 1st degree heart block PR interval > 0.21 seconds Note: can have 1st degree type II (Levs and ?Lenegres, which are degenerative diseases of His/Purkinje system that require pacing) 2nd degree heart block not all P waves followed by QRS complex Type I (Wenchebacks) cycle (2 to 8) of PR lengthening until beat is dropped / can mimic group beating Type II 2:1 (or 3:1 or 4:1) conduction block / here, the problem is in the bundle of His or branches, and therefore, type II is more likely to progress to 3rd degree block Note: new onset Mobitz II or BBB may signal impending MI (probably PDA from  HYPERLINK \l "localizationofinfarct" RCA) 3rd degree heart block complete block / severe bradycardia not compatible with life in long term / dont confuse with a non-conducted p wave / will get IJ (40-60) or IV (20-40) pacing / syncope from this is called Stokes-Adams syndrome Ddx: ischemia,  HYPERLINK \l "hyperkalemia" hyperkalemia,  HYPERLINK \l "hypokalemia" hypokalemia, Ca channel blockers,  HYPERLINK "pharm.doc" \l "digitalis" digitalis, B-blockers (rarely), a-blockers (SA node), HYPERLINK \l "sicksinussyndrome"sick sinus syndrome Treatment:  HYPERLINK \l "pacemakers" medication/pacemakers / asymptomatic, intermittent 3rd degree heart black is class III indication of pacemaker (Lyme disease often reversible, some elderly have >3 sec pauses which are asymptomatic) Pacemakers (treatment of heart block) Atropine ( amp is mg) ( start with 0.6 mg atropine Epinephrine ( 0.25 mg (do not give too much) DA / isoproterenol (avoid with recent or ongoing ischemia) Transthoracic pacing (A/P pads) Synchronous demand ( sends pulse if no R wave is seen in time may need to change sensitivity to avoid background impulses (big P waves) Asynchronous ( do not do this if they have any inherent pacing (could give you R on T) Start with rate < intrinsic rate If no capture ( increase current Get capture then reduce to threshold and then go up to MA of 3 x threshold DDD senses atrial/ventricular contraction and waits for set PR interval before firing AV conduction delay Hypervagotonia (often associated with sinus bradycardia or sinus arrhythmia) Digitalis B-Blockers Ca Channel blockers Class III antiarrhythmics CAD Lenegres disease (diffuse fibrosis of the conduction system) Infiltrative heart disease Aortic root disease (syphilis, spondylitis) Calcification of the mitral and/or aortic annulus Acute infectious disease Myocarditis LBBB or Left Bundle Branch Block ^^ in V5 and V6 check limb leads / QRS > 0.12 / r/o artifactual QRS widening cannot rule out MI or LVH in presence of LBBB can rule in MI if ST changes > than 5 mm in synchronous leads (meaning T wave going same direction as R) V1 broad R wave (>30 msec) / onset of R wave to nadir of S wave > 60 msec / notched downstroke in lead V1 V6 QR or QS complex RBBB or Right Bundle Branch Block ^-^ in V1 and V2 V1 monophasic R wave / biphasic (qR or RS) / triphasic with R > R V6 R/S ratio < 1 Common causes of BBB Clinically normal individual Lenegres disease (idiopathic fibrosis of the conduction tissue) Levs disease (calcification of the cardiac skeleton) Cardiomyopathy Dilated, Hypertrophic (concentric or asymmetric) Infiltrative Tumor, Chagas disease, Myxedema, Amyloidosis Ischemic heart disease MI (acute/old), CAD Aortic Stenosis (AS) Infective endocarditis Cardiac trauma Hyperkalemia Ventricular hypertrophy Rapid heart rates Massive PE Hemiblocks Watch for intermittent change in QRS axis and/or pattern of LAD infarctions cause ant. hemiblock (also can get RBBB) Anterior hemiblock QRS usu. 0.1 to 0.12 Q1S3 LAD from late depolarization (r/o inferior MI, LVH, horizontal heart) Posterior hemiblock RAD (r/o lateral MI, RVH, lung disease) Normal or wide QRS S1Q3 Other slow (or no) rhythms Asystole PEA (pulseless electrical activity many causes) SSS (sick sinus syndrome) BTS (SSS with intermittent tachycardia) Tachyarrhythmias Normal Atrial foci ( 60-80 Junctional foci ( 40-60 Ventricular foci ( 20-40 Atrial tachycardia ( 150-250 Atrial flutter ( 250-350 Atrial fibrillation ( 350-450 Atrial flutter Ventricular flutter rapidly becomes V fib Ventricular parasystole simultaneous pacing of A and V Types of Tachycardias Regular narrow complex Sinus, atrial, AV-reentrant, WPW, atrial flutter, junctional tachycardia Irregular narrow complex Atrial fibrillation, multifocal atrial tachycardia, atrial flutter with variable block Wide complex QRS > 0.12 with normal conduction or > 0.14 with RBB or > 0.16 with LBB Ventricular tachycardia (VT), Torsades de Pointes (HYPERLINK \l "torsades"drugs that cause), supraventricular (SVT) with aberrant conduction, hyperkalemia, TCA toxicity Note: hyperkalemia can cause complete AV block even without widened QRS Diagnosis and Treatment Synchronized countershock Vagal maneuvers Adenosine P1 receptors in AV node / given as 6 then 12 mg IV / chest discomfort, transient hypotension / may terminate reentrant tachycardia / SVT may stop then recur / preexcitation tachycardia should not be affected AV nodal agents Lidocaine 1 mg/kg bolus, 1-4 mg/min / SE: confusion, seizures Magnesium torsades (especially drug-induced) / 1 g MgSO4 given IV Calcium membrane stabilization Atrial Arrhythmias Atrial Tachycardias (follow links for specifics)  HYPERLINK \l "sinustachycardia" Sinus tachycardia Sinus node re-entry Atrial tachycardia Unifocal /  HYPERLINK \l "mat" Multifocal  HYPERLINK \l "atrialflutter" Atrial flutter  HYPERLINK \l "afib" Atrial fibrillation AV Junctional Tachycardia AV re-entry ( HYPERLINK \l "wpw" WPW) orthodromic / antidromic  HYPERLINK \l "avnrt" AV nodal re-entry (common)  HYPERLINK \l "npjt" Non-paroxysmal Junctional (uncommon) Automatic Junctional Tachycardia (uncommon) General points Causes of atrial/junctional irritability epinephrine caffeine, amphetamines, cocaine, other B1 agonists HYPERLINK "pharm.doc" \l "digitalis"digitalis, toxins, EtOH HYPERLINK \l "hyperthyroidism"hyperthyroidism (direct and sensitization to above) low O2 (to some extent) Atrioventricular Relationship atrioventricular dissociation sinus capture beats fusion beats Regular atrial arrhythmias sinus tachyarrhythmia paroxysmal atrial tachycardia (PAT) ( HYPERLINK \l "pat" see other) atrial flutter with constant conduction (HYPERLINK \l "atrialflutter"see other) Supraventricular Tachycardia (SVT) Tachyarrhythmia originating above ventricle (includes PAT, AT, JT, etc.) may have widened QRS (resembling PVT) BBB or aberrancy can try vagal maneuvers 1st, then meds // Note: do not attempt carotid massage if there is a bruit!!! Brugadas Criteria (VT versus SVT with aberrancy) absence of RS complex in all precordial leads? interval from R to nadir of S > 100 msec in any precordial lead? AV dissociation? Are there morphology criteria for VT in both V1 & V6? (suggesting BBB) If yes to any !  HYPERLINK \l "vt" VT If no to all ! SVT w/ aberrancy Premature atrial beat (PAB) P1 looks different / can merge with T-wave SA pacing will be reset to P1 Non-conducted PAB may resemble 3rd degree heart block Paroxysmal atrial tachycardia (PAT) PAT with block is typical for digitalis toxicity Note: Must have AV blocking when controlling SVTs / do not use only a single class IC agent (e.g. flecainide) to control an atrial tachycardia because you might convert a 240 (A) 120 (V) to a 200/200 Atrial Fibrillation (AF) - Irregular 5% over 60 yrs / 10-15% over 80 yrs Causes: mitral valve disease, thyrotoxicosis, HTN, CAD, MI, pulmonary embolism, pericarditis / stress, fever, excessive alcohol intake, volume depletion, idiopathic Prognosis: 60% of new onset AF convert spontaneously within 24 hrs / atrium greater than 4.5 cm and long duration of Afib are more likely to have chronic/relapsing AF Work-up: TSH, consider PE w/u, more Treatment: Control ventricular response Rate control: Digoxin, B-blockers, Amiodarone vs. His ablation and pacemaker B-blockers reduce relapse (60% ( 40%) and when they do relapse, the HR will be lower (may also increase chance of conversion) Digoxin good for rate control (not conversion) / peak action at 90 mins Ca channel blockers (verapamil, diltiazem) for rate control (not conversion) Cardioversion - immediate DC conversion if hemodynamically unstable AFFIRM trial suggest no need to cardiovert most patients with chronic Afib; benefit may be seen more with younger, healthier women as well as patients whose heart failure is so severe that NSR would be of major benefit; some studies (PIAF/STAF/RACE) show that rhythm control may actually have worse outcome for elderly, CAD or non-CHF patients / for CHF patients, sometimes amiodarone is the best option (in spite of many side effects) [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/9/935" NEJM] AF present > 48 hrs or unknown duration Plan 1: 10 days (some say 21) anticoagulation therapy ( cardioversion ( 4 weeks post-anticoagulation Plan 2: if no thrombus seen on TEE (85% of cases) ( cardioversion 24-48 hrs later ( 4 weeks post-anticoagulation [plan 2 has higher initial success rate and lower bleeding events due to shorter duration of anticoagulation, but chance of long-term NSR is same] Spontaneous cardioversion (50% within 24 hrs) Direct current (DC) conversion success rate 90%, low rate of ventricular arrhythmia, premedication before DV conversion has no effect on short term maintenance of NSR Chemical Cardioversion variable success (ventricular arrhythmia rate 0-10%) Class III/Ia are more dangerous for hypertrophied hearts (prolonged QT and torsades) Class I are more dangerous for functionally (ischemic) and anatomically (fibrosis, infiltration) challenged hearts (ventricular tachyarrhythmias) Examples of efficacy: amiodarone (30%/1 hr, 80%/24 hrs), procainamide (65%/1 hr), quinidine (?), propafenone (90%/1hr), digoxin (50%/1 hr) If thrombus present (15% of cases): LA appendage > LA cavity (6:1) / 80% will resolve on repeat TEE within 2 months of anticoagulation Anticoagulation: heparin in short term then coumadin long-term; by 2003, Lovenox still not officially recommended; older patients with chronic or paroxysmal AF without contraindications should receive long-term warfarin (INR 2 to 3). ASA 325 mg/day (20% risk reduction) Risk of stroke: increased with diabetes, > 65 yrs, HTN, CHF, rheumatic heart disease, prior CVA or TIA, TEE showing spontaneous echo contrast in LA, left atrial atheroma, left atrial appendage velocity < 20 cm/s Investigational: focal atrial ablation, atrial pacing/defibrillators Atrial Flutter saw tooth appearing p waves (look in V1) with rate 200-350 / usually with 2:1 or 3:1 AV block / similar (but not identical) treatment as atrial fibrillation / atrial flutter is often curable with ablation / 40% with some tachyarrhythmia / also causes thrombus (needs to be anticoagulated like atrial fibrillation) Wandering Pacemaker benign usually benign, mostly in young persons (athletes) / will have more than one p wave morphology Multifocal atrial tachycardia (MAT) Associated with  HYPERLINK \l "copd" COPD,  HYPERLINK "pharm.doc" \l "digitalis" digitalis,  HYPERLINK "pharm.doc" \l "theophylline" theophylline, severe  HYPERLINK \l "hypokalemia" hypokalemia,  HYPERLINK \l "hypomagnesemia" hypomagnesemia Must have at least 3 different P wave morphologies on ECG / rate 100-130 can use adenosine to attempt to distinguish from coarse atrial fibrillation Premature junctional beat (PJB) May produce aberrant conduction May produce retrograde (inverted) P1 (SA pacing will be reset to P1) Can get junctional bigeminy/trigeminy Paroxysmal junctional tachycardia (PJT) may have aberrant conduction (150-250) Nonparoxysmal junctional tachycardia (NPJT) may be treated with AV nodal agents, possibly including adenosine AV nodal re-entrant tachycardia (AVNRT) circus re-entry (normal impulse goes through AV node, but instead of terminating in ventricle, it goes back up into AV node and loops back around to stimulate ventricle again; hard to distinguish from JT) Treatment: catheter ablation in young patients (90% success) / drug therapy: -blockers, Ca channel blockers, digoxin (be careful in WPW) Wolf Parkinson White AV muscle bridge (accessory pathway or Bundle of Kent) Findings: short PR interval ( < .12 sec) and delta waves atrial arrhythmias may carry over to ventricles (loss of AV protection mechanism) ventricular tachyarrhythmias from re-entry Treatment: for sustained VT or VT with hypotension, use DC cardioversion 1st / avoid AV blocking agents like adenosine, -blockers, Ca channel blockers, digoxin which may only worsen arrhythmias by increasing conduction through accessory pathway / can use  HYPERLINK "pharm.doc" \l "procainamide" procainamide, lidocaine, some say ibutilide Ventricular Arrhythmias Causes of ventricular irritability Low O2 Low K Adrenergic stimulation (to a lesser extent) PVC or Premature Ventricular Contraction 6/min is pathological / > 3 PVCs in a row is VT / > 30 seconds is sustained VT usually opposite polarity of QRS / enormous complex with QRS much longer than > .14 ms / long pause (does not disrupt sinus pacing, thus there is a punctual, but ineffective P wave) may occur in normal, healthy individuals (women > men) (usually disappear after exercise) in which case reassurance is treatment of choice and if needed, can try B-blockers / studies have shown reduction of PVCs (even in post-MI) patients cannot be used as an endpoint on its own (does not improve mortality) R on T During vulnerable period (after peak or during downslope of T) / vulnerable period extended by hypoxia / PVCs with R on T are more worrisome for triggering VT Criteria for wide complex tachycardia 1. AV dissociation (may see fusion or capture beats) 2. QRS width > 0.14 s w/ RBBB, > 0.16 s w/ LBB 3. QRS axis: LAD w/ RBB morphology 4. concordance of QRS in precordial leads SVT vs. VT fusion/captureextreme RADQ in V6VTCADQRS > 0.14yesyesyesSVTuncommonQRS < 0.14rare rarerare  Note: canon a waves in jugular venous pulsations occur from atria contracting against closed tricuspid valve (only seen with VT/AV dissociation) Non-sustained ventricular tachycardia (NSVT) Duration < 30 seconds / yes, it is a signal that something is not right Treatment: B-blockers and type III drugs (lidocaine) Ventricular tachycardia (VT) 150-250 bpm Causes: ischemia, HOCM, AS, long QT Treatment: ACLS measures (shock, medication), refractory cases (consider LVAD) Polymorphic VT Treatment: magnesium + other ACLS measures Torsades de Pointes (twisting of the points) ventricular arrhythmia associated with prolonged QT and characteristic EKG pattern / described by Dessertenne in 1966, related to 2 competing ventricular foci and abnormal electrolytes / whites > blacks / females > males Causes: hypomagnesemia, hypocalcemia, intracranial events, bradyarrhythmias, many drugs (see below) Course: TdP may either revert to normal or evolve into ventricular fibrillation Treatment: give magnesium; cardioversion insufficient (must do external ventricular pacing; overdrive pacing will shorten QT interval) Drugs associated with Torsades de Pointes: Anti/Pro arrhythmics: amiodarone, sotalol, bretylium, procainamide, propafenone, flecainide, encainide, disopyramide Antibiotics: fluoroquinolones, ganciclovir, pentamidine, macrolides (e.g. erythromycin, clarithromycin), amphotericin B, itraconazole, ketoconazole, ? fluconazole, co-trimoxazole, indapamide Protease Inhibitors: amprenavir, indinavir, nelfinavir, ritonavir, saquinavir Antipsychotics: droperidol, phenothiazines, chlorpromazine, thioridazine, moricizine, haldol Antidepressants: doxepin, amitriptyline, imipramine Other: tacrolimus, quinidine, quinine drugs that I cant remember what they are: terfenadine, terodiline, astemizole, bepridil, , maprotiline, ibutilide, ketanserin, perhexiline, prenylamine, probucol, sultopride drugs not commonly prescribed: cocaine, arsenic Prolonged QT syndromes Jervell-Lange-Nielsen (JLN) hereditary deafness and prolonged QT interval / syncope, sudden death Treatment: B-blockers Romano-Ward prolonged QT interval / syncope, sudden death Leopard syndrome [ HYPERLINK "http://dermis.net/dermisroot/en/37635/diagnose.htm" dermis] ACLS Guidelines (will supply pic of algorithm here) For VF or hypotensive VT shock at 200 then 300 then 360 then 360 then amiodarone 150 mg IV x 1 or lidocaine 1-1.5 mg/kg/IV x 1 / may also be indications for magnesium sulfate or procainamide Hypothermia EKG: J-point elevation or Osborn waves [HYPERLINK "pics/ekg-jwave.jpg"pic] and QT prolongation occurs at temperatures below 30C Pericardial Disease [ HYPERLINK \l "restrictivepericarditis" restrictive pericarditis] [ HYPERLINK \l "cardiactamponade" cardiac tamponade]  HYPERLINK \l "pericardialeffusion" Pericardial effusions  HYPERLINK \l "acutepericarditis" Acute pericarditis  HYPERLINK \l "InfectiousPericarditis" Infectious pericarditis ( HYPERLINK \l "viralpericarditis" viral,  HYPERLINK \l "tbpericarditis" TB)  HYPERLINK \l "dresslers" Dresslers syndrome  HYPERLINK \l "uremicpericarditis" Uremic pericarditis Pericardial effusion serous non-bacterial / some WBCs fibrinous uremia, rheumatic heart disease serofibrinous purulent/suppurative infection hemorrhagic blood, fibrin, pus, neoplasm cholesterol rare chronic adhesive result of fibrinous constrictive result of purulent or hemorrhagic Acute Pericarditis Causes: Infectious: (see below) Cardiac: acute MI, post-radiation, postcardiac injury (postpericardiotomy, trauma, Dresslers, chylopericardium), aortic dissection Immune: sarcoidosis,  HYPERLINK \l "sle" SLE,  HYPERLINK \l "ra" RA, scleroderma (less), rheumatic fever, IBD Other: uremia, myxedema Drug induced: procainamide, hydralazine, INH, etc Malignancy: primary (mesothelioma), metastatic malignancy (lung, breast,  HYPERLINK \l "melanoma" melanoma, lymphoma) Presentation: fever (implies infection) occurs before pain (unlike MI where fever is after pain), 1-2 wks after viral illness / pain may resemble MI, radiate to back, shoulders, arms (less), pain may be pleuritic, altered by postural changes Physical Exam: Pericardial friction rub (50%): monophasic, triphasic (early, late, diastolic) < biphasic / may decrease with onset and increased size of pericardial effusion (but can co-exist with effusion) / distinguish from pleural friction rub by having patient hold breath / rub changes w/ position Pericardial Effusion: elevated JVD, pulsus paradoxus, prominent x descent, reduced y descent, peripheral edema, and disproportionate ascites, Kussmauls sign (constrictive pericarditis) Diagnosis: ECG: PR !, J-point !, characteristic ST ! ( restated: diffuse ST elevation (concave) with T wave inversion occurring temporally after ST resolution (unlike MI), PR depression / also ST-elevation to T-wave amplitude in V6 > 0.24 is very suggestive [HYPERLINK "pics/ekg-pericarditis.jpg"pic] Radiographic: pleural effusion [HYPERLINK "pics/pleuraleffusion.jpg"pic] in constrictive pericarditis, calcified pericardium (50%), enlargement of cardiac silhouette (with pericardial effusion > 250 ml) [HYPERLINK "pics/jhid-pericardialeffusion.jpg"pic] / CT or MRI may reveal thickened pericardium / other studies include left/right heart catheterization and fluid challenge Labs: mild elevated WBC, ESR Complications: cardiac tamponade, arrhythmias (resting tachycardia, atrial fibrillation) Treatment: avoid anticoagulation!!! (may bleed causing hemopericardium/tamponade) / NSAIDs 1st line (e.g. indocin 25-50 tid until 1 week after Sx resolve) / steroids 2nd line (20-60 mg P qd) / prolonged/relapse may require colchicine 1 mg/d and/or pericardiectomy to prevent constrictive pericarditis / some argue for colchicine as first line (2009) Prognosis: most cases improve in 2-3 weeks Infectious Pericarditis: Viral: coxsackie A/B, echovirus, adenovirus, mumps, influenza, EBV, VZV, CMV, HSV, HBV(really?) Bacterial: 30% mortality / antibiotics and drainage, not steroids Organisms: S. pneumo and other strep, S. aureus, N. meningitidis and gonorrhea, H. influenzae, Enterobacteriaceae, Campylobacter, Brucella, Actinomyces, Nocardia, Listeria, M. pneumoniae, Legionella, Chlamydia, Borrelia, M. tuberculosis, MAI contiguous spread from chest infection (outside heart or endocarditis) or (peri or post) trauma/surgery bacterial pericarditis from contiguous pneumonia usually occurs only after prolonged, untreated infection Fungus (most of them) Parasites: Toxoplasma, E. histolytica, Schistosomes Viral pericarditis friction rub LLS border / more w/ leaning forward / pain come and goes / diffuse ST elevation / normalized by 1-2 days, then T inversion TB pericarditis 5 to 10% of acute pericarditis / 1% of pulmonary Tb / serous (20%) or serosanguinous (80%) hematogenous or contiguous / granulomatous (Langerhans cells) Effusate: high protein, high PMNs early, high lymphocytes later Complications: constrictive pericarditis (may be predicted by elevated adenosine deaminase), pericardial calcification, myocarditis, dissemination Treatment: HRZE for 8 weeks then INH/rifampin / some evidence favors steroids / pericardiectomy recommended for pericardial thickening (over will have some procedure) Note: 2.6:1 odds that patient will have AIDS, 6:1 if disseminated Tb Dresslers syndrome Presentation: pleuritis, malaise, CP occurring 1-4 weeks to months after MI Findings: pleural/pericardial effusions, fever (up to 40c), leukocytosis, elevated ESR Note: may consider biopsy of heart muscle to rule out ongoing inflammation Treatment: NSAIDs (1st) / steroids (2nd) Course: autoimmune process which may relapse up to 2 yrs later Uremic pericarditis often hemorrhagic / avoid anticoagulation Constrictive pericarditis thickened, fibrotic adherent sac, impaired diastolic filling Causes: radiation-induced pericarditis > cardiac surgery, any other acute pericarditis Presentation: progressive weakness, fatigue, exertional dyspnea (all signs of right-sided heart failure, liver congestion) / often presents long after initial insult (~10 yrs) Exam: Kussmauls sign (increase in JVP during inspiration; rather than decreased), pericardial knock (high-pitched early diastolic just after aortic valve closure), no pulsus paradoxus Diagnosis: MRI is test of choice: show pericardial thickening (> 4 mm), to moderate biatrial enlargement, normal ventricular dimensions, dilated venae cavae CXR may show cardiomegaly and calcified pericardium cardiac catheterization confirms hemodynamic constriction echo with doppler may show constrictive flow pattern TEE may show pericardial thickening (not 1st line test) Treatment: pericardiotomy (outcome based on pericardial substrate and severity of heart failure) Restrictive pericarditis Presentation: similar to constrictive only now were talking about infiltration: amyloidosis > cardiac surgery, radiation therapy (in Africa, endomyocardial fibrosis with eosinophilia much more common) Exam: Kussmaul s sign absent (why?) Diagnosis: as with constrictive, but MRI and/or endomyocardial biopsy may be needed to distinguish Treatment: treat underlying disorder (as much as possible) Cardiac Tamponade  life-threatening emergency Definition: pericardial pressure e" RA pressure / equalization of pressure in the four chambers during diastole / pericardium can accommodate from 200 to 2000 mL depending on acuteness of situation Presentation: SOB from reduced cardiac output, pleuritic CP from stretch of pericardium Becks Triad: hypotension, elevated JVP, small quiet heart Exam: narrow pulse pressures,  HYPERLINK \l "pulsusparadoxus" pulsus paradoxus (drop > 10 mmHg in systolic BP on inspiration; some is physiologic, but not > 10 mmHg) (LA unable to expand so blood pools in lungs as opposed to going into aorta where it would maintain BP), tachycardia, ! JVP (but Kussmaul s sign usu. absent), ! carotid volume 2o ! CO, lung exam clear (E( A L mid lung 2o compression of lung by heart), cannot palpate PMI, distant heart sounds EKG: electrical alternans 2o swinging heart during respiration Treatment: relieve tamponade with paracardiocentesis Note: preload is badly needed ( preload reducers are contraindicated (diuretics, nitrates, etc.) Myocarditis [ HYPERLINK "http://content.nejm.org/cgi/content/full/343/19/1388?" NEJM] [HYPERLINK "http://content.nejm.org/cgi/content/full/356/11/1153"NEJM] Infections: [ HYPERLINK "pics/infectiousmyocarditis.jpg" table] Viral (10-30%) (Enterovirus > Adenovirus, HIV?) Chagas disease (Trypanosoma cruzi) (20% develop CHF) Drugs: Doxorubicin, Anthracyclines + anti-HER2, Cocaine Autoimmune: Idiopathic giant cell myocarditis (affects healthy, young people) Allergic myocarditis (eosinophilia) Other autoimmune: polymyositis, scleroderma, SLE Diagnosis: EKG likely same as pericarditis (diffuse ST elevations) / Dallas criteria, endomyocardial biopsy (gold standard, but often inconclusive and carries 0.25% mortality) / cardiac MRI probably most helpful (90% specificity in diagnosing lymphocytic myocarditis) / echo DIP / cardiac markers non-specific and levels do not correlate with severity of inflammation Treatment: Arrhythmias: probably good idea to push low dose b-block or stronger as needed / be careful with digoxin (only use low doses, may worsen inflammation) consider transfer to hospital equipped with LV assist devices in case of rapid heart failure bed rest (exercise shown to increase viral replication and worsen outcomes; rest for at least a week? 3rd leading cause of sudden cardiac death in athletes), eliminate unnecessary meds (esp. with eosinophilia) avoid anticoagulation (as much as can in case of hemorrhage into pericardium) treat underlying cause / immunosuppression for autoimmune diseases (including giant cell myocarditis) but not helpful for infectious or post-infectious / INF-a currently under investigation for viral myocarditis Fiedlers (young adults) Vascular Diseases (see other) Berry aneurysms A/V fistula (circoid aneurysm) Subclavian steal syndrome Occluded subclavian artery (usually on the left) leads to collateral perfusion of shoulder joint from vertebral artery / symptoms are intermittent arm claudication and syncope and/or ataxia, confusion, vertigo, dysarthria from exercise-induced decreased vertebrobasilar perfusion leading to Treatment: bypass Cervical rib May impair blood flow through subclavian artery / Treatment is resection of rib Heart Transplant survival 76% at 3 yrs / transplant half-life ~9.3 yrs / chronic cardiac transplant rejection manifests as CAD with characteristic long, diffuse, concentric stenosis / only definitive therapy is retransplant Oncology General:  HYPERLINK \l "markers" markers,  HYPERLINK \l "associations" associations,  HYPERLINK \l "tumorbiology" tumor biology,  HYPERLINK \l "tumorspread" patterns of spread,  HYPERLINK \l "bmt" BMT,  HYPERLINK \l "neutropenicfever" neutropenic fever  HYPERLINK \l "leukemia" Leukemia /  HYPERLINK \l "lymphoma" Lymphoma  HYPERLINK \l "pulmonaryneoplasia" Lung  HYPERLINK \l "liverneoplasia" Liver  HYPERLINK \l "gi" GI Endocrine  HYPERLINK \l "epidermaltumors" Skin Renal  HYPERLINK \l "cnsneoplasms" Brain  HYPERLINK \l "male" Male ( HYPERLINK \l "prostateca" Prostate) /  HYPERLINK \l "female" Female ( HYPERLINK \l "breastca" Breast,  HYPERLINK \l "ovary" Ovary)  HYPERLINK "drugs/chemotherapy.doc" Huge list of chemotherapy protocols Tumor markers CA-125 ovarian CA-15-3 CEA colon, pancreas, gastric, breast CA-19-9 pancreas Bombesin neuroblastoma, small cell carcinoma, gastric, pancreas S-100 melanoma, neural tumors A-FP HCC, yolk sac tumor ( HYPERLINK \l "nsgct" NSGCT) / also B-hCG, a1-AT B-hCG choriocarcinoma PSA prostate Tumor Associations Visceral malignancy [ HYPERLINK "http://dermis.net/dermisroot/en/19683/diagnose.htm" dermis]  HYPERLINK \l "acanthosisnigricans" acanthosis nigricans, dermatomyositis, flushing, acquired icthyosis, thrombophlebitis migrans Intrathoracic tumors (lung cancer) clubbing of fingers Hamartomas Cowdens, breast, intestinal, TS, skin, cardiac Lymphoma minimal change disease,  HYPERLINK \l "hsp" HSP,  HYPERLINK \l "gca" GCA, granulomatous angiitis of CNS HBV, HCV HCC  HYPERLINK \l "pan" PAN hairy cell leukemia  HYPERLINK \l "wegeners" Wegeners Hodgkins disease Specific Syndromes  HYPERLINK \l "ts" Tuberous sclerosis astrocytoma, cardiac rhabdomyoma (facial angiofibroma, SZ, retardation) Plummer-Vinson Syndrome SCC of esophagus (atrophic glossitis, upper esophageal webs,  HYPERLINK \l "ida" iron deficiency anemia, women) Muir-Torre syndrome Sebaceous tumors associated with visceral neoplasms AD /  HYPERLINK \l "coloncancer" Colon CA / Increased risk for breast/thyroid CA Cowden Disease (Multiple Hamartoma Syndrome) [HYPERLINK "pics/cowden1.jpg"pic][HYPERLINK "pics/cowden2.jpg"pic] AD / cobblestoning of oral mucosa (trichilemmomas) / breast, thyroid, uterine, brain tumors / also have multiple small hamartomatous polyps in GI tract (not considered premalignant)  HYPERLINK \l "PeutzJeghers" Peutz-Jeghers,  HYPERLINK \l "fap" FAP Paraneoplastic Pemphigus Syndrome ( HYPERLINK \l "paraneoplasticpemphigus" see derm) Lynch syndrome includes hereditary nonpolyposis colon cancer syndrome Tumor Biology invasion/growth factors,  HYPERLINK \l "tumorsuppressors" tumor suppressors,  HYPERLINK \l "carcinogens" carcinogens, radiation, viral Tumor Invasion use plasmin, type IV collagenase, etc. growth factors, angiogenics cleavage products PDGF, V-sis, EGF, CSF-1 protein kinases membrane receptors c-erb-B2 (breast, ovarian, gastric), c-neu, c-fms cytoplasmic receptors c-src, v-src / tyrosine kinase P-vinculin G-proteins h-ras, k-ras, n-ras nuclear proteins c-jun, c-fos, c-myb (transcription factors), c-myc (many cancers), l-myc (SCC lung), bcl-2 (lymphomas), ret (MEN) BM type IV collagen, laminin / bind to and secrete laminin ECM type I collagen, fibronectin / bind to fibronectin platelet covered tumor thrombi / NK cells may destroy tumor cells activation point mutation (ras) / translocation (c-myc) gene amplification (n-myc - neuroblastoma, c-neu -  HYPERLINK \l "breastcancer" breast cancer) Tumor Suppressors Rb retinoblastoma p53 colon, liver, breast Wt Wilms tumor (children) VHL renal cell carcinoma APC colon BRCA-2 breast BRCA-1 breast, ovarian NF-1 neurofibroma NF-2 neurofibroma type II (acoustic) DCC colon, stomach DPC pancreatic Carcinogens alkylating agents polycyclic aromatic hydrocarbons (tobacco combustion, smoked meats) Tobacco increases risk of lung, bladder, esophageal and head and neck cancer (studies have shown passive cigarette smoke imparts 25% increase risks of all associated mortality including cancer, heart, respiratory illness) aromatic amines, azo dyes (butter, cherries) natural (aspergillus flavus in grains, peanuts) nitrosamines, amides (GI cancer) asbestos, vinyl chloride, arsenic, insecticides Radiation UV UVB (xeroderma pigmentosum) ionizing leukemia, thyroid, breast, lung, salivary (NOT skin, bone, GI) / ataxia telangiectasia DNA repair XP, AT,  HYPERLINK \l "fanconis" Fanconis anemia, Blooms syndrome Viral HPV, EBV (nasopharyngeal, Burkitts), HBV (HCC), HTLV-1 (RNA gives T-cell leukemia),  HYPERLINK "micro.doc" \l "hhv8" HHV-8 (Kaposis sarcoma) Patterns of Tumor Spread Elevated LDH or B2-microglobulin levels in lymphomas increase likelihood of CNS mets Solid Tumors that spread to bone (including spinal mets) thyroid, prostate, breast, melanoma, lung / ( HYPERLINK \l "mm" multiple myeloma, leukemias, etc.) Solid Tumors that spread to brain bronchogenic carcinoma > breast > melanoma > renal cell carcinoma > colon, lymphoma Tumors associated with hypercoagulability lung, pancreas, stomach, colon > prostate, ovary >>> breast, brain, kidney, lymphoma Trousseaus syndrome usu. pancreatic or other GI Hepatic or portal vein thrombosis myeloproliferative disorders (PNH, PRV, essential thrombocythemia) Tumors of fibrous tissue Fibroma most common in ovaries Fibrosarcoma lower extremities (45%) > upper extremities (15%) > trunk > head, neck benign fibrous histiocytoma cutis or subcutis / extremities malignant fibrous histiocytoma storiform/pleomorphic (worse) > myxoid, inflammatory / mets mostly to lungs (hematogenously) Treatment: surgical +/- chemotherapy/radiation adjuvant or palliative Fibromatoses relapse but do not metastasize / palmer pattern causes Depuytrens contracture (50% bilateral) / penile fibromatosis causes Peyronies disease (Bill Clinton) Fibromuscular Dysplasia [ HYPERLINK "pics/fibromusculardysplasia.jpg" pic] can compress vasculature mimicking various vasculitides or vaso-occlusive diseases Tumors of adipose tissue lipoma most common soft tissue tumor / mostly subcutaneous, upper half of body liposarcoma 2nd most common adult soft tissue sarcoma / well-differentiated, myxoid (low grade) / round cell, pleomorphic, dedifferentiated (high grade) / retroperitoneum, thigh, perirenal, mesenteric fat, shoulder Tumors of smooth muscle leiomyoma female genital tract / can occur elsewhere, can be painful leiomyosarcoma larger, softer, hemorrhage, necrosis, metastases Other tumors synovial sarcoma may recur and metastasize granular cell tumor benign Cancer with Unknown Primary Usu. > 60 yrs / median survival 4-11 months (best hope is for cancer to be a nearby met from treatable solitary tumor) CUPS syndrome (biopsy proven malignancy with path not c/w primary tumor + unrevealing workup) adenocarcinoma > poorly differentiated carcinoma pancreas, breast, colon, prostate, lung 2% of all cancer diagnoses / 5% of newly diagnosed mets are unknown primary work-up based on findings, consideration of patients life-expectancy (usually 6 months), and then consider whether certain tests will change management / abdominal CT, CXR, occult blood (why do colonoscopy or ERCP if no symptoms), PSA (very different treatment), aFP, B-HCG extragonadal germ cell syndrome: < 50 yrs, midline structures, parenchymal lymph nodes, lung, elevated aFP or B-HCG, rapid growth / cisplatin-based chemotherapy offers 20% chance of cure PET scans may identify primary site but have not been shown to increase survival Tumor Fever can try NSAIDs (thought to reduce fever caused by many ?solid tumors) / often used as a diagnostic/therapeutic tool Cancer Chemotherapy Theory Gompertzian kinetics suggests benefits of adjuvant chemotherapy to treat micromets Combination chemotherapy for maximum cell kill, broader range of kill, slows emergence of resistance Choose some action as single agent / non-overlapping / optimal dose and schedule NOTE: up to 25% of patients treated with chemotherapy will develop secondary chemo-related tumor by 25 years alkylating agents leukemias with deletions of chromosome 5 or 7 (peak 4 to 6 years) topoisomerase II leukemias with deletions (e.g. 11q23) (peak 1 to 3 years) Irradiation Many uses (find listed under various diseases) Mediastinal irradiation: acute or chronic pericarditis (mean onset 9 months; can manifest years later), myocardial fibrosis, accelerated atherosclerosis Renal  HYPERLINK \l "renalstudies" Renal Studies /  HYPERLINK \l "proteinuria" Proteinuria /  HYPERLINK \l "hematuria" Hematuria [ HYPERLINK \l "lytes" Electrolytes]  HYPERLINK \l "arf" Acute Renal Failure (ARF)  HYPERLINK \l "renaldrugtoxicity" drug-Induced, TLS,  HYPERLINK \l "rhabdomyolysis" rhabdomyolysis, hepatorenal  HYPERLINK \l "crf" Chronic Renal Failure (CRF)  HYPERLINK \l "nephritic" Nephritic Glomerulopathies  HYPERLINK \l "psgn" PSGN,  HYPERLINK \l "iganephropathy" IgA nephropathy,  HYPERLINK \l "rpgn" RPGN,  HYPERLINK \l "anca" ANCA,  HYPERLINK \l "gbm" GBM,  HYPERLINK \l "cryoglobulinemia" Cryoglobulinemia HYPERLINK \l "nephrotic"Nephrotic Glomerulopathies  HYPERLINK \l "mcd" minimal change,  HYPERLINK \l "fsgs" FSGS,  HYPERLINK \l "mgn" MGN,  HYPERLINK \l "mpgn" MPGN Renal-Systemic  HYPERLINK \l "hypertension" HTN, DM,  HYPERLINK \l "amyloidosis" amyloidosis, MM,  HYPERLINK \l "gout" Gout, SLE, HYPERLINK \l "renalpan"PAN, HYPERLINK \l "renalwegeners"Wegeners, HYPERLINK \l "renalscleroderma"scleroderma   HYPERLINK \l "renaltubular" Tubular Disease  HYPERLINK \l "atn" ATN,  HYPERLINK \l "rta" RTA, Bartters  HYPERLINK \l "renalthrombotic" Renal Thromboembolic  HYPERLINK \l "renaldic" DIC,  HYPERLINK \l "hus" HUS,  HYPERLINK \l "ttp" TTP,  HYPERLINK \l "hsp" HSP,  HYPERLINK \l "renalendocarditis" Endocarditis, CES,  HYPERLINK \l "alports" Alports  HYPERLINK \l "interstitialnephritis" Interstitial Nephritis analgesic, acute,  HYPERLINK \l "balkan" Balkan, xanthogranulomatis  HYPERLINK \l "renalother" Renal Other  HYPERLINK \l "renalstones" renal stones, hydronephrosis, mechanical,  HYPERLINK \l "renalhypertension" hypertension,  HYPERLINK \l "renalarterystenosis" RAS, nephrogenic systemic fibrosis  HYPERLINK \l "renalmalformations" Renal Malformations anomalies of position, differentiation,  HYPERLINK \l "apkd" APKD  HYPERLINK \l "renaltransplant" Renal Transplantation  HYPERLINK \l "renalneoplasms" Renal Neoplasms  HYPERLINK \l "dialysis" Dialysis Renal Physiology Tidbits [ HYPERLINK "pics/nephron.gif" nephron] Clearance and GFR normal kidney can clear 20 L/day FeNa UNa x SerCr / SerNa x UCr GFR = (UCr x Ur vol) / (PCr x time) BUN can rise much faster than Cr [40/2 is pre-renal / 20/4 is renal] Note: decreased flow in tubules allows back diffusion of urea (but not  HYPERLINK "labs.doc" \l "creatinine" creatinine) GFR = [(140 Age)(Wt)] / [(Cr)(72) x 0.85 (for women)] ATII constricts efferent arteriole ( increases GFR and glomerular pressure Afferent constriction (influx of extracellular Ca affected by Ca channel blockers) Efferent constriction (influx intracellular Ca not affected by Ca channel blockers) Normal protein loss: Men 15-20 mg/kg/day lean body mass 50 +/- 2.3 x inches over/under 60 Women 10-15 mg/kg/day lean body mass 45.5 +/- inches over/under 60 Renal Studies Renal Ultrasound ARF: number, size, shape, hydronephrosis/hydroureter (10%-20% smaller by U/S than IVP), can sometimes detect renal stones, abdominal aneurysms, and renal vein thrombosis Large kidneys: multiple myeloma, amyloidosis, early DM, HIV nephropathy, pyelonephritis Evaluation of renal artery flow (can also get MRI/MRA of renal arteries) Abdominal CT Can diagnose hydronephrosis, 1st line (after KUB) for evaluation of  HYPERLINK \l "renalstones" renal stones, determine if cystic masses (benign or malignant) Intravenous Pyelography (IVP) Can provide information about kidney ultrastructure (size, shape, mass) and function (obstruction) / CT can do most of the same things Retrograde pyelography inject contrast during cystoscopy (only perform after intravenous urography) / used when urography does not visualize kidneys and collecting system and obstruction is suspected Isotopic flow scans (eh) ARF: marginally useful for renal perfusion (DTPA) and obstructive uropathy / hippurate for assessing tubular function Useful for evaluating renal allograft function Renal Biopsy When cause of  HYPERLINK \l "nephrotic" nephrotic syndrome is sought acute inflammatory lesion requiring cytotoxic therapy Note: wire-loop lesions or sub-endothelial deposits are not disease specific / huge sub-endothelial deposit may resemble a thrombus Cystoscopy For urethral obstruction (always) and ureteral obstruction (sometimes) Urinalysis Color Blood Glucose Ketones Protein Bilirubin Urine pH Concentration Sediment Crystals Cells [HYPERLINK "pics/tubularepithelialcell.jpg"pic] Bacteria Casts RBC casts glomerulonephritis [ HYPERLINK "pics/rbccast.jpg" pic] WBC casts glomerulonephritis [HYPERLINK "pics/wbccast.jpg"pic] Muddy brown casts ATN Hyaline casts [HYPERLINK "pics/hyalinecast.jpg"pic] Fatty casts [HYPERLINK "pics/fattycast.jpg"pic] 24 Hr Urine average daily Cr production in men is 16 to 25 mg/kg (women 15 to 20 mg/kg) / 24 hr sample should have this amount of creatinine (otherwise it is an inadequate sample) Drugs that alter serum creatinine reading Interfere with tubular secretion Trimethoprim, cimetidine, probenecid,triamterene, amiloride, spironolactone Interfere with lab measurement ascorbic acid, cephalosporins, flucytosine, levodopa,methyldopa Non-renal causes of elevated BUN GI bleeding catabolic effect: tetracycline, steroids Proteinuria > 30 mg/24 hrs albumin excretion is considered abnormal (microalbuminuria) > 300 mg/24 hrs is nephrotic range proteinuria urine dipstick can detect if more than 500 mg/day / > 90% sensitivity/specificity but doesnt account for variations in urine creatinine spot albumin/creatinine ratio > 30 mg/g creatinine is considered microalbuminuria / > 95% sensitive, specific Transient increased proteinuria (albuminuria): exercise, short-term hyperglycemia, urinary tract infections, marked hypertension, heart failure, and acute febrile illness False positive: menstrual bleeding in women Note: dietary protein intake does not cause microalbuminuria, but patients with diabetic nephropathy are advised to take low protein diet (0.6g/kg/d) Nephrotic Syndrome Primary: S! Secondary: T! of cases Proteinuria (normally prevented by large size, net negative charge) Edema (from salt retention) Hypoalbuminemia Hyperlipidemia (decreased oncotic pressures triggers liver to produce lipoproteins) ! LDL, lipoprotein-A / causes atherosclerosis Hypercoagulable state (!ATIII, protein C/S) Vitamin D deficiency (loss of Vitamin D binding protein) Iron deficiency anemia (loss of transferring) Hypogammaglobulinemia (increased susceptibility to bacterial infection) Diagnosis: Urinalysis: urine dipsticks (albumin only) and sulfosalicylic acid precipitation (albumin, paraproteins, immunoglobulins, and amyloid) 24-hour urine for protein (better for low urine output) / urine protein electrophoresis / serum lipids / lipiduria is suggested by oval fat bodies on microscopic study Biopsy (if no obvious cause and significant proteinuria) / EM, IF, special stains (e.g., Congo red for amyloid) Treatment: Control blood pressure: this is the most important thing, more than ACE even, goal is to use MAP of 80-100? (too low is also bad) ACE inhibitors or ARBs (decrease proteinuria, reduce progression; also, low protein diet helps reduce amount and toxicity of proteinuria) Diuretics (for overload): reasonable goal is 0.5 1 L/day (usually need Lasix (+) to achieve; go slowly; do not volume deplete; note: because HCTZ and Lasix are highly protein bound, there is reduced delivery to kidneys and large doses are often required to get same effect) Control hyperlipidemia: dietary changes + statins / this is not optional, these patients must be on statins (note: lipoprotein-a elevations unresponsive to statins) Note: calcium channel blockers worsen proteinuria by decreasing afferent > efferent thus raising intraglomerular pressure Prognosis: usually takes 5-10 to go from microalbuminuria to overt nephropathy; then 5-15 years to reach ESRD; once ESRD, dialysis patient have average life expectancy of 2 years. Orthostatic proteinuria Only happens when patient has been standing (so use nocturnal urine collection in patients who exercise vigorously) / remain constant at about 0.5-2.5 g/24 hr Treatment: none required / excellent prognosis Tubulointerstitial nephritis Albumin, Tamm-Horsfall protein and B2-microglobulin drug-induced disease, chronic inflammatory disease (e.g.,  HYPERLINK \l "sarcoidosis" sarcoidosis), analgesic nephropathy Treatment: remove offending agent / treat underlying disease Renal Vein Thrombosis (RVT) (lots of proteinuria) Causes: Nephrotic syndrome Renal cell carcinoma with renal vein invasion Pregnancy or estrogen therapy Volume depletion (especially in infants) Extrinsic compression (lymph nodes, tumor, retroperitoneal fibrosis, aortic aneurysm) Presentation: nausea, vomiting, flank pain, hematuria, leukocytosis, renal function compromise, and an increase in renal size Note: adult nephrotic patients (chronic RVT) can be more subtle (big increase in proteinuria or tubular dysfunction such as glycosuria, aminoaciduria, phosphaturia, and impaired urinary acidification) Diagnosis: MRI/MRV (1st) or CT or selective renal venography (U/S and IVP are sometimes okay) Treatment: 1 yr anticoagulation (some advocate thrombolysis if very acute) Hematuria Normal excretion of 500,000-2,000,000 RBC/24 hr (< 3 RBC per HPF) Isolated Hematuria ( stones, trauma, prostate > tumor (15%), Tb Causes and microscopic findings: Intrarenal trauma, renal stones, GN, infection (pyelonephritis), neoplasia (RCC), vascular (renal thrombosis) Extrarenal trauma (Foley), infection (urethritis, prostatitis, cystitis), ureteral stones, neoplasia ( HYPERLINK \l "prostateca" prostate,  HYPERLINK \l "bladderca" bladder) Glomerulonephritis Gross or microscopic hematuria, abnormal proteinuria, red blood cell casts / dysmorphic red cells on phase-contrast LM Diffuse (SLE, vasculitis) Focal (IgA nephritis)gross or microscopic hematuria without proteinuria, thin basement membrane / dysmorphic red cells Vascular diseaseGross or microscopic hematuria without proteinuria isomorphic red cells Tumors (hypernephroma)Isomorphic red cells Trauma, kidney stones, systemic coagulopathiesIsomorphic red cells  Diagnosis: Dipstick (hemoglobinuria vs. myoglobinuria) / positive heme (orthotolidine test) and no RBCs suggests pigmenturia / red urine without hemoglobin or RBCs is rare (beeturia, porphyria) Urine culture IVP for renal masses, cysts, AVM, papillary necrosis, ureteral stricture or obstruction by calculus, bladder tumor, and ureteral deviation / other: angiography and nuclear scans (rarely used to delineate mass lesions) MRI/CT (mass effects, surrounding structures) Cystoscopy (when other tests non revealing) Biopsy (sometimes needed) Complications: iron deficiency anemia (only with chronic, significant hematuria) / obstruction from lower urinary tract clots Treatment: identify/treat underlying disorder / maintain urine volume to prevent clots/obstructions in the lower urinary tract Acute Renal Failure (ARF) (see drug-induced ARF) ( HYPERLINK \l "arfaids" ARF in AIDS) Incidence: 5% of all hospitalized patients / 10-30% in patients in critical care units General: sudden, rapid, potentially reversible renal failure causing nitrogenous waste accumulation GFR of 10-15% /Cr not always reliable marker for GFR / usually 0.5 to 1.0 mg/dl/day increase in Ser Cr, > 1 mg/dl/day suggests obstruction or rhabdo/ HYPERLINK \l "tumorlysissyndrome" tumor lysis syndrome Pre-Renal (30-60%) volume depletion, ! perfusion, renal artery obstruction FeNa <1%, UNa <20 mEq/L (this is the most useful of these in that if elevated, pre-renal is unlikely) Renal Parenchyma (20-40%) ATN: ischemia, toxins, pigments Nephrotoxicity Intrinsic: GN, TIN, vasculitis (HUS/TTP) Systemic: atheroembolic syndrome, scleroderma, malignant HTN ATN, TIN ( FeNa >1%, UNa >20 mEq/L (tubules broken, so cant retain Na) GN ( FeNa <1% (unreliable), UNa variable (kidneys try to retain Na) Post Renal (1-10%) Obstruction: tubular, pelvic, ureteropelvic, ureteral, bladder Drugs: antihistamines, TCA Early ( FeNa <1%, UNa <20 mEq/L (due to intense vasoconstriction) Late ( / FeNa >1%, UNa >20 mEq/L Diagnosis: Azotemia Rising BUN and serum creatinine (can be asymptomatic) / BUN reflects dietary intake, protein breakdown and resorption of GI or soft-tissue hemorrhage / creatinine reflects muscle breakdown (rhabdomyolysis, steroids, tetracycline), renal secretion (blocked by drugs like cimetidine and trimethoprim), chromogens (usually drugs) can cause measurement errors. Urine Output Anuria (< 100 ml/day) usually worse prognosis Oliguria (< 400 ml/day) (most ARF patients) Polyuria (> 800 ml/day) (25%-50%) (common with partial obstruction) H/P surgical, IV contrast, meds, allergies, chronic disease, FHx, signs of volume depletion, CHF acute allergic interstitial nephritis: periorbital edema, eosinophilia, maculopapular rash, and wheezing obstruction: suprapubic or flank mass, symptoms of bladder dysfunction Uremic syndrome: nausea, lethargy, pruritis, pericarditis, uremic frost (skin), asterixis, uremic fetor (breath), platelet dysfunction Note: uremic pruritis responds well to UVB radiation Urinalysis Only hyaline casts: pre-renal or post-renal RBC: calculi, trauma, infection, or tumor WBC: infection, immune-mediated inflammation, or allergic reaction Eosinophiluria: 95% of acute allergic interstitial nephritis (Hansels stain tells E from PMN) Pigmented casts and > tubular epithelial cells in 75% of ATN (casts without RBCs ( hemoglobinuria or myoglobinuria) RBC casts: acute glomerulonephritis Urine culture Chemistries: FeNa < 1 suggests not ATN more than it actually proves pre-renal (exceptions: ARF from rhabdomyolysis and IV contrast are notably associated with FeNa < 1) / BUN/Cr > 20 Radiography: Most useful: renal U/S >> AXR, cystoscopy Less useful: isotopic flow scans, abdominal CT, biopsy Course: azotemic, diuretic, recovery Oliguric (50% mortality): more GI bleeds, sepsis, metabolic acidosis and CNS abnormalities Nonoliguric: 26% mortality Prognosis 60% mortality when surgery/trauma, 30% when medical illness, 10%-15% when pregnancy Ischemic ATN has two times higher mortality over nephrotoxic ATN Complete recovery in 90% if no complications Treatment: Correct: obstruction, nephrotoxic drugs, infections, electrolytes Optimize intravascular volume and cardiac performance (can maintain output with Lasix) Note: mannitol does not help, Lasix may increase urine output (but is more likely to decrease renal perfusion than help kidney recovery, it merely indicates less severe ARF) Investigational: selective D1 agonists (renal dose dopamine is BS), Ca channel blockers (to increase renal perfusion), IGF-1 (may speed recovery of renal function) Fluid/Electrolytes I/Os sensible losses (urine, stool, NG, other tubes) and insensible (400-500 ml/day) sodium and potassium Sodium bicarbonate if serum bicarbonate < 16 mEq/L Oral phosphate-binding antacids (Al3+OH3) if serum phosphate > 6.0 mg/dl No Mg containing drugs Diet: lose 300 mg body weight daily with ARF, wt gain or stability usually means Na and water retention / give 40-60 g/day total protein and 35-50 kcal/kg lean body weight / up to 1.25 g of protein/kg with severe catabolism Drugs: careful adjustment of drug doses (serum creatinine cannot be used to calculate doses because ARF causes a 1.0 mg/dl/day increase in serum creatinine, so cannot calculate appropriate drug doses)  HYPERLINK \l "dialysis" Dialysis, CAVH, CVVH Complications: volume overload hyperkalemia ( > 6.5 or EKG changes is an emergency) hyponatremia, hyperphosphatemia, acidemia, hyperuricemia hypocalcemia (decreased D-1,25, hyperphosphatemia, hypoalbuminemia) hypercalcemia (rarely follows rhabdomyolysis) bleeding (uremia/DIC), seizures (uremia) chronic renal failure (10% show decreased renal function for months, pre-existing renal disease will likely progress to CRF) ARF in AIDS patients (one study) Causes: ATN/Sepsis, HUS/TTP (TMA-like) > HIV meds (indinavir) > rhabdomyolysis (from IVDA) > lymphoma > HIVAN (13:1 M:F, avg. 8 months of HIV) > HBV/HCV > SLE-like Tumor Lysis Syndrome esp. important with lymphoproliferative malignancies; usually 1-3 after starting chemo but may occur spontaneously ( HYPERLINK \l "burkitts" Burkitts, acute  HYPERLINK \l "all" B-cell lymphoblastic leukemia) Risk factors: large tumor burden, high LDH, not being on allopurinol Mechanism: CaPO4 deposition ( HYPERLINK \l "rhabdomyolysis" see rhabdomyolysis) / uric acid damages renal tubules Labs: urinary uric acid:urinary creatinine ratio > 1 (normal < 0.60-0.75) supports uric acid nephropathy (higher than in rhabdo where urate is elevated but itself does not cause nephropathy) PO4 usu. elevated but may not be in spontaneous TLS (because tumor cells can incorporate it) ! lactic acid, !K, !Ca Treatment: volume repletion / consider dialysis when uric acid reaches 15-20 / can also give uricase to metabolize uric acid to allantoins (should have already given  HYPERLINK "pharm.doc" \l "allopurinol" allopurinol) / phosphate binders can be given / alkalinization of urine not proven to prevent tubular damage from urate crystals (may increase CaPO4 precipitation as well and further decrease Ca levels) Rhabdomyolysis ( HYPERLINK \l "rhabdomyolysis" see other) Atheroembolic Syndrome ( HYPERLINK \l "fatembolism" see cardiac) cause of renal failure Hepatorenal failure (see liver) Note: almost never see without CNS signs Drug-Induced Nephrotoxicity  HYPERLINK \l "drugprerenal" Prerenal  HYPERLINK \l "drugrenal" Renal  HYPERLINK \l "drugpostrenal" Postrenal  HYPERLINK \l "drugacidbase" Drug-induced acid/base abnormalities 20% of ARF is drug-related Prerenal (due to drug effect) ! serum Cr at least 0.5 mg/dL over 24 hours / FeNa < 1%, Uosm > 500, benign sediment Causes: diuretics, NSAIDs, ACE inhibitors, IV contrast, tacrolimus ( vasoconstriction IL-2 ( volume depletion from capillary leak cyclosporine ( vasoconstriction of afferent/efferent arterioles decreases GFR mannitol > 300 g can cause prerenal failure Treatment: discontinuing offending agents often returns renal function to baseline General Renal Toxicity FENA >2%, Uosm < 350, urinary sedimentshows granular/dark brown casts and tubular epithelial cells / nonoliguric renal failure / hypomagnesemia (urinary magnesium wasting and ADH resistance) / can occur despite appropriate serum levels and after drug discontinuation IV contrast Antibiotics: aminoglycosides, amphotericin B, cephaloridine,streptozocin, pentamidine, mithramycin, quinolones, foscarnet, tetracyclines (made before 1950?) Chemo: cisplatin, ifosfamide, mithramycin, vincristine, methotrexate, cyclophosphamide (rare) Other: methoxyflurane, tacrolimus, carbamazepine, IVIG IV contrast CRF, DM, volume depletion, and MM predispose to IV contrast toxicity Renal protection protocol: Mucomyst (600 mg bid prior to administration) and IV fluids plus aminophylline 5 mg/kg during contrast administration Aminoglycosides reabsorption by pinocytosis can increase half-life over 100 hours (normal 3 hours) / Treatment is primarily supportive Amphotericin B 1) decreases renal blood flow because of acute renal vasoconstriction in a dose-dependent manner (causes ATN) 2) direct tubular injury in cumulative doses exceeding 2 to 3 g /  HYPERLINK \l "rta1" classic distal RTA, concentrating defects (it punches holes in the membrane), and potassium wasting / usually nonoliguric and reversible on discontinuation Cisplatin up to 50% get enzymuria, Mg and K wasting (Medstudy says only K, not Mg), and ATN / urine output of at least 100 mL/hr decreases risk Rhabdomyolysis lovastatin, ethanol, codeine, barbiturates, diazepam (elevated CPK, brown casts) Severe hemolysis quinine, quinidine, sulfonamides, hydralazine,triamterene, nitrofurantoin, mephenytoin Acute interstitial nephritis (AIN) penicillins, cephalosporins, rifampin, sulfonamides, thiazide, cimetidine,phenytoin, allopurinol, cytosine arabinoside, furosemide, interferon, NSAIDs, ciprofloxacin Findings: fever, rash, arthralgias, eosinophilia, renal failure (may be absent in 30%) UA showspyuria, WBC casts, eosinophiluria / nephrotic range/proteinuria with NSAIDs Note: above findings Treatment: steroids may* speed recovery in aggressive AIN NSAID nephritis (esp. fenoprofen and mefenamate) / nephrotic range proteinuria (80%), minimal change disease (10%), membranous nephropathy (rare) / signs of hypersensitivity often absent due to anti-inflammatory action, FeNa often < 1%, *steroids are not beneficial for NSAID nephritis (and some say not for other AIN either) HUS (see other) afferent arteriolar thrombosis Cyclosporine, mitomycin C, cocaine, tacrolimus,conjugated estrogens, quinine, 5-fluorouracil Note: plasmapheresis less useful HUS from mitomycin C Glomerulopathy (membranous) Causes: gold, penicillamine, captopril, NSAIDs, mercury Findings: edema, moderate to severe proteinuria, hematuria, RBC casts (sometimes) / nephrotic range proteinuria esp. in penicillamine, gold and captopril (rare) / complete resolution may take up to several years (esp. gold) Intratubular obstruction due toprecipitation Acyclovir ( > 500 mg/m2), MTX, sulfonamides (only at super high doses), ethylene glycol, high-dose vitamin C Findings: urine sediment can be benign, or if severe cancause an ATN-like sediment Chronic interstitial fibrosis with orwithout papillary necrosis (see other) Phenacetin, NSAIDs, acetaminophen, aspirin,cyclosporine, FK-506, lithium Findings: history of long-term medication use Postrenal Causes Ureteral obstruction due toretroperitoneal fibrosis B-blockers (pindolol,atenolol), migraine meds (ergotamine, dihydroergotamine), methysergide, hydralazine, methyldopa Findings: usually benign urine sediment, ultrasound revealshydronephrosis Chronic Renal Failure (CRF) substantial ( < 20% normal) and irreversible reduction in renal function Major causes: DM >> HTN (20%), tubulointerstitial (7%),  HYPERLINK \l "apkd" APKD (5%) Prerenal: severe, long-standing renal artery stenosis and bilateral renal arterial embolism Renal: chronic glomerulonephritis, chronic TIN, Alports, SLE, diabetes, amyloidosis, HTN,  HYPERLINK \l "apkd" cystic diseases, neoplasia, and radiation nephritis Postrenal: chronic urinary obstruction Complications: normochromic normocytic anemia, renal osteodystrophy (via PTH), metabolic acidosis, malnutrition, decreased immunity, HTN, dyslipidemia, LVH, neuropathy Electrolyte imbalances (hypocalcemia, hyperkalemia, hyperphosphatemia) Treatment: provide supplemental 1,25-D3, CaCO3 (binds intestinal phosphate and provides Ca) Uremia CNS: lethargy, somnolence, confusion, and neuromuscular irritability (gradual or abrupt) CVS: HTN, CHF, pericarditis (can be abrupt) GI: anorexia, N/V (very common) Bones: pain from secondary hyperparathyroidism Other: fatigue, pruritis, and sleep disturbances Uremic Immunodeficiency T-cell abnormalities (lymphopenia), reduced response to vaccination Other Complications: Hematologic: chronic anemia (from reduction in erythropoietin and mildly reduced red cell half-life) and bleeding CVS: HTN, pericarditis, cardiomyopathy, arrhythmias, and CHF CNS: generalized seizures, confusion, lethargy, emotional lability, myopathy, peripheral neuropathy, and syndromes related to nerve compression (carpal tunnel) GI: ulcers, gastroduodenitis, colitis, angiomas Endocrine: secondary hyperparathyroidism, euthyroid hypothyoxinemia, hyperprolactinemia, bad GnRH axis (amenorrhea, impotence), gynecomastia Immune: lymphocytopenia, anergy, increased anticomplement activity, abnormal monocyte motility Metabolic: renal osteodystrophy (osteitis fibrosa and osteomalacia) and altered drug-metabolism Treatment: Meds ACE inhibitors: cause mild (10 ml/min) decrease in GFR but overwhelmingly proven effective by multiple mechanisms avoid peripheral calcium blockers: used alone may speed progression of renal failure Blood pressure control: MAP of 92 (not too low, too low actually does harm) / MDRD study showed this is only helpful if proteinuria is 0.5 to 1 g/day restrict protein < 0.6 g/kg lean body weight restrict dietary sodium < 4 g/day (unless residual urine obligates greater daily losses) restrict K+, Mg2+, PO43+ and fluid intake to match daily losses pregnancy can accelerate pre-existing renal disease give vitamin D early on to decrease PTH levels (which if unchecked, speed renal damage) correct acidosis (which also contributes to renal damage) correct lipid abnormalities (for usual reasons) correct anemia with erythropoietin (ideal target level still not determined; some evidence suggests overly aggressive correction can worsen heart failure; mechanisms not completely worked out 11/06) Dialysis or transplant for clinical uremia, severe azotemia (GFR < 10 ml/min), intractable hyperkalemia or acidemia, intravascular volume overload Nephritic Glomerulopathies Findings: hematuria and/or RBC casts, variable proteinuria, oliguria, hypertension (fluid retention and disturbed renal homeostasis), azotemia, edema (salt and water retention) Immune complex diseases (some of these overlap with nephrotic section) Primary: IgA nephropathy, Anti-GBM (C3), membranoproliferative I and II (MPGN) (C4), membranous (C3) / mesangioproliferative (MSGN) / fibrillary glomerulonephritis Systemic: SLE, HCV/HBV-related cryoglobulinemia (C4), post-infectious glomerulonephritis: PSGN (C3), infective endocarditis, vasculitides (W, C-S, PAN, mPAN, HSP (IgA),) Acute Poststreptococcal GN (PSGN) follows Strep A infection (pharyngitis or skin) by 10 days (different strains from those causing RF; renal involvement not impacted by antibiotic) Presentation: hematuria, edema, proteinuria, decreased urine output, possible HTN Labs: acute phase with decreased complement (C3 more than C4) / may have (+) ASO titres Pathology: diffuse proliferation / exudative PMNs / crescents / coarse granular immune deposits by IF/EM (sub-epithelial > sub-endothelial > intramembranous) Course: usually self-limiting / occasionally progress to RPGN or chronic latent stage (more common and less likely to produce chronic renal disease in younger patients) Treatment: B-lactam, diuretics and antihypertensives as needed, rarely steroids IgA Nephropathy or Mesangial Glomerulopathy or (Bergers Disease) - good prognosis most common GN in the world / 15-30 yrs Presentation: similar to HSP / sore throat followed shortly with nephritic syndrome, hematuria micro (older), macro (younger) / synpharyngitic Pathology: mesangial proliferation / IgA and other deposition by IF / dense deposits in mesangium by EM Labs: elevated IgA (50%) Prognosis: good in 80% cases, more proteinuria is worse Treatment: fish oil, IVIG, CSA Goodpastures Syndrome (Anti-GBM) ( HYPERLINK \l "goodpastures" see other) poor prognosis Occurs in two forms young men, hemoptysis and hematuria older people (male=female) / RPGN with no lung involvement Labs: C-ANCA (+) in up to 40%, this may improve prognosis / complement usually normal Pathology: linear deposition of C3 and IgG by IF / no dense deposits by EM Treatment: immunosuppressives, plasmapheresis Cryoglobulinemia Type I - usually asymptomatic monoclonal Igs (usually IgM) Causes: hematologic cancers (Waldenstroms, myeloma, lymphoma) Manifestations: may cause MPGN Type II monoclonal IgM against polyclonal IgG (causes precipitation) / immune-complex vasculitides (50% renal involvement) Causes:  HYPERLINK \l "hcvrenal" HCV (most common), HBV, bacterial, parasite lymphoproliferative, autoimmune (collagen), skin (PAN, PCT), essential mixed monoclonal/polyclonal cryoglobulinemia Manifestations: Skin: raynauds 40% mono / 25% poly vascular purpura (almost always involves lower extremities) leg ulcers up to 8% mono / 30% poly acrocyanosis/necrosis 15-40% urticaria complement, mast cell livedo reticularis (1% mono / < 5% poly) Arthritis 60% poly, < 10% mono Renal disease monoclonal ( endomembranous deposits of precipitate polyclonal ( proliferative glomerulonephritis immune complex azotemia (late) Hemorrhagic Liver poly (esp. AP) GI 5-20% poly (acute abdominal pain) CNS vasculitis of vasa vasorum up to 40% symmetric, peripheral neuropathy secondary to associated disease (amyloid, vasculitis) Sjgrens (80% have cryoglobulinemia) Diagnosis: quantitative cryoglobulins < 2 normal / cryocrit (% cryoIgs/serum) / SPEP /  HYPERLINK \l "complementstudies" low serum complement (C4 more than C3) Treatment: avoid cold / bed rest for ulcers / low-dose corticosteroids / IFN-alpha (60-70% response, 30% sustained) / cytotoxic agents Type III - usually no clinical significance mixed polyclonal (no monoclonal component) Causes: infections, autoimmune (SLE), liver disease (HBV, HCV), renal disease (proliferative GN), essential mixed polyclonal cryoglobulinemia Crescentic Glomerulopathy (RPGN) Immune Complex Deposition Goodpastures collagen vascular diseases as a potential evolution of most any other forms of GN Pauci-immune (ANCA) glomerulonephritis  HYPERLINK \l "wegeners" Wegeners (C-ANCA, proteinase 3) microscopic polyangiitis (P-ANCA, MPO)  HYPERLINK \l "churgstrauss" Churg-Strauss (asthma and eosinophilia) Idiopathic RPGN (renal limited vasculitis) 50% of glomeruli involved / over weeks to months / non-specific symptoms Pathology: epithelial proliferation and capillary necrosis / IF and EM depend on etiology Course: rapidly fatal Treatment: massive IV steroids, Cytoxan Nephrotic Glomerulopathies ( HYPERLINK \l "mcd" MCD,  HYPERLINK \l "fsgs" FSGS,  HYPERLINK \l "mgn" MGN,  HYPERLINK \l "mpgn" MPGN) Nephrotic syndrome ( HYPERLINK \l "nephroticsyndrome" see proteinuria) Minimal Change Disease (lipoid nephrosis, Nil disease) most common cause of nephrotic syndrome in children peak at 2-3 yrs, 10-12 yrs Pathology: effacement of podocytes / usually not hypertensive Cause: usu. idiopathic Drugs: NSAIDS, rifampin, IFN-a, heroin, iron dextran Other: lymphoma, HIV, IgA, diabetes, Fabrys, sialidosis Treatment: if needed, steroids, cyclosporin, others / ?ACE inhibitors Focal Segmental Glomerulosclerosis (FSGS) 25% of adult nephropathies / common in children, young black men, association with obesity / HTN / most common idiopathic nephrotic GN in blacks Primary: typical > collapsing (blacks) > glomerular tip Secondary causes/associations: HIV, IVDA, obesity, sickle cell, congenital heart disease Presentation: mild to massive proteinuria, hematuria (50%), HTN (33%), renal insufficiency (33%) / collapsing variant: more proteinuria, more ARF, viral/URI Sx from days to weeks before nephrosis Labs: low albumin (can be < 2), decreased immunoglobulins, increased lipids, normal compliment Ultrasound: normal to large echogenic kidneys Renal biopsy: shows FSGS / can be confused with hereditary nephritis, IgA nephropathy, Wegeners / EM can diagnose these other causes Treatment: steroids 60-80 4 wks then 40-60 mg 3d/wk 4 wks then taper / alternate steroid regimens used / late relapse, more steroids / early relapse, cyclosporine or Cytoxan ACE inhibitors (yes, yes and yes) / works by inhibition of TGF-B Prognosis: variable (more proteinuria is worse), often refractory to therapy HIV nephropathy poor prognosis 20% of hospitalized AIDS patients develop ARF / often collapsing variant with same characteristics / black males with IVDA / more on East coast / no HTN (maybe) Treatment: similar to idiopathic, ACE inhibitors may help, HIV meds ? Note: HIV patients also get RF from idiopathic, HCV, heroin, drugs, prerenal C1Q nephropathy Rare mimic of FSGS occurring mostly in young, black men Membranous Glomerulopathy (MGN) poor prognosis most common adult idiopathic nephrotic syndrome in whites / 40-60 yrs/ men > women Pathology: thickened BM matrix and vessel walls / more mesangial proliferation with systemic causes / sub-epithelial IgG and C3 granular deposits by IF (Heyman model) / spikes alternate with deposits Secondary causes: HBV, syphilis, SLE, solid tumors (20% of MGN), thyroiditis, malaria, gold, d-penicillamine, PCN, captopril Course: focal then global sclerosis / fairly responsive to steroids, cytoxic therapy / left untreated: S! spontaneously regress, S! stabilize, S! slow progression to ESRD (women, children have better prognosis) Membranoproliferative Glomerulopathy (MPGN) (nephrotic/nephritic) very poor prognosis primary or secondary forms / more in children, teenagers Pathology: increased cellularity and mesangial matrix / mesangial proliferation with duplication of the glomerular basement membrane, splitting of capillary BM (silver stain) / immune deposits and low serum compliment (C3 more than C4) types I subendothelial immune complexes (C3 and IgG) type II dense deposit disease (alternate pathway of complement) type III Burkholder subtype and Strife and Anders subtype Hepatitis C Glomerulopathy Findings:  HYPERLINK \l "cryoglobulinemia" cryoglobulinemia, MPGN on biopsy, systemic manifestations (50%), abnormal LFT (70%), low complement (C4 more than C3) (80%), RF (70%) Treatment: plasma exchange, treat the HCV (IFN-a, etc), cytotoxic agents General Characterizations Systemic diseases with secondary immune-mediated glomerulonephritis infection-related (including HBV, HCV, cryoglobulinemia types II or III, endocarditis, schistosomiasis, HIV-associated) autoimmune diseases (such as class IV lupus nephritis), dysproteinemia-associated (including light chain deposition disease, amyloidosis, cryoglobulinemia types I or II, fibrillary, and immunotactoid GN) Membranoproliferative pattern but lack immune deposits diabetic nephropathy, hepatic glomerulopathy, and chronic TMAs (HUS, TTP, APA), radiation nephritis, sickle cell nephropathy, eclampsia, and  HYPERLINK \l "transplantglomerulopathy" transplant glomerulopathy Renal Other  HYPERLINK \l "hydronephrosis" hydronephrosis,  HYPERLINK \l "renalmechanical" mechanical,  HYPERLINK \l "renalhypertension" hypertension,  HYPERLINK \l "renalarterystenosis" renal artery stenosis,  HYPERLINK \l "acidbase" acid-base,  HYPERLINK \l "rta" RTA Acute Hydronephrosis takes 24 hrs to develop / 24 hrs to resolve Diagnosis: decreased urine output, FeNa, ultrasound not IVP (may see ascites) Psychogenic polydipsia Fluid builds up in bladder, it cant keep up Mechanical obstruction Note: if one ureter is blocked, the other may go into spasm or intermittent spasm causing oliguria (10-20% of cases) [is this really true?] Renal disease causing hypertension Chronic Renal Failure ( HYPERLINK \l "crf" see other) Renal Artery Stenosis (RAS) Causes systemic HTN via renin-angiotensin pathway Causes: idiopathic, fibromuscular dysplasia in young women Diagnosis: U/S doppler renal artery, lab measurement of renin-angiotensin, captopril-based renal study Treatment: ACE inhibitors useful to counter hyper-renin state seen in unilateral renal artery stenosis (this occurs at the expense of the GFR in the stenotic kidney). Obviously, this can be a problem with bilateral renal artery stenosis as the GFR in both kidneys may be too low. Hypertension causing renal disease benign nephrosclerosis hyaline arteriolosclerosis and focal atrophy malignant nephrosclerosis tiny hemorrhages (flea-bitten) /infarcts / fibrinoid necrosis and onion skin proliferation Nephrogenic systemic fibrosis (NSF) or Nephrogenic fibrosing dermopathy (NFD) rare but rapidly progressive, serious, can be fatal / clinically resembles systemic scleroderma / believed to be caused by gadolinium MRI contrast dye) given in patients with moderate to severe kidney disease Systemic Diseases Affecting Kidney Diabetes Mellitus ( HYPERLINK \l "diabetes" see other) most common cause of adult nephrotic syndrome ACE inhibitors are beneficial even in normoalbuminuric patients (current thinking is that they should be used up to a Cr of ~ 4.5, at which point its too late) Amyloidosis [ HYPERLINK "http://content.nejm.org/cgi/content/full/344/12/917" NEJM] primary or secondary (tumors, chronic skin disease such as skin poppers or IVDA) 20% of cases are localized amyloidosis ( involve lungs, benign course) Presentation: weakness/fatigue, weight loss, autonomic disturbance (including GI tract), nerve dysfunction, hoarseness, tongue (macroglossia, tooth indentations, waxy deposits), edema, skin (bruising, waxy deposits) Lymphadenopathy (> 33%): may present with stable pulmonary nodules Neuropathy (35%), retinopathy [HYPERLINK "pics/eye-amyloidosis.jpg"pic] slowly progressive, distal, symmetric, dysautonomia, mechanisms unclear / may occur early, up to 4 yrs before diagnosis  HYPERLINK "ddx.doc" \l "mononeuritis" mononeuritis multiplex carpal tunnel syndrome (25%) (palmar cutaneous n. does not go through the tunnel) Heart constrictive cardiomyopathy Renal failure: deposits found anywhere in kidney / r/o fibrillary GN / kidneys first enlarge, then shrink / proteinuria and/or nephrotic syndrome Diagnosis: SPEP (IgG kappa monoclonal protein (usu. < 2000), may have elevated ESR, EMG, MRI might reveal thickening in areas / echocardiogram may shows starry sky pattern Biopsy of sural nerve, fat pad biopsy, lymph node, bone marrow Pathology: acellular increase, sub-epi, sub-endo or spikes in BM, 8-10 nm fibrils by EM (random distribution) / stain with Congo red (apple-green birefringence), Gomoris trichrome for myelin, crystal violet, thioflavin T / eosinophilic, glossy Treatment: high-dose melphalan with autologous stem cell rescue may delay progression of disease / measure response at 3 months then yearly Multiple Myeloma ( HYPERLINK \l "multiplemyeloma" see leukemias) Gout ( HYPERLINK \l "gout" see rheum) tophi deposition in kidney is relatively infrequent complication Bacterial Endocarditis (HYPERLINK \l "endocarditis"see other) embolic or immune complex deposits / MGN or MPGN Systemic Lupus Erythematosis ( HYPERLINK \l "sle" see rheum) anti-nuclear Ab (against snRPS) / anti-dsDNA factor Membranoproliferative good prognosis Focal GN okay, but may become diffuse later Diffuse proliferative most common, bad prognosis, wire loop capillaries Vasculitis Interstitial nephritis Membranous C3, Ig, C1q / indolent course childhood lupus: prognosis determined by extent of renal involvement / immunosuppressive treatments often lead to opportunistic infection as the other major cause of death Polyarteritis Nodosa ( HYPERLINK \l "pan" see vasculitides) hypersensitivity angiitis (microscopic form) has glomerular involvement (focal or proliferative) classic PAN (infarcts in kidney) Wegeners Granulomatosis ( HYPERLINK \l "wegeners" see vasculitides) most-common cause of RPGN / cANCA / similar to microscopic PAN Scleroderma ( HYPERLINK \l "scleroderma" see connective) hyaluronic acid accumulation in medium and small arteries similar lesions as malignant HT (may have normal BP) Thrombotic Disease [ HYPERLINK \l "hypercoagulability" hypercoagulability] [HYPERLINK "ddx.doc" \l "hypercoagulability"Ddx for hypercoagulable state]  HYPERLINK \l "focalthrombosis" Focal  HYPERLINK \l "pe" PE,  HYPERLINK \l "dvt" DVT,  HYPERLINK \l "pvt" PVT,  HYPERLINK \l "fatembolism" fat embolism  HYPERLINK \l "systemicthrombosis" Systemic  HYPERLINK \l "renaldic" DIC,  HYPERLINK \l "hellp" HELLP,  HYPERLINK \l "ttp" TTP,  HYPERLINK \l "hus" HUS,  HYPERLINK \l "hsp" HSP Focal Thrombosis [ HYPERLINK "pics/riskofthromboembolism.jpg" risk of thromboembolism] Acute Arterial Occlusion ( HYPERLINK \l "acutearterialocclusion" see other) Superficial thrombophlebitis [HYPERLINK "pics/thrombophlebitis-apa.gif"pic] Treatment: does not cause PE, so no anticoagulation; can do bedside thrombectomy or simply NSAIDS, applied heat; usually pain goes away within a few days DVT Cancers associated with DVT: lung, pancreas (Trousseaus), stomach, colon > prostate, ovary >>> breast, brain, kidney, lymphoma Other risk factors: late pregnancy (milk leg), OTC, smoking Treatment: see PE / if confined to calf, consider withholding anticoagulation and re-imaging / treatment duration highly individualized (depends on cause and patient profile) / 1/07 current recommendations [ HYPERLINK "http://www.annals.org/cgi/content/full/146/3/211" annals][ HYPERLINK "http://www.annals.org/cgi/content/full/146/3/211" annals] Pulmonary Embolism (HYPERLINK \l "pe"see lungs) Prosthetic Valve Thrombosis (PVT) 4% risk per patient/year without anticoagulation (0.016%/day), 2% with anti-platelet drugs, 1% with warfarin / mitral, caged-ball and multiple prostheses increases risk / known thrombus carries high risk of stroke (~10%) / consider operation for mobile thrombi or non-responders to medical therapy / consider thrombolysis (repeat TEE every few hours, continue 24-72 hrs) in high-risk surgical candidates with left-sided PVT / medical therapy is heparin ( warfarin ( ASA Fat Embolism Multiple cholesterol embolization (atheroembolic syndrome) Risk Factors: vascular disease, catheterization, grafting, repair procedures, warfarin (mechanism unclear) Findings: ecchymoses and necrosis similar to vasculitis: livedo reticularis (skin) [ HYPERLINK "pics/livedoreticularis-bad.jpg" pic][ HYPERLINK "http://dermis.net/dermisroot/en/42784/diagnose.htm" dermis], Hollenhorst plaques (eyes), renal failure (progressive, step-wise) / note: peripheral pulses are preserved, despite marked peripheral ischemia Bergmans Triad: mental status changes, petechiae, dyspnea / complications: ARDS, DIC Diagnosis: eosinophilia/eosinophiluria, renal biopsy is immediately diagnostic as ethanol preparation washes out cholesterol emboli leaving empty spaces Treatment: steroid therapy may be harmful (unlike true vasculitides), if necessary, PEEP, treat any DIC Prognosis: usu. severe but a significant number of patients have some recovery of renal function Neutral Fat Embolism 12-36 h after bone trauma or fracture Systemic Thrombosis Disseminated Intravascular Coagulation (DIC) [HYPERLINK "http://content.nejm.org/cgi/content/full/341/8/586"NEJM] Fulminant DIC Intravascular hemolysis:  HYPERLINK \l "transfusionreaction" hemolytic transfusion reaction, autoimmune diseases Infection:  HYPERLINK \l "sepsis" sepsis (gram positive or gram negative), meningococcemia, viremia Malignancy: mets, leukemia, other Ob/Gyn: pre-eclampsia, amniotic fluid emboli, retained products of conception,  HYPERLINK \l "hellp" HELLP Burns/Crush/Trauma Acute liver disease: obstructive jaundice, acute hepatic failure Vascular disorders: giant hemangiomas, other Prosthetic devices: LeVeen or Denver shunts, aortic balloon assist devices Drugs: HYPERLINK "psycdrug.doc" \l "lamictal"lamotrigine, penicillamine? Low-grade DIC cardiovascular, peripheral vascular, renal vascular, autoimmune disorders, hematologic disorders, inflammatory disorders Labs: increased D-dimers, fibrinogen split products, decreased fibrinogen Peripheral smear: RBC fragments [ HYPERLINK "pics/rbcfragments-dic.jpg" pic], schizocytes [HYPERLINK "pics/schizocytes-dic.jpg"pic] Treatment: remove trigger / treat underlying problem Stop intravascular clotting process (this is complicated)  HYPERLINK "pharm.doc" \l "activatedproteinc" activated protein C (promising new agent) use of heparin (early on) is debated ATIII concentrates / dose (given q 8 hrs) = (desired - initial level) 0.6 total body weight (kg) Other choices: IV heparin, LMWH, Hirudin, antiplatelet agents (less effective but sometimes a safer choice) Note: ~75% will respond to above therapeutic steps / failure is probably component depletion / replace factors (try to leave out fibrinogen) Components (as indicated): platelet concentrates, packed red cells (washed), ATIII concentrate, FFP, prothrombin complex, cryoprecipitate Relatively Safe to Give: washed PRBCs, platelets, ATIII concentrates (if available), and nonclotting protein containing volume expanders (plasma protein fraction, albumin, and hydroxyethyl starch) Inhibit residual fibrinogenolysis Aminocaproic acid given as initial 5 to 10 g by slow IV push then 2 to 4 g/hr for 24 hrs or until bleeding stops / may cause ventricular arrhythmias, severe hypotension, and severe hypokalemia Tranexamic acid (newer) given as 1 to 2 g IV q 8 to 12 hrs / more potent, may have fewer side effects HELLP (hemolysis, elevated LFTs, low platelets) ( HYPERLINK \l "preeclampsia" see pre-eclampsia) occurs in late 3rd trimester in pregnancy (70% antepartum, 30% post-partum, usually < 48 hrs, almost always < 7 days) Presentation: +/- elevated BP, fever (less common), may have proteinuria, severe renal failure, thrombocytopenia / 5-30% with  HYPERLINK \l "dic" DIC Ddx:  HYPERLINK \l "appendicitis" appendicitis, diabetes, gallbladder disease, gastroenteritis, PUD, glomerulonephritis, hepatic encephalopathy,  HYPERLINK \l "itp" ITP, renal stones, pyelonephritis, SLE, HUS, TTP,  HYPERLINK "micro.doc" \l "viralhepatitis" viral hepatitis Course: delivery alone is not always curative, consider plasma exchange with FFP if not resolved by 72 hrs / recurrence risk for HELLP is 5-30%, for preeclampsia (40%) Treatment: anti-platelet agents recommended by many for treatment and some say for prevention of recurrence Thrombotic Thrombocytopenic Purpura (TTP) 1 in 1000 / female:male 10:1 Malignancy: gastric >> breast, colon, small cell lung Drugs: tacrolimus, mitomycin C, cyclosporin, gemcitabine, bleomycin, cisplatin, plavix (rare, would happen in first 2 weeks of plavix therapy) Infections: HIV, others Presentation: fever, viral prodrome hemorrhage, pallor, CNS signs, jaundice, pulmonary edema / young women Pentad: thrombocytopenia, microangiopathic hemolytic anemia, CNS, renal, fever CNS (confusion, mental status, seizures et al) Renal is often mild, but in 80-90% (proteinuria, hematuria, azotemia) GI (N/V/diarrhea) Heart: classically not, but may create subclinical damage Prognosis: involvement of brain and kidney (50%) / mortality is 90% (10% with treatment but long-term problems arise from heavy use of blood products) Labs: coagulation tests usually normal (unlike DIC), proteinuria, elevated BUN, elevated LDH (out of proportion), Coombs negative, fibrin split products (but not DIC levels), bone marrow Bx ( megakaryocyte hyperplasia, schistocytes (should be plentiful) Diagnosis: sometimes difficult, use labs, skin/gingival biopsy of petechiae, renal biopsy Pathology: extra large forms of vWF circulate due to decreased activity of vWF degrading enzyme ADAMTS 13 (probably due to IgG inhibitors) / platelets stick too much ( microangiopathic thrombi and hemolytic anemia (schistocytes from RBCs being sheared in thrombi) Treatment: plasmapheresis follow platelet count and LDH high dose steroids (possibly other immunosuppressives antiplatelet drugs: ASA 325-1500 / dyprimamidole avoid giving platelets (only aggravates the problem) 2nd line: splenectomy (controversial), chemotherapy, IVIG Prognosis: up to 85% remission with proper treatment TTP-like syndrome (TMA) in HIV patients (~10% < 50CD4, ~3% < 100) (same treatment) Association (50%) with CMV viremia Evans syndrome autoimmune hemolytic anemia and thrombocytopenia / positive Coombs test and by microspherocytes rather than schistocytes on peripheral smear / more common in children / idiopathic or related to hematologic malignancy Hemolytic Uremic Syndrome (HUS) similar findings as TTP but without neurological involvement / more severe renal disease Mechanism: probably different than TTP acute renal failure (mostly in children) associated with microangiopathic hemolytic anemia, thrombocytopenia and thrombosis, can lead to brain edema, seizures (give BZ or Dilantin) / some or all findings may be present / usually occurs after gastroenteritis, but can occur with just UTI / idiopathic form (AR and AD) Other bacteria: has been associated with Pneumococcus, aeromonas, HIV Drugs: cyclosporin A, tacrolimus, mitomycin C, OCPs, OKT3, irradiation, gemcitabine, quinine, Ticlid Children (90%):  HYPERLINK "micro.doc" \l "ehec" E. Coli 0157/H7,  HYPERLINK "micro.doc" \l "shigella" Shigella (verocytotoxins) cortical necrosis?, Adults: HUS from infections, post-partum, systemic disease (cancers, etc) worse prognosis Note: in blacks, E. Coli toxin is an uncommon cause of HUS (unlike Shigella) Treatment: life threatening condition that requires IVIG and/or plasmapheresis, steroids?, transfusions as a sequelae of childhood pneumonia? Henoch-Schnlein-Purpura (HSP) Children 5-15 yrs (occasionally adults) / like  HYPERLINK \l "iganephropathy" IgA nephropathy plus GI problems Presentation: palpable purpura (usu. lower extremities, buttocks) [HYPERLINK "pics/hsp.jpg"pic], arthritis, arthralgia, abdominal (GI pain, bleed), renal (glomerulonephritis), CNS, hepatic are rare Note: regular erythema blanches whereas true purpura does not Complications: abdominal intussusception (large > small); barium enema may be curative renal: more in adults, nephritis (30%), may require  HYPERLINK \l "hemodyalysis" hemodialysis (20%), chronic renal failure (2%) Associations: lymphoma Diagnosis: urinalysis, abdominal ultrasound, Pathology: skin biopsy - IM shows around blood vessels and dermal zones / neutrophilic predominance around blood vessels / IgG deposition and some C3 Treatment: steroids may help GI manifestations but not renal / severe cases may require other immunosuppressives, plasma exchange, IVIG /  HYPERLINK "pharm.doc" \l "dapsone" dapsone can help skin, joints, GI manifestations / antihistamines for pruritis / follow up with urinalysis Pyelonephritis Acute pyelonephritis ( HYPERLINK \l "uti" see UTI) 50% have ureteric valve regurge / damage often localized to upper, lower poles (blunt calices), papillary necrosis, pyonephrosis, perinephric abscesses coarse granular casts become fine granular casts Chronic pyelonephritis VUR / adherent capsule / U-shaped scar (late) / hyaline casts or thyroidization of tubules glomerular fibrosis, atrophy (focal segmental) / account for 15% of renal transplants Interstitial Nephritis higher risk of transitional cell carcinoma Acute interstitial nephritis Drugs: B-lactams, NSAIDS (nephrotic picture), diuretics, phenytoin, phenobarbital, cimetidine, sulfinpyrazone, methyl-dopa Labs: eosinophils in urine (early in morning) Chronic interstitial nephritis Drugs: NSAIDs (nephrotic, decreased GFR, papillary necrosis, edema), analgesics, lithium (many mechanisms, also causes interstitial fibrosis and nephrogenic diabetes insipidus), gold Toxins:  HYPERLINK \l "cadmium" cadmium,  HYPERLINK \l "lead" lead (Pb),  HYPERLINK \l "copper" copper (Cu),  HYPERLINK \l "mercury" mercury (Hg) Crystalline: uric acid, oxalate (primary, ethylene glycol, methoxyflurane) Amyloid (nephrotic 75%) Sarcoid (hypercalcemia from 1,25-OH +/- hyperglobulinemia causing  HYPERLINK \l "rta1" distal RTA) Analgesic abuse nephropathy prolonged analgesic use including NSAIDs, acetaminophen, ASA (especially in combination) 2% of ESRD in US / > 2 to 3 kg cumulative dose Pathology: chronic interstitial nephritis bilateral papillary necrosis (25 to 40%) seen on IVP patchy necrosis of the loop of Henle and medullary interstitium Diagnosis: biopsy ( tubular atrophy and interstitial fibrosis with occasional histiocytes U/S ( small-sized kidneys (50% to 65%) / middle-aged women Balkan nephritis causes fever, skin rash, renal failure Xanthogranulomatous pyelonephritis rare / foam cells / Proteus sp. / resembles  HYPERLINK \l "rcc" renal cell carcinoma Renal papillary necrosis sort of like ATN on macroscopic scale / papillae can slough off causing obstruction Causes: DM, obstruction, pyelonephritis, analgesic abuse, sickle cell (and sickle cell trait), hypoxia and volume depletion in infants, graft rejection Renal Tubular Disease  HYPERLINK \l "atn" ATN,  HYPERLINK \l "rta" RTA,  HYPERLINK \l "di" DI,  HYPERLINK \l "fanconis" Fanconis, etc. Acute Tubular Necrosis (ATN) most common pre-renal / decreased GFR / high recovery rate with proper management / 50% may not have oliguria Causes:  HYPERLINK "pharm.doc" \l "nsaids" NSAIDS,  HYPERLINK "pharm.doc" \l "aminoglycosides" aminoglycosides, IV contrast,  HYPERLINK \l "rhabdomyolysis" rhabdomyolysis,  HYPERLINK \l "rvt" thrombus Diagnosis: FeNa (results are altered by diuretic use), muddy brown casts Treatment:  HYPERLINK \l "dialysis" dialysis, fluid, diuretics, DOPA (increases output, but not GFR, will not lower creatinine level) / future: anti-endothelins, GF? toxic nephrosis continuous damage in proximal tubule ischemic tubular necrosis patchy damage focal tubular necrosis hydropic change fatty change hypokalemic nephropathy chronic tubular disease myeloma kidney ( HYPERLINK \l "multiplemyeloma" see mm) Bence-Jones light chain fragments combine with Tamm-Horsfall proteins, create tubular casts causing obstruction/inflammation Acid-Base Metabolism Anion gap Anion Gap = [Na]  [Cl +HCO3] normal: 8-12 MUDPILES (methanol, uremia, DKA, Paraldehyde, isopropyl, lactate, ethano/ethelyne glycol, salicylates/starvation) Increased acid production (noncarbonic acid) Increased -hydroxybutyric acid and acetoacetic acid production Insulin deficiency (diabetic ketoacidosis). Starvation or fasting. Ethanol intoxication. Increased lactic acid production tissue hypoxia, sepsis, exercise, ethanol ingestion Systemic diseases (e.g., leukemia, diabetes mellitus, cirrhosis, pancreatitis) Inborn errors of metabolism (IEMs) (carbohydrates, urea cycle, amino acids, organic acids). Increased short-chain fatty acids (acetate, propionate, butyrate, d-lactate) from colonic fermentation viral gastroenteritis Other causes of carbohydrate malabsorption Intoxications: methanol, ethylene glycol, paraldehyde, salicylate/NSAID, Increased sulfuric acid Decreased acid excretion: acute and chronic renal failure Anion Gap Ethanol no Methanol yes Isopropyl yes Respiratory compensation for primary metabolic acidosis For every 1 mEq decrease in HCO3 the PCO2 should decrease by 1-1.5 mmHg Osmolality Plasma osmolality (mOsm/kg) = 2([Na+] + [K+]) + [BUN]/2.8 + [glucose]/18 + ethanol/4.6 [ HYPERLINK "pics/plasmaosmolality.gif" pic] Normal Osmolar Gap < 10 mOsm/kg HCO3 metabolism kidney increases serum bicarbonate via reabsorption and addition of new bicarbonate into serum via excretion of titratable acids and the formation of ammonia formation HCO3 Deficit HCO3 to replace (mEq) = Wt (kg) x (0.4)(15-measured HCO3) or = (base deficit )(wt in kg)(0.4) / 2 Note: elevated AG may result from alkalosis freeing up negative charges on proteins (albumin), however, this cannot increase AG > 22 Lactic acidosis ( HYPERLINK \l "sepsis" see sepsis) Severe metabolic and respiratory acidosis pancreatitis, vomiting, hypokalemia, tissue necrosis, hypovolemia Treatment: THAM (unproven) Renal Tubular Acidosis (RTA) All RTAs associated with increased  HYPERLINK \l "renalstones" renal stones (calcium oxalate) from increased pH Urine anion gap [Na + K] Cl ?HCO3 If renal function intact, Ur AG will be negative due to excretion of ammonium chloride salts (high Cl) / Note: must consider unmeasured anions and cations (like Ca) Urine MM, hypoalbuminemia TTKG (UrK / PlaK) / (UrOsm / PlaOsm) > 8 ( kidney is wasting K ( suggests RTA < 3 ( kidney is not wasting K ( suggest other cause for hypokalemia Classic Distal RTA (Type I RTA) (hypokalemia) Mechanism: H+ back leak, negative Urine AG Drugs: cyclosporine, amphotericin B, vitamin D intoxication, lithium, analgesics, toluene, cyclamate Proximal RTA (Type II RTA) (normal or hypokalemia) Mechanism: profound HCO3 wasting from kidney / normal to low K (volume contraction causes increased aldosterone) Drugs: carbonic anhydrase inhibitors ( HYPERLINK "pharm.doc" \l "acetazolamide" acetazolamide, sulfanilamide), mafenamide acetate, and 6-mercaptopurine, sulfanilamide, heavy metals Note: difficult to correct with HCO3, because you simply cant give it fast enough Type 4 RTA (hyperkalemia) Mechanism: HYPERLINK \l "hypoaldosteronism"hypoaldosteronism, anti-aldosterone, oranti-adrenergic, or blocking Na+ channels (voltage effect) Decreased aldosterone effect ( hyperkalemia and acidosis1 ( more acidosis from hyperkalemia2 1aldosterone also helps HTPase H+ secretion (requires luminal electronegativity) 2hyperkalemia also inhibits NH3 secretion (proximal kidney), which reduces titratable acidity [thus promoting acidosis] Findings: decreased urinary excretion of K+ despite highserum levels (low  HYPERLINK \l "ttkg" TTKG) Drugs: NSAIDs (via PG inhibition) ACE inhibitors, K-sparing diuretics (amiloride, triamterene) Heparin (blocks production of aldosterone) B-blockers, cyclosporine, pentamidine Trimethoprim (bactrim) (block Na+ transporter, decreased tubular electronegativity ( less K+ efflux) Systemic diseases: Addisons, SLE, sickle cell, amyloid, chronic partial obstruction, diabetes (especially older males with CHF; hyporeninemic hypoaldosteronism) Treatment: Eliminate cause if possible Bicarbonate (rather than NaCl) as the extra bicarbonate will help keep the tubule electronegative and help eliminate potassium Lasix may be used (! K washout and/or delivery of more Na to ! K excretion) Drug-Induced Electrolyte and Acid/Base Abnormalities hypokalemia/hypomagnesemia (increased urinary excretion) gentamicin, cisplatin, diuretics, carboplatin Findings: increased urinary excretion of K+ and Mg++ despite low serum levels hypomagnesemia or hypokalemia (increased urinary excretion) aminoglycoside and cisplatin hypomagnesemia, hypokalemia, metabolic alkalosis (increased K+ and H+ secretion) thiazide and loop diuretics hypokalemia and metabolic alkalosis hypovolemia ( hyperaldosteronism (increased K excretion) / volume depletion also causes increased HCO3 reabsorption and prolongs metabolic alkalosis (e.g. NG suction) hyponatremia ( HYPERLINK \l "hyponatremia" see lytes) increased ADH secretion/sensitivity with decreasedwater excretion NSAIDs potentiate ADH action (reduction of prostaglandins that inhibit ADH) Findings: Uosm is less than maximally dilute in the face oflow serum Na+ Thiazide diuretics (see below), chlorpropamide, vincristine,IV cyclophosphamide, Cytoxan,clofibrate, narcotics, haloperidol, thioridazine,amitriptyline, fluphenazine, NSAIDs,acetaminophen Thiazide diuretics no medullary washout (allows ADH-water resorption Loop diuretics medullary washout ( less ADH-water resorption Note: any diuretic can cause significant NaCl loss with hyponatremia from combination of volume depletion, salt restriction, continued free water intake Cyclophosphamide and vincristine direct antidiuretic effect in the distal tubule - impaired free water excretion Nephrogenic diabetes insipidus (anti-ADH) (HYPERLINK \l "diabetesinsipidus"see central DI) Mechanism: impaired response to ADH Causes: lithium, cyclophosphamide,ifosfamide, vincristine, demeclocycline / ?hypokalemia and hypercalcemia >12 causes mild nephrogenic DI / rare congenital XLR form / metastatic breast cancer Treatment: thiazides to prevent kidney from diluting urine too much, increase water intake, decreased salt intake Meliturias, amino acidurias Fanconis syndrome inherited or acquired (see ARF drugs) Mechanism:  HYPERLINK \l "proximalrta" proximal RTA with tubular glucosuria (despite euglycemia), phosphaturia, aminoaciduria, bicarbonaturia, saluresis, kaliuresis, and decreased ammonium excretion Presentation: rickets, short stature, uremia Renal Stones Presentation: unilateral flank pain, colicky, may radiate to groin Ddx: appendicitis,  HYPERLINK \l "pid" PID,  HYPERLINK \l "diverticulitis" diverticulitis,  HYPERLINK \l "aaa" abdominal aortic aneurysm, HYPERLINK \l "bladdercancer"bladder cancer Diagnosis: clinical and radiological Radiography: KUB ( 75-90% of stones are radiopaque (non-opaque: cysteine, struvite, uric acid) CT ( sensitivity (96%) specificity (100%) [best study; non-contrast CT] IVP ( sensitivity (87%) specificity (96%) U/S ( sensitivity (15%) specificity (90%) [better for pregnancy] Note: CT shows both opaque and non-opaque stones; can sometimes distinguish urate vs. struvite vs. calcium oxalate but get both studies because KUB will separate opaque from non-opaque Types of stones: calcium oxalate (60%), calcium PO43- (20%), NH4+Mg2+ PO43- or NH4+/Urate (Struvite) (10%), uric acid (5-10%), cysteine (1%) Treatment: hydration (~2L/day urine output), pain control, strain urine to catch stone (can analyze to make specific diagnosis), intervention (see below) Note: some advocate NSAIDs over narcotics in patients who are not obstructed and with normal renal function (avoid overhydration as NSAIDs reduce GFR) Intervention: shock wave lithotripsy vs. surgical removal (e.g. endoscopic) Urgent Intervention: obstructed, infected upper urinary tract, impending renal deterioration, intractable pain or vomiting, anuria, high-grade obstruction of solitary or transplant kidney Course: most stones < 4-5 mm will pass w/out surgical intervention, if not passed after 4 weeks (complication rate 20%) Note: infected renal stones must be considered as complicated UTI with regard to antibiotic treatment (duration) Calcium stones hypercalcemia (hyper PTH, malignancy, other) GI diseases (small bowel bypass, inflammatory bowel diseases) often cause increased resorption of oxalate and increased CaOx stones renal tubular acidosis (increased urine pH, alkalinization of urine increases formation of CaPO4 stones) Struvite Stones (Staghorn calculi) not opaque often from UTI with Proteus, staph causing NH4+Mg2+ PO43- stones / often gigantic (will not pass into ureter) / pH > 8 Urate Stones not opaque hyperuricemia (gout, leukemia, other malignancy), gout present in 20% of patients with urate stones,  HYPERLINK \l "leschnyhan" Lesch-Nyhan Treatment: alkalization of urine helps prevent crystallization of urate stones (takes about 9 days to dissolve 2 cm urate stones) / urate is underexcreted in acid urine matrix stones (other urease-producing bacteria) indinavir stones (organic stones seen in pts taking  HYPERLINK "pharm.doc" \l "indinavir" indinavir) Cysteine Stones ( HYPERLINK \l "homocystinuria" see other) lucent or opaque 1/7000 (rare) / hereditary defect in tubular amino acid transport of cysteine, ornithine, lysine, arginine (COLA) ( homocystinuria ( hexagonal-shaped stones Treatment: diuresis (3L/day) and alkalization of urine (pH > 7) +/- D-penicillamine or tiopronin / moderate salt/protein restriction? / 50% may still require intervention Course: start early in life and if untreated progress to ESRD Renal malformations Anomalies of urethra and bladder ureteral valves kinks in dilated ureter / obstruction vesicoureteral reflux common / serious / pyelonephritis diverticulum congenital or acquired exstrophy of the bladder very rare / abdominal wall defect posterior urethral valves obstruction - oligohydramnios - pulmonary hypoplasia / males Anomalies of position and formation Renal agenesis unilateral - always check before nephrectomy bilateral (Potters) - facial, lower extremity deformations / not compatible w/ life Renal hypoplasia oligomeganephronia (Dolls kidney) - small, reduced number of pyramids Ask-Upmark kidney - transverse, linear scar from failed lobule Duplication of renal pelvis, ureter 80% unilateral / common / asymptomatic or obstructive, infection Simple ectopia Crossed ectopia ureter crosses midline Renal fusion horseshoe kidney / may lead to compression / 1/500 Anomalies of differentiation Simple cysts of population > 50 yrs Acquired cystic disease adults /  HYPERLINK \l "hemodialysis" hemodialysis / association with adenoma, carcinoma Microcystic disease (with nephrotic syndrome) ~ maternal antibodies / rare / early death in infants Dysplasia (cystic renal dysplasia) most common cystic dysplasia in children / failure of differentiation of mesenchyme Infantile PKD rare AR, fatal, bilateral / many small cysts / hepatic fibrosis, bile duct proliferation Adult Polycystic Kidney Disease (APKD) age 40 / AD, APKD-1 (chromosome 16 del) / 70% have renal disease by 70 yrs (may have false negative or poorly recognized FH or sporadic mutation) Presentation: flank pain, hematuria, low-grade proteinuria, systemic HTN (can have even with normal UA and serum creatinine), renal failure Complications: hepatic cysts (33%), Berry aneurysms (12%, do MRI if FH of ICH), mitral valve prolapse (25%) or aortic/tricuspid insufficiency, colonic diverticulosis (most common extra-renal finding, more likely to perforate) Medullary cystic disease (sponge kidney) 2 types 1) non-uremic - normal renal function (normal urine sediment) 2) uremic - earlier onset, renal failure Alports Syndrome AD or XLR / defective GBM synthesis / onset age 5-20 yrs progressive renal failure, CN VIII deafness and eye lesions / get a biopsy Pathology: biochemical changes in BM, variation/layering, IF not useful Renal Transplant Hyperacute rejection preformed cytotoxic antibodies destroy kidney within hours Acute rejection T cell mediated occurs over months / treat with steroids, antithymocyte antibodies and/or immunosuppression Chronic rejection gradual kidney decline, proteinuria, HTN / graft may survive several years Immunosuppression:  HYPERLINK "pharm.doc" \l "steroids" steroids,  HYPERLINK "pharm.doc" \l "cyclosporine" cyclosporine, azathioprine, ATG, OKT3, MMF Note: 100x risk of malignancy due to chronic immunosuppression (often lymphoma), also increased risk of infection Transplant glomerulopathy most common cause of renal failure in transplant patients Treatment: ACE inhibitors for chronic allograft nephropathy [ HYPERLINK "http://www.ajkd.org/cgi/content/full/35/1/58" article1] [ HYPERLINK "http://www.ajkd.org/cgi/content/full/35/1/154" article2] / post-transplant erythrocytosis (occurs in 10-20%) ( consider using ACE inhibitors / 10-40% of patients with unilateral renal artery stenosis develop ARF (usu. 10-14 d and usu. reversible) Membranous GN most common glomerulopathy cyclosporin toxicity, tubular vacuolization (not specific), arteriolar hyalinization (may occur) Note: long-term cyclosporin and tacrolimus may induce chronic interstitial fibrosis / diagnosis can be confused with rejection / renal biopsy to distinguish interstitial fibrosis from acute or chronic rejection Renal Cancer Benign angiomyolipoma adenoma - from renal tubule oncocytoma -epithelial tumor Renal Cell Carcinoma poor prognosis Males 2x > female; 50-70 yrs Types: granular cell, tubular adenocarcinoma, Wilms, sarcoma Pathology: clear cells rich in lipid or glycogen, distinct vascular pattern by arteriography Presentation: hematuria, flank pain, palpable mass (classic triad occurs only in 10-20%) Paraneoplastic syndromes: erythrocytosis, hypercalcemia, hepatic dysfunction,  HYPERLINK \l "fuo" fever of unknown origin, amyloidosis Diagnosis: IVP, CT Treatment: nephrectomy (only potentially curative option);  HYPERLINK "pharm.doc" \l "il2" Il-2 and  HYPERLINK "pharm.doc" \l "ifna" IFN-alpha is helpful in 10-20%; radiation can have some effect; metastatic disease carries dismal prognosis Prognosis: poor / metastases have mets at presentation: lungs, bones, lymph nodes Von-Hippel-Lindau (VHL deletion) hemangioblastoma, pancreatic cysts or pancreatic cancer, cerebellum, medulla, multiple bilateral renal cysts or renal cell carcinoma / Hatfields and McCoys Dialysis Indications for: electrolytes ( HYPERLINK \l "hyperkalemia" K, Mg), uremia, acidosis, volume overload, ingestions, severe !urate Hemodialysis Acute Complications risk of cardiac arrhythmias can last up to 5 hrs after HD (risk may be predicted by larger QTc dispersions > 65 ms bad (normal 40-50 ms) / typical pre-post HD values are 60 ( 90 Avoid overly aggressive dialysis get relative hyperosmotic CNS (brain swelling) volume shifts may result in cardiac problems post-dialysis state of confusion, HA, nausea Increased Infections UTI most common (Candida, Enterococci for HD / Staph for non-HD patients) Chronic Complications line sepsis from dialysis catheters, and infection of grafts >> fistulas dialysis amyloidosis occurs after many yrs of dialysis (50% by 13 yrs) due to buildup of amyloid protein (11-kDa b2-microglobulin molecules too large to pass through membranes) / Only effective treatment is  HYPERLINK \l "renaltransplant" renal transplant Calciphylaxis [ HYPERLINK "pics/calciphylaxis.jpg" pic] Presentation: plaque-like with dusky or purple discoloration / extremely painful / progression to ulceration and formation of eschars / occur in up to 4% of dialysis patients (male:female 1:3) / must distinguish from more common arterial, ocular, periarticular, soft-tissue calcifications / hyperparathyroidism (80%), hyperphosphatemia (70%), elevated calcium-phosphate product (30%) / note: lab abnormalities may not be present later on when disease presents Diagnosis: biopsy (may want to avoid) / bone scan (can be useful) Ddx: calcinosis cutis, dystrophic calcification (sites of injured tissue), medial calcific sclerosis (larger vessels) Treatment: avoid vitamin D and calcium (use non-calcium aluminum binders; may give calcimetic agents (Cinacalcet) to help keep PTH levels down) / bisphosphonates, sodium thiosulfate, tPA, hyperbaric oxygen all have shown some success / role of parathyroidectomy debated Nephrogenic fibrosing dermopathy (NFD) rare condition described in 90s / may be caused by use of gadolinium dye in MRI Hemofiltration 12-16 L Hemodialysis 2 L Peritoneal dialysis May decrease risk of bleed/hypotension with CNS trauma and MI 1 infection per 30-40 patient months, is PD adequate? Ultrafiltration (e.g. CVVH or continuous venovenous hemofiltration) highly permeable membranes allow low hydrostatic pressures and flows so patients own BP is the driving force / advantage is can do in patients with very low blood pressures (who could not tolerate fluid fluids of regular HD) / best way to remove large amounts of volume in shortest time possible (much faster than regular HD) Renal Physiology II Acid/Base Increase proximal tubule H+ secretion and HCO3 reabsorption (and vice versa) Acidosis Increased PCO2 Hypokalemia (decreased intracellular K favors HCO3 reabsorption) Cl depletion as with volume depletion (H+ is exchanged for Na instead of Cl, this effect is NOT due to aldosterone) The distal tubule and collecting duct sees the same influences with the addition of aldosterone effects ABG Renal response to respiratory acidosis .1 acute (still takes 24-48 hrs) .5 chronic Renal response to respiratory alkalosis .25 acute .5 chronic CO2 falls 1.25 mmHg per 1 mmol/L drop in HCO3 CO2 rises between .2 to .9 mmHg per 1 mmol/L drop in HCO3 Base excess will be normal in acute situation but changed in chronic? Note: always check for combinations of respiratory and metabolic perturbations. Electrolytes or Lytes  HYPERLINK \l "sodium" Sodium  HYPERLINK \l "potassium" Potassium  HYPERLINK \l "calcium" Calcium  HYPERLINK \l "magnesium" Magnesium  HYPERLINK \l "phosphate" Phosphate  HYPERLINK \l "hypernatremia" Hyper Na+  HYPERLINK \l "hyperkalemia" Hyper K+  HYPERLINK \l "hypercalcemia" Hyper Ca2+  HYPERLINK \l "hypermagnesemia" Hyper Mg2+  HYPERLINK \l "hyperphosphatemia" Hyper PO43+  HYPERLINK \l "hyponatremia" Hypo Na+  HYPERLINK \l "hypokalemia" Hypo K+  HYPERLINK \l "hypocalcemia" Hypo Ca2+  HYPERLINK \l "hypomagnesemia" Hypo Mg2+  HYPERLINK \l "hypophosphatemia" Hypo PO43+  HYPERLINK \l "hypoglycemia" hypoglycemia POTASSIUM [K+] Normal range: 3.5 to 5.0 mmol/L (extracellular) and 150 mmol/L (intracellular) Total body stores run 50 to 55 mEq/kg (3000-4000 mmol intracellular; 300-400 mmol extracellular) Normal intake is ~100 mEq/day Normal output is 50 to150 mEq/day (95% renal, 5% stool, sweat) Increased cellular uptake: insulin, B2 agonists, alkalosis, alpha antagonists Decreased cellular uptake: acidosis, hyperglycemia, increase in osmolality, exercise, B2 antagonists, alpha agonists When aldosterone is constant, acidosis decreases K secretion and alkalosis increases K secretion (direct effects on tubular cells of course, alkalosis enhances potassium excretion in exchange for resorption of H+ and Na+ ions in the distal renal tubule Acidosis enhances renal conservation of K+ in the distal tubule High concentrations of H+ ion also may displace intracellular K+, causing an apparent hyperkalemia Renal Physiology increased tubular Na+ delivery and subsequent reabsorption favors secretion K+, increased flow decreases luminal [K+] and favors secretion Hypokalemia Renal losses (UK+ > 20 mEq/day) Diuretics, osmotic diuresis ( HYPERLINK \l "dka" DKA, other) antibiotics (AG, amphotericin, penicillins), type I classic distal RTA, hyperaldosteronism (Conns), glucocorticoid excess, magnesium deficiency, chronic metabolic alkalosis, Bartters, Fanconis, ureterosigmoidostomy Extrarenal losses (UK+ < 20 mEq/day) Diarrhea, intestinal fistulas, inadequate potassium intake, strenuous exercise (shift out of cells and urinary loss) Cellular shift Acute alkalosis (hyperventilation, GI losses, intestinal fistulas), insulin, vitamin B12 therapy, hypokalemic periodic paralysis, medications (lithium and salbutamol) Note: GI losses (vomiting and NG suctioning) is due acutely to alkalosis from H+ loss, but then from increased Tm for HCO3 with volume contraction (increased resorption of HCO3 in proximal tubule) Findings: CVS: PACs, PVCs, digoxin toxicity ECG: [HYPERLINK "pics/f-hypokalemia.jpg"hypokalemia ECG] [HYPERLINK "pics/ecgpotassium.gif"potassium ECG] prolonged QT interval T wave flattening or inversion prominent U waves ST depression MS: cramps, pain Abd: paralytic ileus Neuro: weakness, paresthesias, and depressed DTRs ABG: Metabolic alkalosis Serum Ca2+: hypokalemia and hypocalcemia may coexist Serum Mg2+: hypokalemia and hypomagnesemia may coexist Treatment: think of 10 mEq for every 0.1 deficit (unless significant deficit exists) be careful not to give more than 40 mEq IV at one time DKA: careful not to drop the K too fast by giving insulin/fluids Hyperkalemia Excessive intake Iatrogenic supplementation (IV or PO) Salt substitutes High-dose potassium penicillin Blood transfusions Decreased excretion Renal failure (acute or chronic) (GFR < 10 to 15) Drugs: spironolactone, amiloride, triamterene / lithium, cyclosporin, heparin, trimethoprim Addisons disease Hypoaldosteronism Distal tubular dysfunction Cellular shift (0.6 mmol/L for each 0.1 decrease in pH) Acidemia [except (ketones, lactic acid) because they cross membrane and do not create voltage gradient] Insulin deficiency Tissue destruction (hemolysis, crush injuries, rhabdomyolysis, burns, and tumor lysis) Medications (arginine, B-blockers, digoxin, and succinylcholine) Hyperkalemic familial periodic paralysis (rare) Factitious Prolonged tourniquet application before blood draw Hemolysis of blood sample Leukocytosis Thrombocytosis Findings: CVS: Fatal arrhythmias Neuro: Weakness, paresthesias, depressed DTRs ECG: ECG changes progress relative to severity of hyperkalemia [HYPERLINK "pics/ecgpotassium.gif"potassium ECG] First( Peaked T waves Shortened QT intervals Depressed ST segments Decreased R wave amplitude Prolonged PR interval Small or absent P waves (flattened P waves) Widened QRS complexes Last( Sine wave pattern Complications: Pancreatitis More-rhabdo? Transfusion, inflammatory - Acidosis (b/c K+ decreases ability of tri-transporter to pump NH3 into tubule thus restricting NH4 excretion) Iatrogenic Renal failure Hypomagnesemia Hypoaldosteronism Treatment: start getting worried > 6.0, super worried > 7.0 / lack of EKG changes is reassuring but does not mean you ignore it / [some renal patients are allowed to get into the 6s prior to next dialysis treatment if you know you will be able to get dialysis soon] calcium (to stabilize cardiac membrane) kayexylate resin PO/enema (enema works faster) insulin/D50 (drives K into cells) -agonists (drives K into cells) bicarbonate (especially with Type 4 RTA) CALCIUM [Ca2+] Increased renal Ca reabsorption: metabolic alkalosis, volume contraction Decreased renal Ca reabsorption: phosphate depletion, metabolic acidosis, ECF volume expansion, loop diuretics Note: ionized calcium decreases with dialysis due to decrease in acidity. Ionized calcium increases with increased acidity. Therefore, patients in renal failure might maintain normal Cai although the total calcium stores are decreased. Hypercalcemia Corrected calcium level: add 0.8 mg/dL for every 1 g/dL of albumin below 4 g/dL. [normal 8.8 to 10.4 mg/dL] Younger, asymptomatic ( hyperparathyroidism from parathyroid adenoma Older, sicker ( malignancy Causes: Increased intake or absorption of Ca2+ milk-alkali syndrome (taking twice normal dose for  HYPERLINK \l "osteoporosis" osteoporosis) Vitamin D or A intoxication  HYPERLINK \l "sarcoid" sarcoidosis or other granulomatous disease (in addition to increased absorption from the GI tract, sarcoidosis increases conversion of 25-(OH) vitamin D to 1,25-(OH)2 vitamin D Increased mobilization from bone HYPERLINK \l "hyperpth"Primary hyperparathyroidism (likely parathyroid adenoma)  HYPERLINK \l "hyperthyroid" Primary hyperthyroidism (increased bone turnover) Secondary hyperthyroidism associated with renal failure  HYPERLINK \l "pagets" Pagets disease Long-term immobilization Malignancy (often when Ca level very high) with bone invasion: lung, breast, prostate total 80% / others:  HYPERLINK \l "mm" multiple myeloma, renal, thyroid, colon, lymphoma, bladder most combination blastic/lytic (lytic causes more !Ca, better seen on XR; prostate mostly blastic, better seen by bone scan) without bone mets:  HYPERLINK \l "pthrp" PTHrp secreted by tumor (squamous cell carcinoma of lung, kidney, pancreatic, cervix, ovary, colon, head and neck tumors, esophagus, hypernephroma) lymphomas ( 1,25-(OH)2 vitamin D increased bony resorption via prostaglandin E2 osteoclast-stimulating factor (lymphoproliferative disorders) Drugs:  HYPERLINK "pharm.doc" \l "lithium" lithium,  HYPERLINK "pharm.doc" \l "hctz" HCTZ, phosphate  HYPERLINK \l "adrenalinsufficiency" Adrenal insufficiency  HYPERLINK \l "acromegaly" Acromegaly Recovery from ARF following rhabdomyolysis Decreased excretion Familial hypocalciuric hypercalcemia SLE Findings: < 12 g/dL (polyuria, dehydration) > 13 (more symptoms: stones, bones, groans, moans, psychiatric overtones) CVS: bradycardia, complete heart block, hypertension, and digoxin sensitivity ECG: shortened QTc interval short or absent ST segment prolonged PR interval MS: insomnia, restlessness, delirium, dementia, lethargy , and coma HEENT: corneal calcification Abd: GI upset, anorexia, nausea, vomiting, constipation, ulcers, pancreatitis GU: polyuria, polydipsia (nephrogenic DI) and nephrolithiasis Neuro: muscle weakness, hyporeflexia, bone pain and pathologic fractures Other: ABG: may show hyperchlorhydric metabolic acidosis PTH: If no known malignancy is found, a serum PTH should be drawn. A high PTH is indicative of hyperparathyroidism; a low PTH requires workup for occult malignancy Diagnosis: Ca2+ < 12 ( real hyperparathyroid (elevated iPTH and urine cAMP) vs. paraneoplastic (iPLP and decreased iPTH) band keratinopathy (corneal lesions) Treatment: moderate (2.9-3.2 mmol/L) ( volume expansion and diuresis (UO > 2500 mL/day) IV Fluids 500 ml NS bolus IV (careful with CHF) Lasix 20 to 40 mg IV q 2 to 4 hrs to ensure UO > 2500 mL/day and increase renal calcium wasting (i.e. no thiazides) severe (> 13 mg/dL or > 3.2 mmol/L or symptomatic) calcitonin [short-lived effect; can cause tachyphylaxis] bisphosphonates: disodium etidronate (EHDP) or pamidronate (5 to 10 mg/kg/day IV over 2 hours for 3 days; careful with renal insufficiency as rapid infusion of pamidronate may exacerbate renal failure), repeat in 7 days if needed; longer term (20 mg/kg/day PO for 30 days) [onset: 1-2 days; may cause ! PO4, ! Mg, ! Ca, fever]  HYPERLINK \l "hemodialysis" hemodialysis for hypercalcemia ( > 4.5 mmol/L) plicamycin (Mithracin) inhibits bone resorption of Ca2+ (15 to 25 /kg in 1 L NS over 3 to 6 hours) (onset ~ 48 hrs) [only use in emergency situation, many side effects] chronic: steroids, oral PO4, NSAIDs (only in PG-induced hypercalcemia) prednisone decreases Ca2+ absorption in malignancy and may have antitumor effects (10 to 25 mg PO q 6 hrs) [onset: 2 to 3 days] PO4 causes Ca2+ causes CaPO4 deposition / give if serum PO4 < 1 mmol/L (with working kidneys (5 ml PO 3 to 4 times daily until serum PO4- is 1.6 mmol/L) Hypocalcemia Causes: Decreased intake or absorption Malabsorption, intestinal bypass, short bowel syndrome Vitamin D deficiency or chronic renal failure (decreased production of 25-(OH) vitamin D or 1,25-(OH)2 vitamin Dl) Increased excretion Medications (aminoglycosides, loop diuretics, renal failure) Decreased production or mobilization from bone Hypoparathyroidism (after subtotal thyroidectomy or parathyroidectomy) Pseudohypoparathyroidism Acute hyperphosphatemia (tumor lysis syndrome, ARF, and rhabdomyolysis) Acute pancreatitis (deposition) and other necrosis Sepsis (mechanism unclear) Hypomagnesemia ( HYPERLINK \l "hypomagnesemia" see Mg2+) Alkalosis (hyperventilation, GI losses, and intestinal fistulas) Neoplasm Paradoxical hypocalcemia from osteoblastic mets from lung, breast, or prostate Medullary carcinoma of the thyroid ( calcitonin Tumor lysis syndrome Drugs: protamine, heparin, glucagons, transfusions Transient: hypoalbuminemia (0.8 mgCa/g albumin), alkalotic state, pancreatitis, sepsis, burns, ARF Findings: Cardiac: arrhythmias and dilated cardiomyopathy ECG: prolonged QT interval without U waves T wave flattening or inversion MS: confusion, irritability, and depression HEENT: papilledema and diplopia, stridor (laryngospasm) Abd: abdominal cramping Neuro: paresthesias of the fingers/toes, increased DTRs, carpopedal spasm, tetany, and seizures Chvosteks sign: facial muscle spasm elicited by light tapping on the facial nerve at the angle of the jaw; may be present in ~10% of the population with normal [Ca2+] Trousseaus sign: carpal spasm elicited by placement of a blood pressure cuff on the arm and inflation to above SBP for 3 to 5 minutes (often painful for the patient) Chronic hypocalcemia: eye (increased ICP and papilledema), CNS (spasms of hand, face, respiratory muscles), mental status changes (irritability, depression, psychosis), cardiac arrhythmias, intestinal cramps, malabsorption Treatment: Replace calcium (calcitriol and oral calcium) (monitor quantity of Ca2+consumed, watch for symptoms of circumoral or fingertip tingling) Long-term calcium supplementation rarely required PHOSPHATE [PO43-] Hyperphosphatemia Causes: CaPO4 deposition (conduction problems, calcification of blood vessels) Findings: hypocalcemia CaPO4 deposition in tissues (can occur when Ca2+ x PO4 index > 60) / see tumor-lysis syndrome Treatment: what can you do about it? HD doesnt take off PO4 very well Hypophosphatemia Causes: Decreased intake, excess GI PO43+ binders, vitamin D deficiency Hyperventilation or sudden alkalinization of serum Mechanism: increased intracellular pH ( increased PFK action/glycolysis ( shift of PO43+ into cells (this effect can persist for a brief period even after normal ventilation) / refeeding stage of severe malnutrition with administration of carbohydrate Findings: Presentation: confusion, weakness, anorexia, malaise, paresthesias Severe hypophosphataemia (< 1) respiratory muscle weakness, CNS dysfunction (EEG and EMG changes), rhabdomyolysis, dilated cardiomyopathy, hemolytic anemia Mechanism: decreased intracellular ATP, decreased 2-3 DPG and altered hemoglobin O2 affinity ( tissue ischemia MAGNESIUM [Mg2+] Normal range: 1.3 to 2.1 mEq/L Reabsorption: 25% proximal / 50-60% Loop of Henle / passive and active reabsorption (mechanism unclear) / Mg2+ competes with Ca2+ for reabsorption in TAL Magnesium is required for proper function of many cellular mechanisms including the Na+ / K+- ATPase pump. Derangements in magnesium levels should be sought in conditions associated with abnormalities in potassium or calcium concentrations. Mg2+, K+, PO43+ usually simultaneously decreased with poor dietary intake PO43+ deficiency causes K and Mg deficiency via catabolic state Hypermagnesemia Causes: Medications: lithium Magnesium-containing drugs in settings of renal failure Tumor metastases to bone Hypothyroidism Viral hepatitis Acidosis Findings: symptoms generally not apparent until the level is > 4 mEq/L VS: Bradycardia CVS: Hypotension ECG: shortened QT Shortened PR interval Heart block Peaked T waves Increased QRS duration Lung: respiratory depression Abd: nausea and vomiting Skin: flushing Neuro: loss of DTRs, and muscular paralysis Treatment: Identify and eliminate source calcium gluconate (100-200 mg IV over 5-10 minutes) effects are immediate but transient Dialysis for severe hypermagnesemia (esp. with renal failure) Hypomagnesemia Hypomagnesemia is most commonly due to urinary or GI losses RBC Mg2+ content decreases earlier than muscle Mg2+/N ratio Effects on Ca2+ metabolism 1.2-1.6 mg/dl increased PTH ( ! Ca2+ < 1 mg/dl decreased PTH (blocks release and action) ( ! Ca2+ reduced renal synthesis of 1,25(OH)2D ( ! Ca2+ Effects on K+ metabolism (mechanism less well understood) Difficult to correct K+ without correcting Mg2+ (somehow causes renal wasting of K+) Causes: Diminished PO intake Malabsorption Malnutrition (prolonged IV therapy, and alcoholism) GI losses Diarrhea (laxative abuse, gastroenteritis, and inflammatory bowel disease) Fistulas and NG drainage Vomiting Renal: renal wasting syndromes, recovery from ATN Drugs: cisplatin, cyclosporin A, G-CSF, digoxin, aminoglycosides, amphotericin B, diuretics Endocrine Cell uptake/redistribution (including alcohol intake and withdrawal) Insensible losses Findings: (early ( GI, late ( neuro) Psych: confusion, mood alteration, psychosis, and coma Neuro: nystagmus, paresthesias, tremors, weakness, vertigo, ataxia, and seizures CVS: ventricular arrhythmias, increased digoxin toxicity ECG:  HYPERLINK \l "afib" Atrial fibrillation Prolonged PR interval  HYPERLINK \l "qt" Prolonged QT / Torsades de pointes T wave flattening Abd: anorexia, vomiting, and difficulty swallowing Treatment: Severe/acute magnesium deficiencies MgSO4 2 g (8 mEq/g as a 20% solution) IV over 2 to 5 minutes, followed by 10 g IV over next 24 hrs, followed by 4-6 /day IV/PO x 5/d (if normal renal function) Note: may take > 1 day to correct / may take 2-7 days to correct hypocalcemia Treat chronic magnesium deficiencies. MgSO4 3 to 6 g/day IV or PO for 3 days (assuming normal renal function) Prevention MgSO4 1 to 2 g/day may be added to IV fluids (assuming normal renal function) SODIUM [Na+] Pseudohyponatremia 100 glucose lowers Na by 1.4 to 1.6 (effects become apparent with glucose > 300) Hypernatremia Causes: Diabetes insipidus (UNa variable) central/renal Osmotic diuresis (UNa > 20 mEq/L) hyperglycemia, urea, and mannitol administration Extrarenal water loss (UNa < 10 mEq/L) vomiting, NG suction, diarrhea, insensible losses Excessive sodium gain (UNa > 20 mEq/L) iatrogenic (excessive sodium administration), primary hyperaldosteronism, Cushings, hypertonic dialysis Findings: (from brain dehydration and volume depletion) MS: lethargy, apathy, confusion (< 125), restlessness, irritability/agitation ( obtundation/coma Respiratory : respiratory paralysis GU: polyuria, polydipsia Neuro: muscular irritability, hyperreflexia, ataxia, and seizures ( usu. < 120) Labs: SerNa, SerOsm, UNa, Hyponatremia Hypovolemic Renal (UNa > 20 mmol/L): diuretics, hypoaldosteronism (also type IV RTA), type II RTA with metabolic acidosis, salt-losing nephritis, osmotic diuresis, (esp.), ketonuria, Bartters syndrome, diuretic phase of ATN Extrarenal (UNa < 20 mmol/L): GI losses (vomiting, diarrhea, NG), sequestration (pancreatitis, peritonitis), burns, damaged muscle, sweating Hypervolemic acute/chronic renal failure (UNa > 20 mmol/L) cirrhosis, CHF (UNa < 20 mmol/L) Euvolemic  HYPERLINK \l "siadh" SIADH Tumors above diaphragm + pancreatic, duodenal, GI/GU CNS disorders (tumor, trauma, meningitis, encephalitis) Hypopituitary (loss of negative feedback exerted by cortisol on ADH release) pulmonary (pneumonia, neoplasms) Drugs (chlorpropamide, clofibrate, narcotics, neuroleptics, carbamazepine, TCAs, SSRIs, oral hypoglycemics, cyclophosphamide, vincristine, vinblastine) / NSAIDs and somatostatin potentiate ADH normal response to surgery increased SIADH usually lasts up to 3-5 days / resolves without any specific therapy along with a physiologic diuresis Pseudohyponatremia normal serum Osm: hyperlipidemia, hyperproteinemia increased serum Osm: hyperglycemia (/18), urea (/2.8), mannitol, alcohol (ethanol, methanol, and isopropyl alcohol), ethylene glycol Hypothyroidism Pain, emotional stress Addisons or inadequate cortisol replacement (UNa > 20 mmol/L) Findings: MS: lethargy, apathy, disorientation, agitation, coma Neuro: weakness, ?decreased DTRs, seizures Labs: ser Na, ser Osm, serum protein, lipids, glucose (each 100 mg/dl above normal decreases ser Na by 0.4 mEq/L), urine Na Treatment: do not correct faster than 2 mEq/L/hr (cellular dehydration in CNS may cause central pontine myelinolysis and other brain damage) Beer potomania, tea and toast syndrome Typical Na excretion ~ 100 mEq/day (2 L/day urine x 50 mEq/L of Na assuming a maximally dilute urine) Typical dietary Na intake is about 150 mEq/day Normal kidneys can dilute urine to 50 mEq/L, thus 18 L (if you drank that much) would necessitate a 900 mEq loss / The patient becomes hyponatremic when the volume of fluid intake necessitates the excretion of more sodium than the dietary intake / But someone who takes in a low sodium diet need only drink say 5-6 L/day to become hyponatremic Pulmonary [ HYPERLINK \l "pfts" PFTs /  HYPERLINK \l "pulmonaryprocedures" Pulmonary Procedures /  HYPERLINK \l "abg" ABGs /  HYPERLINK \l "peep" PEEP]  HYPERLINK \l "pe" Pulmonary Embolism,  HYPERLINK \l "pneumothorax"  HYPERLINK \l "pneumothorax" Pneumothorax,  HYPERLINK \l "abscess" Lung Abscess,  HYPERLINK \l "alveolarhemorrhage" Alveolar Hemorrhage,  HYPERLINK \l "ards" ARDS  HYPERLINK \l "pleurisy" Pleurisy,  HYPERLINK \l "pleuraleffusion" Pleural Effusion,  HYPERLINK \l "pleuralfibrosis" Pleural Fibrosis  HYPERLINK \l "bronchitis" Bronchitis,  HYPERLINK \l "bronchiectasis" Bronchiectasis,  HYPERLINK \l "atelectasis" Atelectasis,  HYPERLINK \l "lungobstructive" Obstructive ( HYPERLINK \l "copd" COPD,  HYPERLINK \l "asthma" Asthma HYPERLINK \l "rad" ,  HYPERLINK \l "emphysema" Emphysema),  HYPERLINK \l "lungrestrictive" Restrictive Lung Disease Sleep Apnea ( HYPERLINK \l "osa" OSA,  HYPERLINK \l "csa" CSA)  HYPERLINK \l "lungca" Lung Cancer  HYPERLINK \l "pneumonia" Pneumonia Typical:  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus, Staphylococcus,  HYPERLINK \l "strepa" Group A Strep,  HYPERLINK \l "hinfluenza" H influenza Atypical:  HYPERLINK \l "mycoplasma" Mycoplasma,  HYPERLINK \l "chlamydia" Chlamydia,  HYPERLINK \l "psittacosis" Psittacosis,  HYPERLINK \l "legionella" Legionella Other:  HYPERLINK \l "gnr" GNR,  HYPERLINK \l "pcp" PCP,  HYPERLINK \l "compromised" Compromised,  HYPERLINK \l "postop" Post-Op,  HYPERLINK \l "aspiration" Aspiration, HYPERLINK "micro.doc" \l "mtb"Tuberculosis, fungus/parasites  HYPERLINK \l "pneumoniaviral" Viral,  HYPERLINK \l "pneumoniafungal" Fungal,  HYPERLINK \l "pneumoniahiv" AIDS-related  HYPERLINK \l "ild" ILD  HYPERLINK \l "ipf" Idiopathic Pulmonary Fibrosis (UIP,  HYPERLINK \l "desquamative" DIP, AIP, NSIP)  HYPERLINK \l "lip" Lymphocytic IP,  HYPERLINK \l "histiocytosis" Histiocytoses (Langerhans IP)  HYPERLINK \l "rbail" RBAIL,  HYPERLINK \l "boop" BOOP,  HYPERLINK \l "iph" IPH  HYPERLINK \l "occupational" Occupational  HYPERLINK \l "inorganic" Inorganic Dust,  HYPERLINK \l "organic" Organic Dust,  HYPERLINK \l "otherchemicals" Other chemicals Other  HYPERLINK \l "goodpastures" Goodpastures,  HYPERLINK \l "Hypersensitivitypneumonitis" Hypersensitivity Pneumonitis,  HYPERLINK \l "eosinophilic" Eosinophilic Pneumonias,  HYPERLINK \l "aspergillus" Allergic Aspergillus Pneumonia,  HYPERLINK \l "pap" Pulmonary Alveolar Proteinosis Pulmonary Physiology Upright paO2 = 104 (0.27 x age) Supine paO2 = 104 (0.4 x age) [shunting of blood to apical lobes] PO2 from 60-80 mild hypoxemia (lower than normal, but still may have O2 of 90%) PO2 from 40-60 hypoxemia (O2 rapidly falls from 90% to 70%) Increase T, CO2, acidity all shift hemoglobin dissociation curve to right allows oxygen to be released to tissues Arterial Blood Gases Acid-Base Tricks Acute: 0.08 pH for each deviation by 10 in CO2 (from ABG) Chronic: 0.03 pH rule for chronic compensation Note: a pH of 7.60 can lead to arrhythmias, seizures Base Excess HCO3 changes with respiration, so BE is the measured HCO3 compared to the normal HCO3 corrected for CO2 PAO2 = FiO2 (760 PH20) PaCO2/RQ [usu. 0.8] A-a gradient is usually 10-20 in normal, young adult A-a gradient in normal person is caused by VQ mismatch / bronchial and left ventricular venous drainage Pathological A-a gradient Shunting (R to L) AV shunt (anywhere), PE (shunt in lungs) VQ mismatch asthma, chronic bronchitis, emphysema, PE Diffusion defect sarcoidosis, chronic interstitial pneumonia, fibrosis ARDS PaO2/FiO2 < 200 (corresponds to PaO2 < 40), PWP < 18 mm Hg Treatment: can give 0.6 FiO2 for up to 24 hrs (too much O2 can increase Atelectasis) / nasal cannula usually equates to .25 FiO2 + 0.25 for each Liter oxygen delivery = cardiac output x oxygen carrying capacity oxygen carrying capacity = Hgb x O2 x 1.34 + PaO2 (0.003) PFTs [HYPERLINK "pics/pft.jpg"diagram] spirometry, flow-volume loops, lung capacity,  HYPERLINK \l "dlco" DLCO General ventilation respiratory center in the brain stem influenced by input from carotid (PaO2) and central (PaCO2, [H+]) chemoreceptors; proprioceptive receptors in muscles, tendons, and joints; and impulses from the cerebral cortex. Static Lung Volumes and Capacities body plethysomography is preferred method (patient sitting in box) helium dilution (easier to do but underestimates lung volumes in emphysema, HYPERLINK \l "cf"CF) Vital capacity (VC or "slow VC") is the maximum volume of air that can be expired slowly after a full inspiratory effort / decreases as a restrictive lung disorder (e.g., pulmonary edema, interstitial fibrosis) / VC also reflects the strength of the respiratory muscles and is often used to monitor the course of neuromuscular disorders Forced vital capacity (FVC) similar to VC, is the volume of air expired with maximal force. It is usually measured along with expiratory flow rates in simple spirometry The VC can be considerably greater than the FVC in patients with airway obstruction. During the FVC maneuver, terminal airways can close prematurely (i.e., before the true residual volume is reached), trapping gas distally and preventing its measurement by the spirometer. Total lung capacity (TLC) total volume of air within the chest after a maximum inspiration. Functional residual capacity (FRC) volume of air in the lungs at the end of a normal expiration when all respiratory muscles are relaxed. Physiologically, it is the most important lung volume because it approximates the normal tidal breathing range. Outward elastic recoil forces of the chest wall tend to increase lung volume but are balanced by the inward elastic recoil of the lungs, which tends to reduce it; these forces are normally equal and opposite at about 40% of TLC. Loss of lung elastic recoil in emphysema increases FRC. Conversely, the increased lung stiffness in pulmonary edema, interstitial fibrosis, and other restrictive disorders decreases FRC. Kyphoscoliosis leads to a decrease in FRC (in 3%) and in other lung volumes because a stiff, noncompliant chest wall restricts lung expansion. Inspiratory capacity (IC) difference between TLC and FRC The FRC has two components: residual volume (RV), the volume of air remaining in the lungs at the end of a maximal expiration, and expiratory reserve volume (ERV); ERV = FRC - RV. The RV normally accounts for about 25% of TLC). Changes in RV parallel those in the FRC with two exceptions: In restrictive lung and chest wall disorders, RV decreases less than do the FRC and TLC and in small airways disease, premature closure during expiration leads to air trapping, so that the RV is elevated while the FRC and FEV1 remain close to normal. In COPD and asthma, the RV increases more than the TLC does, resulting in some decrease in the VC The characteristic abnormality seen in obesity is a decreased ERV, caused by a markedly decreased FRC with a relatively well-preserved RV. Dynamic Lung Volumes and Flow Rates Forced expiratory volume in 1 sec (FEV1) is the volume of air forcefully expired during the first second after a full breath and normally accounts for > 75% of the FVC FEF25-75% is less effort-dependent than the FEV1 and is a more sensitive indicator of early airway obstruction. FEV1 ! by bronchospasm (asthma), impacted secretions (bronchitis), loss of elastic recoil (emphysema) Fixed obstruction of upper airway ( equal reduction of inspiratory and expiratory flow rates FEV1! in restrictive lung disorders Maximal voluntary ventilation (MVV) Diffusing capacity (DLco) Increased by ! contact with blood/red cells: CHF,  HYPERLINK \l "prv" polycythemia,  HYPERLINK \l "dah" alveolar hemorrhage Decreased by: anemia, parenchymal lung disease, removal of lung tissue often used to distinguish asthma (normal DLco) from COPD (abnormal DLco) Note: VQ mismatch does not affect DLco because trapped air will not see the CO gas anyway Use of positive pressure optimal Hb for most acutely ill patients with severe hypoxemia ~10-12 g/dL correcting acute alkalemia improves Hb performance Note: for assessing hyperventilation, use CO2 as a guide (not just air movement) PEEP can increase 2.5 every couple hours / must decrease more slowly (to avoid alveolar collapse, no more than 2.5 every 6-8 hrs and check) PEEP helps get blood out of lungs (useful for pulmonary edema) PEEP makes it easier for the heart to pump (useful for heart failure) CPAP (continuous positive airway pressure) useful for acute Atelectasis or pulmonary edema BIPAP indications: RR > 25, pH < 7.35, acute increase in pCO2 Pulmonary Procedures  HYPERLINK \l "thoracentesis" Thoracentesis  HYPERLINK \l "thoracoscopy" Thoracoscopy  HYPERLINK \l "tubethoracostomy" Tube Thoracostomy Thoracotomy  HYPERLINK \l "bronchoscopy" Bronchoscopy Mediastinoscopy Mediastinotomy  HYPERLINK \l "pnbp" Percutaneous Needle Biopsy Of Pleura  HYPERLINK \l "ptna" Percutaneous Transthoracic Needle Aspiration Thoracentesis diagnostic ( HYPERLINK \l "pleuraleffusion" see pleural effusion) / therapeutic [HYPERLINK "procedurevids/"video] Contraindications include lack of patient cooperation; an uncorrected coagulopathy; respiratory insufficiency or instability (unless therapeutic thoracentesis is being performed to correct it); cardiac hemodynamic or rhythm instability; and unstable angina. Relative contraindications include mechanical ventilation and bullous lung disease. Local chest wall infection must be excluded before passing a needle into the pleural space. Complications are uncommon, although the exact incidence is unknown. They include pneumothorax due to air leaking through the needle or due to trauma to underlying lung; hemorrhage into the pleural space or chest wall due to needle damage to the subcostal vessels; vasovagal or simple syncope; air embolism (rare but catastrophic); introduction of infection; puncture of the spleen or liver due to low or unusually deep needle insertion; and reexpansion pulmonary edema, usually associated with rapid removal of > 1 L of pleural fluid. Death is extremely rare. Percutaneous Needle Biopsy Of Pleura A needle biopsy of the pleura is performed when thoracentesis with pleural fluid cytology does not yield a specific diagnosis, usually for exudative effusions when TB, other granulomatous infections, or malignancy is suspected. The diagnostic yield of pleural biopsy depends on the cause of the effusion. In patients with TB, pleural biopsy is much more sensitive than thoracentesis and pleural fluid culture alone; 80% of cases are diagnosed with the first biopsy, and 10% more with a second biopsy. Of patients with pleural malignancy, 90% can be diagnosed with a combination of pleural fluid cytology and needle biopsy of the pleura. Contraindications are the same as those of thoracentesis Complications are similar to those of thoracentesis, but the incidence of pneumothorax and hemorrhage is slightly higher. Thoracoscopy Endoscopic examination of the pleural space after induced pneumothorax. Note: Thoracoscopy must be distinguished from video-assisted thoracic surgery (VATS). Thoracoscopy is primarily used for diagnosis of pleural disease and for pleurodesis. It is most often performed by surgeons but may be performed by other trained physicians. In contrast, VATS is used exclusively by surgeons to perform minimally invasive thoracic surgery. Contraindications are the same as those for thoracentesis. In addition, thoracoscopy cannot be used if a patient is unable to tolerate a general anesthetic or the unilateral lung collapse that occurs during the procedure. Extensive pleural adhesions greatly increase the risk of complications. Complications are similar to those of thoracentesis plus those of a general anesthetic. Pleural tears, with bleeding and/or prolonged air leakage, can occur. Tube Thoracostomy Complications include hemorrhage from intercostal vessel injury, subcutaneous emphysema, injury due to a malpositioned tube (e.g., into the major fissure, and occasionally into the lung), and local infection or pain. Reexpansion pulmonary edema due to increased capillary permeability may occur in the reexpanded lung, especially after prolonged lung collapse and rapid reinflation. Tube insertion may be difficult because of adhesions or a very thick pleura. Other problems include inadequate drainage of the pleural space due to clots or gelatinous inflammatory material and plugging or kinking of the tube. Bronchoscopy Contraindications include lack of cooperation or combativeness in a patient; unstable cardiovascular status due to hypotension, low cardiac output, arrhythmias, or ischemic heart diseases; an uncorrected bleeding diathesis (thrombasthenia of uremia is especially troublesome); severe anemia; and hypersensitivity to lidocaine. Elective bronchoscopy should be deferred 6 wk in patients who have had an acute MI. If a patient who has unstable gas exchange, inadequate systemic O2 transport, or active bronchospasm needs bronchoscopy, the patient can be intubated and ventilated to perform it safely. Complications include morbidity in 8 to 15 and death in 1 to 4 of 10,000 patients. Patients at greatest risk include the elderly and patients with severe COPD, coronary artery disease, pneumonia with hypoxemia, advanced neoplasia, or mental dysfunction. Many of the complications--such as respiratory depression and, rarely, CNS toxicity or seizures due to lidocaine absorption--are related to the use of sedation or anesthetics. Other complications include pneumothorax (5% overall, with higher rates after transbronchial lung biopsy); hemorrhage (rare unless a biopsy is performed); cardiac arrhythmias (premature atrial contractions in 32% and premature ventricular contractions in 20%); postbronchoscopy fever (16%), with pneumonia rarely and no bacteremia; bronchospasm (unusual unless the patient has poorly controlled asthma); and laryngospasm (rare). Bronchoalveolar lavage (BAL) accomplishes a "liquid biopsy" of the distal airways and alveoli. The tip of the bronchoscope is wedged in a 3rd- or 4th-generation bronchus; sterile saline is infused, then suctioned back, thus retrieving cells, protein, and microorganisms. Supernatant fluid and cell pellets obtained in this procedure are useful in the diagnosis of neoplastic diseases, infections (especially in immunocompromised hosts), and interstitial lung diseases. Yields are very high, and risks minimal. Transbronchial lung biopsy, performed with forceps through a flexible bronchoscope, provides small specimens of alveolar tissue and other tissue outside the airways. It is used mainly in patients with pulmonary infections, diffuse interstitial lung disease, lymphangitic carcinomatosis, or undiagnosed peripheral lung masses > 2 cm in diameter and in immunocompromised hosts with infiltrates, fever, and gas exchange defects. It can be performed without fluoroscopy, but use of fluoroscopy may reduce the risk of pneumothorax. Although transbronchial biopsy increases mortality to 12 of 10,000 patients and morbidity to 27 of 1000, it has a very high yield so that it often obviates the need for open thoracotomy, especially when combined with bronchoalveolar lavage. Major contraindications include uncorrectable clotting defects, pulmonary hypertension, cardiopulmonary instability, and poor patient cooperation. Submucosal and transbronchial needle aspiration provides tissue from endobronchial neoplasms, extrabronchial masses, and subcarinal, paratracheal, and mediastinal nodes for cytology and culture. It adds no detectable risk to basic bronchoscopy. Complications are related primarily to general anesthesia Percutaneous Transthoracic Needle Aspiration This procedure is used to obtain cytologic specimens from lung and mediastinal lesions, especially peripheral nodules in the lung parenchyma and pleural space. Less frequently, it is used to obtain specimens from infected areas of lung for direct smear and culture for identification of specific pathogens. A diagnosis is usually made in > 90% of patients with malignancy and in > 85% of those with benign disease. Contraindications include lack of cooperation or combativeness in a patient, cardiovascular instability, ventilatory support, contralateral pneumonectomy, suspected vascular lesion, hydatid cyst, pulmonary arterial or venous hypertension, intractable coughing, and clotting defects. Bullous lung disease is a relative contraindication, especially if areas of emphysematous lung would be traversed to access the lesion. Complications include hemoptysis, usually of < 50 mL (in 10 to 25% of patients); pneumothorax (in 20 to 30%); and air embolism (occasionally). Mortality is < 1%. Percutaneous large-bore cutting needle biopsy to obtain a core of lung tissue can be performed if peripheral lung lesions obliterate the pleural space. In this setting, the procedure is safe and has a very high diagnostic yield. Lung biopsy with a percutaneous trephine drill needle is rarely performed. Mediastinoscopy Endoscopic examination of the mediastinum. Mediastinoscopy is used to stage lung cancer, especially when enlarged nodes are seen on chest x-ray or CT scan. Some physicians believe that all patients with lung cancer should have invasive staging procedures; others use staging procedures only in patients with abnormal nodes seen on imaging. Mediastinoscopy may be used to diagnose mediastinal masses or to sample nodes in patients who might have lymphoma or granulomatous diseases. Contraindications include inability to tolerate a general anesthetic; superior vena cava syndrome; previous mediastinal irradiation, mediastinoscopy, median sternotomy, or tracheostomy; and aneurysm of the aortic arch. Mediastinoscopy is performed using a general anesthetic in an operating room. A mediastinoscope is passed through a suprasternal notch incision, allowing access to some carinal and hilar nodes, to peribronchial and paratracheal nodes, and to the superior posterior mediastinum. Complications occur in < 1% of patients. They include bleeding, vocal cord paralysis secondary to recurrent laryngeal nerve damage, and chylothorax due to thoracic duct injury. Mediastinotomy Anterior mediastinotomy (Chamberlain procedure) is surgical entry of the mediastinum via an incision made through the 2nd left intercostal space adjacent to the sternum. It gives direct access to the aortopulmonary window nodes, which are inaccessible to mediastinoscopy. The aortopulmonary window nodes are a common site of metastases from left upper lobe cancers. Complications are related to the surgical procedure and include pneumothorax, wound infection, and, rarely, damage to the great vessels. Thoracotomy Contraindications include unstable systemic status (e.g., cardiopulmonary, nutritional, metabolic, renal), i.e., inability to tolerate the injury of major surgery. Complications are greater than those for any other pulmonary biopsy procedure because of the risks of general anesthesia, surgical trauma, and a longer hospitalization with more postoperative discomfort. Hemorrhage, infection, pneumothorax, bronchopleural fistula, and reactions to anesthetics are the greatest hazards. Tracheal aspiration Complications: laryngospasm, bronchospasm, respiratory arrest, cardiac arrhythmias or arrest, erosion of the respiratory epithelium with bleeding, and introduction of infection Transtracheal aspiration: bleeding (in 10% of patients), subcutaneous air (in 7%), air embolism, posterior wall puncture, uncontrolled cough, decreased gas exchange, and hypotension Pulmonary Embolism Incidence: 3rd leading cause of acute death / 1 in 1000 / 150,000 to 200,000 deaths/year in the United States / males > females / increased age, most occur < 1 month after delivery / probably underdiagnosed by 170,000/yr Recurrence: 5% recurrence if DVT (even treated; 10% recur if initial PE) Mechanisms: Virchows Triad: local trauma, hypercoagulable state, venous stasis / small clot causes disproportional increase in pulmonary MAP due to vasoconstriction from inflammatory mediators (serotonin, thromboxane, PAF) and vagus nerve / saddle embolus (massive) / paradoxical embolism (R to L shunt) Pathology: pulmonary hypertension, hypoxia, RVF, mortality Presentation: 5-10% present with normal O2 saturation and Aa gradient / some hemoptysis (usually not massive) / massive PE causes tachycardia, loud P2, RHF signs, pulsus paradoxus / chest pain and hemoptysis usually takes a few hours to develop Symptoms: dyspnea (80%), pleuritic pain (70%), apprehension (60%), cough (50%), hemoptysis (30%), diaphoresis (40%), syncope (10%, > elderly) Physical findings: tachypnea (90%), rales (60%), accentuated P2 (50%), tachycardia (40%), mild fever (40%), phlebitis (30%), cyanosis (20%), right-sided S3 (large emboli with acute pulmonary hypertension) Causes:  HYPERLINK \l "dvt" DVT, air (usually iatrogenic), cholesterol, tumor, amniotic fluid (mimics sepsis), foreign body (arthroplasty cement, talc) / 40% trauma/surgery, 40% idiopathic/undiagnosed, 20% genetic predisposition, 10% heart disease (e.g. arrhythmias) / 10-20%  HYPERLINK \l "hypercoagulability" hypercoagulable state ( HYPERLINK \l "factorvleiden" factor V Leiden most common) / 10% will have malignancy [HYPERLINK "more/dvt-pe.doc"more] (lung, pancreas, stomach, colon > prostate, ovary, other > gallbladder, breast, kidney) Risk factors: surgery/trauma, obesity / oral contraceptives, pregnancy, post-partum / cancer or cancer-chemotherapy / immobilization / central venous catheter / diabetic ketoacidosis Differential Diagnosis: MI (75% of PE misdiagnosed as MI), unstable angina, pneumonia, bronchitis, COPD exacerbation, CHF, asthma, pericarditis, primary pulmonary hypertension, rib fracture, pneumothorax, costochondritis, musculoskeletal pain, anxiety Work-up: [HYPERLINK "pics/brown-PE8.jpg"algorithm] EKG: sinus tachycardia, new-onset Afib/flutter, non-specific ST changes are most common finding / classical finding (S1Q3T3): I deep S, III Q wave, inverted T III / V1-4 inverted T waves (only 15%) [HYPERLINK "pics/PE3.jpg"pic] CXR: r/o pneumothorax et al / Westermarks oligemia (15%) [HYPERLINK "pics/PE1.jpg"pic] / raised hemi-diaphragm / pleural-based parenchymal radiodensity with rounded profile toward hilus (Hamptons lump or hump) / pleural effusion (transudate or exudates) / Palla sign (enlargement of right descending pulmonary artery) ABG on RA (expect respiratory alkalosis, PaO2 < 80 / PaCO2 < 30) VQ scan: [HYPERLINK "pics/PE2.jpg"pic] [HYPERLINK "pics/PE5.jpg"pic2] [normal: stop / high: treat / low-intermediate (up to 40% have PE) / most PE have moderate to low probability VQ scans / often want to go directly to CT for 2 reasons 1) pre-existing lung disease usually causes non-informative study 2) CT is much faster to get (especially during off-hours) / T-99 [HYPERLINK "pics/PE4.jpg"pic] / 60% of COPD patients have indeterminate scans CT angiogram [HYPERLINK "pics/PE7.jpg"pic]: better for central pulmonary arteries, not peripheral / not so good for diagnosing sub-segmental PE / Note: if not PE, CT reveals the alternate diagnosis > 30% of cases / some choose pulmonary angiogram 1st if patients renal function only allows one test / false negatives (patient hemodynamics, motion artifact, oblique running arteries, note: interlobar artery in r. lung not well seen) / false positives (hilar, bronchopulmonary lymph nodes, artifacts, reduced pulmonary perfusion) / Note: differing opinions (obstruction, PE, etc.) is the rule if reviewed by > 1 radiologist, youll see Pulmonary angiogram [HYPERLINK "pics/PE6.jpg"pic]: gold standard / 1% morbidity/mortality of test / rarely done unless equivocal or negative VQ/CT and high suspicion for PE Ultrasound: looking for DVT in lower extremities (most come from pelvis however) / more than will have leg vein clot (sensitivity is high if study done properly), which means S! will have no DVT Echocardiogram: may see RV dilation/strain/failure (which is leading cause of death from PE, and which may provide support for use of  HYPERLINK "pharm.doc" \l "thrombolytics" thrombolytics) / depressed RV function with apical sparing is McConnells sign (does not always mean PE) / this is an adjuvant test used to determine RV function (and may also provide alternative explanations for patients symptoms) but is NOT a diagnostic test for PE D-dimers: if lab does proper assay, can have 90% sensitivity with lower specificity (cannot rule in, but does have high negative predictive value) Prevention: any medical or surgical patient at high risk for venous thrombosis (older than 40, limited mobility, one risk factor; there are many [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/14/1438" NEJM]) should receive sc heparin 5000 U bid/tid or sc Lovenox 30 mg qd or Fragmin / for high bleeding risk, compression stockings or (better) pneumatic compression device Treatment: [ HYPERLINK "http://www.annals.org/cgi/content/full/146/3/211" annals][ HYPERLINK "http://www.annals.org/cgi/content/full/146/3/211" annals] Anticoagulation (heparin or  HYPERLINK "pharm.doc" \l "lmwh" LMWH then  HYPERLINK "pharm.doc" \l "coumadin" coumadin as soon as PTT is therapeutic, same day with LMWH) / 5% overall recurrence rate / 2% overall risk of major bleed / Duration: 6 months if risk-factor associated, indefinite if no identifiable risk-factors. [ HYPERLINK "http://www.annals.org/cgi/content/full/139/1/19" annals] / recent studies suggest once-daily LMWH may be as good as twice-daily (2009) and measure factor-Xa levels (best way to ensure therapeutic and safe range (esp. with renal insufficiency) Thrombolysis controversial when to use. [HYPERLINK "http://content.nejm.org/cgi/content/full/347/15/1143"NEJM] says use  HYPERLINK "pharm.doc" \l "alteplase" alteplase + heparin when concern for RV failure is high. [HYPERLINK "http://content.nejm.org/cgi/content/full/347/15/1131"NEJM] / accepted risk of ICH about 3% Thrombectomy for pts who have RHF and cannot tolerate or fail thrombolysis IVC filters (vena cava interruption) with known DVTs, poor cardiopulmonary reserve, PE in spite of anti-coagulation or contraindications to anti-coagulation (recent CVA or CNS surgery, CNS malignancy, GI bleed) / many complications of filters (overall 10-20%) [HYPERLINK "pics/PE9.jpg"pic] Note: expect rapid changes here with onslaught of new methods of anti-coagulation (11/00) Lemierres syndrome Classical organisms: fusobacterium, Prevotela, Peptostreptococcus, Eikenella involvement of posterior compartment of the lateral pharyngeal space, bacteremia, septic IJ thrombophlebitis Contiguous spread: carotid artery rupture, hoarseness, CN IX XII involvement,  HYPERLINK \l "horners" Horners syndrome Septic embolization: pulmonary, suppurative arthritis, osteomyelitis, abscesses, skin lesions, hepatic abscesses +/- cholestasis Diagnosis: CT/MRI/ultrasound, high degree of clinical suspicion Treatment: prolonged IV antibiotics against anaerobes / 1st metronidazole, 2nd clindamycin, chloramphenicol (often produce B-lactamases) surgical ligation or IJ excision may be necessary some feel heparin is useful Pulmonary Edema Causes: CHF, diastolic dysfunction (with arrhythmias or HTN), ARDS, volume overload, others not yet listed CXR clues: perihilar hazing, peribronchial cuffing, sub-pulmonic effusions (cannot see vessels overlying diaphragm), increased size of cardiac silhouette Treatment: oxygen, furosemide, morphine (reduce pain/anxiety and arterial/venodilation), nitroglycerine/nitroprusside, intubation/positive pressure ventilation (CPAP), HD/CVVH if renal failure Flash pulmonary edema from super-high HTN or restrictive pericarditis Pulmonary hypertension Causes: left-sided heart failure, idiopathic, restrictive lung disease (sarcoidosis, ILD, scleroderma), chronic PE, high-altitude, kyphoscoliosis Treatment: correction of underlying cause can sometimes reverse HTN, decrease RVH O2 to minimize ongoing hypoxemia ( vasoconstriction ( more pulmonary HTN correct acid-base problems high-dose Ca channel blockers (25% response) IV epoprostenol ( HYPERLINK "pharm.doc" \l "flolan" Flolan) can help in very select group of patients consider lifelong anticoagulation +/- IVC if chronic PE cardiopulmonary or pulmonary transplantation careful diuresis to relieve symptoms of right sided failure Primary pulmonary hypertension (PPHT) Causes: mitral stenosis, recurrent PE, sickle cell, collagen vascular diseases, congenital cardiac problems, cor triatriatum Low pressure pulmonary edema Uremia causes release of fluid into airspace / butterfly wing distribution on CXR Pneumonia [ HYPERLINK \l "childhoodpneumonia" pediatric pneumonia] [ HYPERLINK "ddx.doc" \l "cavitary" see cavitary lung lesions] [ HYPERLINK "micro.doc" \l "agepneumonia" age breakdown] 2 million per year / 40-70K deaths/yr / 6th leading cause of death overall / most common fatal nosocomial infection Presentation: cough, fever, sputum, pleurisy / elderly report fewer symptoms (even though they are there) Findings: tachypnea, crackles, bronchial breath sounds Types: lobar pneumonia, segmental pneumonia, bronchopneumonia, interstitial pneumonia, pneumonitis Organisms: Typical:  HYPERLINK "micro.doc" \l "pneumococcus" S. Pneumo (1st), H. influenza, S. aureus, Moraxella Atypical: HYPERLINK "micro.doc" \l "mpneumoniae"Mycoplasma,  HYPERLINK "micro.doc" \l "klebsiella" Klebsiella,  HYPERLINK "micro.doc" \l "legionella" Legionella,  HYPERLINK "micro.doc" \l "chlamydia" Chlamydia,  HYPERLINK "micro.doc" \l "coxiella" Coxiella Virus:  HYPERLINK \l "rsv" RSV, parainfluenza, influenza A/B, VZV Other:  HYPERLINK "micro.doc" \l "tb" Tuberculosis,  HYPERLINK "micro.doc" \l "pseudomonas" Pseudomonas, fungus (Cocci, Histo, etc), Nocardia, Actinomyces, PCP, parasites,  HYPERLINK "http://www.merck.com/pubs/mmanual/section13/chapter157/157d.htm" \l "A013-157-0878" Tularemia, Yersinia, RMSF, U. urealyticum (neonates), Prevotela (aspiration), Fusobacterium (aspiration), S. agalactiae Note: Enterobacter, Citrobacter and Flavobacterium almost never cause pneumonia, even on ventilator) Children18 4040-6060-virusmycoplasmaS. pneumoS. pneumomycoplasmachlamydiaH. influenzaanaerobeschlamydiaS. pneumoanaerobesH. influenzaS. pneumovirusGNRmycoplasmaS. aureusvirus Diagnosis: 30-50% with no identified pathogen and bacterial picture CXR (60% with parapneumonic effusion; 5-10% develop  HYPERLINK \l "empyema" empyema)  HYPERLINK \l "Thoracentesis" Thoracentesis (if  HYPERLINK \l "pleuraleffusion" pleural effusion > 10mm on lateral decubitus film, loculated, evidence of pleural thickening on CT) Sputum: helpful if minimally contaminated (>25 PMN, <10 epithelials/LPF) Blood cultures: positive in 30-40% S. pneumo Serology: useful for Legionella, Mycoplasma, Chlamydia Ddx:  HYPERLINK \l "aspirationpneumonitis" aspiration pneumonitis, sarcoidosis, lymphoma, many other non-infectious lung diseases Labs: elevated ALT/AST: Q fever, psittacosis, Legionella (these are the only ones that do this) / elevated total bilirubin suggests S. pneumo or Legionella Treatment respiratory supportive care / PORT study addresses whether to hospitalize or not (based on demographics and exam findings) antibiotics: 3rd generation cephalosporin + macrolides or quinolone (Levaquin, Tequin) consider need for vancomycin (staph), cefepime +/- AG (pseudomonas), clindamycin (anaerobes), anti-fungal, more Course: pneumonia severity index or PSI (age, gender, comorbid disease, exam findingsO2 sat, lab dataBUN, Na) gives prognosis and helps determine if patient should be admitted Radiographic resolution: directly correlated with patient age / 80% of pts < 40 yrs have complete resolution by 6 wks / 20% of pts > 80 yrs / CXR resolution: may take several weeks / lack of at least partial radiographic resolution by 6 weeks (even asymptomatic) ( consider alternative causes (e.g., obstructing lesions/noninfectious causes) / bronchoscopy with BAL and TBBs (minimal morbidity, preferred initial invasive procedure) Tidbits: diffuse interstitial infiltrates: PCP, viral pleural effusions almost never in PCP  HYPERLINK "ddx.doc" \l "cavitary" cavitations & abscess ( necrotizing (staph, Tb, klebsiella, fungus) bronchopneumonia - low virulence organisms GI symptoms suggest Legionella relative bradycardia: subtract one from last digit of fever, multiple by 10 and add to 100 (105 degrees predicts HR of 140, anything less, even 120 is relative bradycardia) / seen in Legionella, Q fever, psittacosis, Salmonella (CAD only in HIV), others COPD/smoking ( ! H. influenza 80% of childhood pneumonia is viral Bacterial Pneumonia (More) U. urealyticum neonatal pneumonia Prevotela aspiration pneumonia Fusobacterium aspiration pneumonia Actinomyces chronic pneumonia  HYPERLINK "micro.doc" \l "mai" MAI most common AFB  HYPERLINK "micro.doc" \l "mtb" MTb AFB rhodococcus equi AFB echinococcus S. agalactiae Klebsiella Legionella 2nd-3rd most common HYPERLINK "micro.doc" \l "francisella"Francisella tularemia Yersinia pestis Pseudomonas aeruginosa AIDS / nosocomial AIDS HYPERLINK "micro.doc" \l "pneumocystis"PCP look in exudate for cysts with central dot HYPERLINK \l "kaposis"Kaposis sarcoma most common neoplasm Mucormycosis underlying disease Viral Pneumonia CMV large cells with eosinophilic inclusions / immunocompromised HSV multinucleate / ground-glass change in nucleus / cowdry A inclusions VZV looks like HSV  HYPERLINK "micro.doc" \l "measles" Measles multinucleate and giant cells Adenovirus basophilic nuclear smudges / smaller cowdry A inclusions / uncommon but bad  HYPERLINK "micro.doc" \l "influenza" Influenza often with bacterial superinfection  HYPERLINK \l "rsv" RSV small cowdry type A Parainfluenza immunocompromised / eosinophilic inclusions Hantavirus interstitial pneumonia / edema and effusion Fungal Pneumonia HYPERLINK "micro.doc" \l "cryptococcus"Cryptococcus most common fungal Aspergillosis associate with asthmatics  HYPERLINK "micro.doc" \l "histoplasma" Histoplasma central US / oval budding yeasts  HYPERLINK "micro.doc" \l "coccidioides" Coccidioides SW US / no budding  HYPERLINK "micro.doc" \l "cryptococcus" Cryptococcus pigeon droppings  HYPERLINK "micro.doc" \l "blastomyces" Blastomyces  HYPERLINK "micro.doc" \l "candida" Candidiasis immunocompromised / yeasts Malassezia furfur parenteral alimentation (TPN) Torulopsis glabrata immunocompromised / smaller yeasts Pseudoallescheria boydii immunocompromised / hyphae Parasite: ascariasis, filariasis,  HYPERLINK "micro.doc" \l "vlm" VLM, paragonimiasis / transient infiltrates, moderate eosinophilia Nosocomial Pneumonia Incidence with mechanical ventilation 10-60% (mortality 30-70%) Prevention: semirecumbent position / continuous aspiration ventilator mechanism Use lower threshold of positive PCB culture 10e2 (not 10e3) Usual organisms: Pseudomonas, Acinetobacter, gram positives Treatment: piperacillin/tazobactam +/- cipro ceftazidime/tobramycin meropenem may need to add vancomycin if MRSA suspected Aspiration pneumonia Community acquired: anaerobes (necrosis, abscess,  HYPERLINK \l "empyema" empyema, pyopneumothorax) Nosocomial: GNR, S. aureus CXR: infiltrate in dependent lung segment (often superior segment of a lower lobe R > L; or posterior segment of an upper lobe) Treatment: Community acquired: clindamycin or metronidazole + b-lactam Nosocomial: aminoglycoside or ciprofloxacin + antipseudomonal B-lactam or clindamycin + aztreonam Pneumococcus ( HYPERLINK "micro.doc" \l "pneumococcus" see micro) T! of bacteremic community-acquired pneumonias / sporadic (most in Winter) / 5 to 25% of healthy persons are carriers / > 80 serotypes (type 3 is worst) / stages: congestion ( red hepatization ( gray hepatization ( resolution Presentation: often preceded by a URI / sudden onset, single shaking chill; persistent chills suggest another diagnosis / fever (38-40.5 C / 100.4-105 F), pain with breathing on the affected side (pleurisy), cough, dyspnea, and sputum / pain may be referred and, with lower lobe involvement, may suggest intra-abdominal sepsis, such as appendicitis / HR 100-140 / nausea, vomiting, malaise, and myalgias / dry cough ( purulent, blood-streaked or rusty sputum Complications : progressive pneumonia, ARDS, sepsis contiguous infection (e.g., empyema or purulent pericarditis) pleural effusions are found in about 25% of patients by chest x-ray, but < 1% have empyema. Bacteremia ( septic arthritis, endocarditis, meningitis, and peritonitis (in patients with ascites) pulmonary superinfections Diagnosis: clinical, CXR, sputum Cx / definitive diagnosis ( Cx of pleural fluid, blood, BAL CXR often with dense consolidation of single lobe (lobar pneumonia) with typical air bronchograms Prognosis: overall mortality rate is about 10%, and treatment has minimal effect on mortality during the first 5 days of illness / poor prognosis ( age extremes, especially < 1 yr or > 60 yr; positive blood cultures; involvement of > 1 lobe; a peripheral WBC count < 5000/L; presence of associated disorders (e.g., cirrhosis, heart failure, immunosuppression, agammaglobulinemia, anatomic or functional asplenia, and uremia); involvement of certain serotypes (especially 3 and 8); and development of extrapulmonary complications (e.g., meningitis or endocarditis). mildly ill usu. defervesce in 24-48 h; however, seriously ill patients, particularly those with the poor prognostic features noted above, often require e" 4 days to become afebrile. Therapy should not be modified if there is gradual clinical improvement and the etiology is confirmed. when patients do not improve, these factors should be considered: wrong etiologic diagnosis, adverse drug reaction, far-advanced disease (most common), superinfection, inadequate host defenses due to associated conditions, noncompliance with the drug regimen by outpatients, antibiotic resistance of the involved strain of S. pneumoniae, and complications, such as empyema requiring drainage or metastatic foci of infection requiring a higher dosage of penicillin (e.g., meningitis, endocarditis, or septic arthritis). Treatment respiratory supportive care, blood culture, antibiotics ceftriaxone or cefotaxime or cefepime levofloxacin or gatifloxicin or moxifloxicin vancomycin +/- rifampin Note: macrolides actually are active against pneumococcus, the issues is that they may be more active in tissue, and not provide adequate blood/CSF coverage (given high propensity of Pneumococcus toward bacteremia) Prevention: HYPERLINK "pharm.doc" \l "pneumovax"pneumovax Staphylococcus 2% of community-acquired pneumonias, 10-15% of nosocomial pneumonias Infants, elderly, hospitalized, debilitated patients, children, CF, bacterial superinfection (esp., influenza A and B, IVDA (Staph. tricuspid valve endocarditis ( embolic pneumonia) Presentation: usually fulminant, can be indolent (chronic pneumonia or chronic abscess) Like S. pneumo plus rigors, necrosis/abscess, pneumatoceles (esp. infants/children), a fulminant course /  HYPERLINK \l "empyema" empyema is common, esp. postthoracotomy, chest tubes after trauma Diagnosis: positive sputum, blood cultures, empyema fluid, BAL CXR: bronchopneumonia (+/- abscess, effusion); lobar consolidation is uncommon / pneumatoceles strongly suggest staphylococcus / embolic staphylococcal pneumonia is characterized by multiple infiltrates that occur at discontiguous sites and tend to cavitate; this pattern suggests an endovascular source (e.g., right-sided endocarditis or septic thrombophlebitis). Treatment: MRSA occurs in 30-40% of nosocomially acquired (and community-acquired MRSA is on the rise) / consider vancomycin / otherwise, use bacteriocidal agents: oxacillin or nafcillin or cephalothin or cefamandole / clindamycin and some quinolones have activity Prognosis: mortality generally 30 to 40%, in part due to the serious associated conditions most patients have / sometimes even in normal adults / response to antibiotics slow; convalescence is prolonged Group A Strep relatively rare cause of pneumonia / epidemic > sporadic / sometimes in associations with measles, chickenpox, pertussis, influenza, streptococcal pharyngitis, scarlet fever, or toxic shock syndrome Presentation: similar to S. pneumo, but maybe less bacteremic symptoms CXR: bronchopneumonia with large pleural effusion / lobular pneumonia / abscess Labs: may see significant increase in the  HYPERLINK "labs.doc" \l "aso" ASO titer with serial tests Prognosis: response to therapy tends to be slow, but overall mortality is very low Treatment: Penicillin G or cephalosporins, erythromycin, clindamycin / large pleural effusions are usually managed with repeated thoracentesis or closed catheter drainage / purulent collections and loculated effusions should be drained by tube thoracostomy GNR Only 2% of CAP but most nosocomial pneumonias / infants, the elderly, alcoholics, and debilitated or immunocompromised hosts (esp. neutropenia) / happens because sick patients oropharynx are colonized with GNR and then all they have to do is microaspirate Organisms:  HYPERLINK "micro.doc" \l "klebsiella" Klebsiella 1st, Pseudomonas, E. coli, Enterobacter, Proteus, Serratia, Acinetobacter Presentation: similar to other pneumonias except more rapid decline, abscess formation Diagnosis: clinical context (neutropenia, nosocomial pneumonia) / false positives from upper airway colonizers a problem (esp. if already received antibiotics then sputum superinfection must be distinguished from patient superinfection) / positive cultures from blood, pleural fluid, or BAL Treatment: cephalosporin (cefepime, Fortaz?) or imipenem or ciprofloxacin (or levaquin?) or Zosyn or Timentin +/- AG H Influenza Treatment: 30% of H. influenzae strains produce -lactamase and are resistant to ampicillin Bactrim 1 or 2 DS 160/800 mg bid or cefuroxime 0.25 to 1 g IV q 6 h or cefaclor 500 mg po q 6 h for adults or doxycycline 100 mg po bid / fluoroquinolones and azithromycin also active Vaccine: H. influenzae type b (Hib) conjugate Chlamydia ( HYPERLINK "micro.doc" \l "Chlamydia" see micro) Presentation: similar to mycoplasmal pneumonia (pharyngitis, bronchitis, pneumonitis, cough, fever, sputum production but are not seriously ill) C. pneumoniae has been found in 5 to 10% of older adults with community-acquired pneumonia and often produces disease severe enough to require hospitalization. This organism has also been implicated in 5 to 10% of cases of nosocomial pneumonia, but relatively little is known about its epidemiology. C. trachomatis is a common cause of pneumonia in infants aged 3 to 8 wk but is not an important cause of pneumonia in older children or adults. Diagnosis: clinical but can culture, direct IF, PCR, serological Treatment: macrolide or tetracycline x 10-21 days Course: response is slower than mycoplasmal pneumonia; symptoms recur if therapy is discontinued prematurely; young adults do well, but mortality in the elderly is 5-10% Psittacosis ( HYPERLINK "micro.doc" \l "chlamydia" micro) Viral Pneumonia Children:  HYPERLINK "micro.doc" \l "rsv" RSV, parainfluenza virus, influenza A and B Adult: influenza A and B > adenovirus > VZV, EBV< coxsackievirus, Hantavirus Elderly: influenza, parainfluenza, RSV Immunocompromised: same as above plus CMV Presentation: bronchitis, bronchiolitis, pneumonia; usu. headache, fever, myalgia, cough, may have mucopurulent sputum Diagnosis: clinical and/or epidemiological (during flu season, associated exanthems, etc.) CXR: interstitial pneumonia or peribronchial thickening; lobar consolidation and pleural effusions uncommon (unless bacterial superinfection) Labs: WBC can be low or elevated Treatment: depends on suspected cause ( HYPERLINK "micro.doc" \l "hsv" anti-HSV meds,  HYPERLINK "micro.doc" \l "vzv" VZV,  HYPERLINK "micro.doc" \l "cmv" CMV (?add CMV-Ig), influenza); also must cover if suspected superimposed bacterial (usu. staph and strep) Pneumocystis carinii (PCP) ( HYPERLINK "micro.doc" \l "pcp" see micro) Compromised Host Ddx for non-infectious causes: pulmonary hemorrhage, pulmonary edema, radiation injury, pulmonary toxicity due to cytotoxic drugs, and tumor infiltrates Localized: bacteria, mycobacteria, fungi, or Nocardia sp Diffuse interstitial: viral, PCP, drug or radiation injury, pulmonary edema Diffuse nodular lesions: mycobacteria, Nocardia sp, fungi, or tumor Cavitary: mycobacteria, Nocardia sp, fungi, bacteria Transplant recipients with bilateral interstitial pneumonia: CMV Pleura-based consolidation: aspergillosis Post-Op Pneumonia More with thoracic or abdominal surgery / usual pathogen in empyema after chest surgery is Staphylococcus aureus. About 40% of posttraumatic pneumonias are complications of fractured ribs or chest trauma; the rest are divided about equally among skull fractures or other head injuries, other fractures, burns, and major contusions / only about 10% of such infections follow operations performed under local or IV anesthesia Causes: GNR, S. aureus, pneumococci, Haemophilus influenzae, or combinations of these. Lung Cancer Presentation: fever, chest pain, weight loss, fatigue, weakness, decreased activity, worsening cough, dyspnea, decreased appetite, weight loss, and pain / malignant serosanguineous pleural effusions are common and are often large and recurrent. Diagnosis (also see  HYPERLINK \l "spn" SPN below) [ HYPERLINK "http://content.nejm.org/cgi/content/full/352/26/2714" NEJM] CXR (mass, effusion) bronchial narrowing and irregularity, parenchymal infiltration, or atelectasis. Cavitation may be visible in an obstructed area or within a peripheral tumor. Pleural effusions are often associated with infiltrating or peripheral tumors thoracentesis (60% yield in NSCLC; would be IIIB T4) / pH usu. > 7.3 (< 7.2 worse prognosis) / WBC < 4000 cells/mm3 (< 25% neutrophils; more suggests infection) CT (chest, head, liver) bronchoscopy MRI (its role is evolving) CT (still debated whether screening is beneficial or cost-effective 3/07) bone scan LFT bronchial biopsy, washings mediastinoscopy with lymph node biopsy exploratory thoracotomy required in < 10% of cases to establish the diagnosis (if any evidence of mets, probably no benefit; such as lymph nodes, skin, liver, pleura) Ddx: foreign bodies, nonsegmental pneumonia, endobronchial and focal pulmonary manifestations of TB, systemic mycoses, autoimmune disease, metastatic disease caused by an extrathoracic primary cancer. Solitary pulmonary nodules are difficult to differentiate. Metastases to the lungs are common from primary cancers of the breast, colon, prostate, kidney, thyroid, stomach, cervix, rectum, testis, bone and melanoma Treatment: radiation / chemotherapy (see other sources) Primary Lung Cancer Staging: T - location (3 cm cutoff) N - nodes involved M - metastases (brain, bone, liver) CXR: concave (good), convex (bad) Smokers (85%) squamous, small cell, adenocarcinoma, large cell Non-smokers (15%) T! are adenocarcinoma (even most adenocarcinomas are from smoking), bronchoalveolar adenoma, other Central ( squamous, small cell, adenocarcinoma (!) Peripheral ( large cell, adenocarcinoma (!) Pattern of spread all types also commonly spread via the lymphatics / large cell also more through bloodstream Bronchogenic Carcinomas (SCLC vs. NSCLC) divided into small cell and non-small cell (adenocarcinoma, large cell, squamous cell) Note: treatment is chemotherapy and/or radiation for SLCL (rarely surgery) and resection (if possible) and/or chemo for NSCLC / 10% of NSCLC develop some form of  HYPERLINK \l "hoa" HOA (Pierre-Marie-Bamberger syndrome) [ HYPERLINK "pics/hoa-bonescan.jpg" pic] Small Cell Carcinoma (SCC) (20%) central oat cell / metastases / smoking / often secrete ectopic hormones (SIADH, ACTH) causing symptoms of hypokalemia (ACTH) or hyponatremia (ADH) / hemoptysis uncommon Associations:  HYPERLINK \l "LambertEaton" Lambert-Eaton syndrome Treatment: chemotherapy (not resectable) / 20% can be cured if caught very early Squamous Cell Carcinoma (30%) central metastasis uncommon / smoking / PTH-related (PTHrP) ( hypercalcemia / HOA with clubbing Adenocarcinoma (35%) peripheral > central characteristic HOA w/ clubbing / makes up 70% of lung cancers in non-smokers Large Cell (10%) peripheral smoking / usually spreading through the bloodstream Bronchoalveolar adenoma peripheral not associated with smoking / multifocal origin but often does not extend beyond the lungs / watery, profuse, blood-streaked hemoptysis Bronchial carcinoid (5%) benign or malignant / male = female Complications: may obstruct lumen, frequent bleeding, recurrent pneumonia, pleural pain /  HYPERLINK \l "carcinoid" carcinoid syndrome (3%) Course: prolonged / mets (uncommonly) to regional lymph nodes Pancoast tumor refers to an apical carcinoma causing  HYPERLINK \l "pancoast" pancoast syndrome Other Lung Tumors Lymphoma usually solitary, can be multifocal Sarcoma malignant Carcinosarcoma Kaposis sarcoma (see HIV) Adenoid cystic .5% Mucoepidermoid carcinoma .2% Malignant fibrous histiocytoma Melanoma Blastoma Mucoepidermal Angiomas may regress Squamous papillomatosis often recur Benign Tumors Chondromatous hamartoma popcorn or bulls eye pattern of calcification / cartilage, connective tissue, epithelium Sclerosing hemangioma 80% female / calcification on X-ray / blood spaces Horners syndrome invasion of the cervical thoracic sympathetic nerves (paravertebral stellate ganglion) (often by lung cancer) Findings: enophthalmos, miosis, ptosis, ipsilateral facial anhidrosis, narrowing of palpedral fissure [HYPERLINK "pics/eye-horners.jpg"pic][HYPERLINK "pics/eye-horners1.jpg"pic][HYPERLINK "pics/eye-horners2.jpg"pic] Ddx: brainstem or posterior circulation CVA, carotid artery dissection, cavernous sinus thrombosis, trauma, metastatic disease Pancoast syndrome infiltration of brachial plexus and neighboring ribs and vertebrae, may involve phrenic nerve / Findings: pain, numbness, and weakness of the affected arm and/or Horners syndrome (see above) Superior vena cava syndrome (SVC syndrome or SVCS) obstruction of venous drainage ( dilation of collateral veins in upper chest, neck ( edema and plethora of face, neck, upper part of the torso, including the breasts; suffusion and edema of the conjunctiva; breathlessness when supine; CNS symptoms (headache, visual distortion, MS, dizziness, syncope); dysphagia, hoarseness Causes: lung cancer (small cell, squamous cell), other malignant neoplasms (lymphoma, Hodgkins disease, small cell carcinoma, squamous cell carcinoma, germ cell tumors, and breast cancer),  HYPERLINK "micro.doc" \l "mtb" TB, fungal infections, retrosternal thyroid, aortic aneurysms, fibrosing mediastinitis, benign tumors Treatment: if airway impaired, may need urgent bronchoscopy with stenting, surgical consultation / if lymphoma strongly suspected, may begin steroids even before tissue diagnosis Hematogenous metastatic spread to the liver, brain, adrenals, and bone Paraneoplastic syndromes hypertrophic pulmonary osteoarthropathy (the best known), clubbing of the fingers and toes and periosteal elevation of the distal parts of long bones occur. All levels of the nervous system may be affected--principally causing encephalopathy, subacute cerebellar degeneration, encephalomyelitis, the CNS paraneoplastic 60% become symptomatic (CNS-wise) wise before any symptoms from primary tumor occur can test for variety of antibodies [ HYPERLINK "pics/paraneoplasticantibodies.jpg" table]; no specific antibodies are found in 40% (that may change) may use PET scan or MRI to locate mets or primary [ HYPERLINK "pics/breastcancermets-mri.jpg" MRI] (note can have false positive on axilla of side of injection of tracer material) Eaton-Lambert syndrome ( HYPERLINK \l "LambertEaton" see other) and peripheral neuropathy Paraneoplastic cerebellar degeneration [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/6/612" NEJM] may present as progressive cerebellar ataxia [ HYPERLINK "pics/progressivecerebellarataxia-ddx.jpg" table] / 20% have mild memory and cognitive impairment (paraneoplastic limbic encephalitis), new onset seizures (complex partial) Associated malignancies: small cell lung cancer > breast, ovarian, testicular, Hodgkins MRI: patchy increased T2 without enhancement on T1 distinguishes from brain tumor, other / Purkinje cell dropout in cerebellum shows as atrophy EEG: focal temporal sharp waves Labs: antineuronal nuclear antibody type 1 (ANNA-1, anti-Hu) usu. positive with SCLC anti-Yo seen with breast, ovarian tumors anti-Tr, anti-glutamate receptor antibodies Polymyositis and dermatomyositis metabolic syndromes due to production of substances with hormonal activity Small cell carcinomas may secrete ectopic ACTH, resulting in Cushings syndrome, or ADH, causing water retention and hyponatremia, and are also associated with the carcinoid syndrome (flushing, wheezing, diarrhea, and cardiac valvular lesions). Squamous cell carcinomas may secrete parathyroid hormone-like substances that produce hypercalcemia. Other endocrine syndromes associated with primary lung carcinomas include gynecomastia, hyperglycemia, thyrotoxicosis, and skin pigmentation. Hematologic disorders, including thrombocytopenic purpura, leukemoid reaction, myelophthisic anemia, polycythemia, and marantic thrombosis, may also occur. Findings: gynecomastia, skin pigmentation Other associations: thyrotoxicosis, TTP, leukemoid reaction, polycythemia, myelophthisic anemia Single Pulmonary Nodule (SPN) 50% (< 3 cm) prove malignant / coin lesion without surrounding atelectasis or adenopathy Benign: 80% infectious granulomas, 10%  HYPERLINK \l "hamartoma" hamartomas, 10% other Malignant: > 3 cm is probably malignant; most are  HYPERLINK \l "bronchogeniccarcinoma" bronchogenic carcinoma Ddx: Coccidioides, Histoplasma, Tb, RA, Wegeners Bayesian approach ( pre-test risk of malignancy vs. need for early removal / if patient < 35 yrs, non-smoker, can follow radiographically first Risk factors: age, smoking, hemoptysis, size, edge characteristics on CT, prior malignancy Other: carcinogens, travel, endemic mycoses, prior lung disease Guidelines for following: constantly changing; (~4-8 mm seems to be a size parameter below which the optimal frequency of repeat CT is debated) CXR: size / growth rate / margin: corona radiata (80-90% malignant) calcification: laminated or central ( granuloma popcorn ( hamartoma diffuse ( benign eccentric/stippled ( malignant less specific ( cavitations [HYPERLINK "pics/cavitation-consolidation-ct.jpg"CXR], satellite lesions CT: more sensitive for other lesions, calcifications, guiding TNAB if thought to be benign ( < 35 yrs, stable for 2 yrs, classic calcification pattern) ( repeat CXR q 3 months for 1st yr, q 4-6 mo for 2nd year if thought to be malignant ( VATS ( frozen ( thoracotomy/lobectomy indeterminate (usually will prove malignant) PET (18FDG PET scanning): has 95% sensitivity, 75% specificity (also good for demonstrating positive nodes) / false negatives more likely with tumors < 1 cm, bronchoalveolar carcinomas, carcinoid tumors / false positives from inflammation Bronchoscopy (better for central): sensitivity 80% > 3 cm (50% peripheral) / 2-3 cm (40-60% yield) / < 1.5 cm (10% yield) Transthoracic needle biopsy (better for peripheral): 80-95% sensitivity, 50-85% specificity; better than bronchoscopy for peripheral lesions Pulmonary Cystic Disease Real vs. paracysts / < 3 mm in size emphysema bronchiectasis honeycombing basilar: IPF, RA, scleroderma,  HYPERLINK \l "asbestosis" asbestosis apical: Langerhans (20-40 yrs, upper>lower), Sarcoid (peripheral or bronchovascular), LAM (women) Reactive Airway Disease (Asthma) [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/21/2226" NEJM] Intrinsic: physical or infections Extrinsic: inhalants or (rarely) food Early: 10-20 mins / 1 to 2 hrs / IgE Late: 3 to 4 hrs / 12 hrs / inflammatory infiltrates / reversible bronchoconstriction / viral, allergens, stress, parasympathetic response to rhinitis, reflux (GERD) or other Epidemiology: most common pulmonary disease in children / most common reason for pediatric hospitalization / 90% of RAD present < 6 yrs Presentation: may have history of wheezing with URIs and exercise, nighttime, early AM coughing Common precipitates: cigarette smoke, pet dander, dust, mites, weather changes, and seasonal or food allergies Exam (during acute asthma attack): cough, dyspnea, wheezing, tachypnea, subcostal retractions, nasal flaring, tracheal tugging and a prolonged expiratory phase, pulsus paradoxus, hypoxemia, decreased I/E / mental status changes, hypercarbia indicate impending respiratory arrest CXR: normal to hyperinflation / lung markings commonly increased (more in chronic) / atelectasis most often affects RML / flattening of the diaphragm / exacerbations may see segmental atelectasis Diagnosis: clinical +/- confirmatory tests (PFTs vs. methacholine) 12 to 20% ! FEV1 w/ bronchodilators considered significant / absence of response to single bronchodilator exposure does not preclude benefit to maintenance therapy methacholine challenge causes bronchoconstriction in 95% of patients with RAD (20% decrease in FEV1) / can reverse it faster with B2 agonists / false positives may occur in 7% of general population and also CHF, allergic rhinitis, viral URI, COPD, CF Peak flow meter take level for body size (set at 100%): 80% is significant / 50% is an emergency PFT: degree of airway obstruction and disturbance in gas exchange, measure response to inhaled allergens and chemicals, quantify response to drugs, follow patients over the long term Static lung volumes and capacities reveal various abnormalities, although these may not be detected when mild disease is in remission. Total lung capacity, functional residual capacity, and residual volume are usually increased. Vital capacity may be normal or decreased. Labs: eosinophilia (> 250 to 400 cells/L) / degree of eosinophilia often correlates with severity of asthma / reduction can reflect adequate treatment with corticosteroids Ddx (see below for more): viral pneumonia, bacterial pneumonia. foreign body aspiration, anaphylaxis/angioneurotic edema, bacteremia/sepsis Treatment: Mental Education: peak flow monitoring (peak flow decreases to < 80% of personal best ( go to twice-a-day monitoring; diurnal variation > 20% indicates airway instability and need to adjust regimen Remove/avoid: environmental triggers, aspirin (esp. with nasal polyposis, can also have this with NSAIDS rarely, tartrazine or yellow no. 5), sulfites (shrimp, red wine, beer), B-blockers Anxiety may be extreme in many stages of asthma because of hypoxia and the feeling of asphyxiation. Treatment of the underlying respiratory problems, including judicious use of O2 therapy, is the preferred approach, especially when conducted by calm, attentive, supportive medical personnel. The use of sedatives in nonintubated patients is associated with increased mortality and the need for mechanical ventilation Medications B-agonists relax bronchial smooth muscle, modulate mediator release (by increasing c-AMP), protect from many bronchoconstrictors, inhibit microvascular leakage, increase mucociliary clearance / side effects more common for oral agents because higher doses required (useful for nocturnal asthma)  HYPERLINK "pharm.doc" \l "albuterol" albuterol 2.5 mg in 3cc nebs q 2 hrs (short acting) Anticholinergics ( HYPERLINK "pharm.doc" \l "atrovent" ipratropium bromide) competitively inhibiting muscarinic cholinergic receptors / block reflex bronchoconstriction due to irritants or to reflux esophagitis Solumedrol 25 mg IV q 6 hrs (long acting)  HYPERLINK "pharm.doc" \l "cromolyn" Cromolyn to stabilize mast cell membrane (who will take medicine QID besides kids)  HYPERLINK "pharm.doc" \l "corticosteroids" Corticosteroids block late response (not the early response) to inhaled allergens and lead to subsequent bronchial hyperresponsiveness (bronchial hyperresponsiveness gradually decreases with long-term therapy) oral inhaled corticosteroids 4-6 hours onset, 5 day course recommended to decrease inflammation and reactivation, long-term use has a 5-10% incidence of oral candidiasis (use of spacer helps, rinse throat with water and spit)  HYPERLINK "pharm.doc" \l "Theophylline" Theophylline (a methylxanthine) relaxes bronchial smooth muscle and has modest anti-inflammatory activity. Mechanism unclear / inhibits intracellular calcium release decreasing microvascular leakage, inhibits late response, decreases eosinophils and T lymphocyte infiltration, increases myocardial and diaphragmatic contractility. Used for long-term control as adjunct to B-agonists / long-acting theophylline useful for nocturnal asthma / narrow therapeutic index and can cause severe adverse reactions (keel levels 10 - 15 g/mL (56 and 83 mol/L). Leukotriene modifiers: montelukast and zafirlukast (Singulair), selective competitive inhibitors of LTD4 and LTE4 receptors, and zileuton, a 5-lipoxygenase inhibitor. Taken PO for long-term control and prevention of symptoms in patients / zileuton may cause a dose-related increase in ALT or AST / montelukast does not. With zafirlukast, drug interactions mediated by cytochrome P-450 enzymes Mild intermittent short acting B2 agonists/ACh blockers PRN Mild persistent (> 2/wk) long acting B2 agonists (has come under debate) /ACh blockers / add inhaled steroids or cromolyn Moderate persistent (daily) B2 agonists (short and long) + inhaled steroids Severe persistent B2 agonist + oral steroids Acute RAD hospitalization 5 day PO steroid course nebulized epinephrine (B2 agonist) immediate bronchodilation Note: during severe respiratory distress, an elevated and rising PaCO2 would indicate impending respiratory failure. During tachypnea, a PaCO2 not well below 40 indicates poor ventilation. Recent Studies Salmetrol/Fluticasone combination better than single agent Fluticasone meta-analysis of 1377 patients, 7% increased FEV1, no adverse effects Fluticasone 4-24 weeks lung function >> nedocromil, theophylline, montelukast, 8% oral candidiasis, no significant HPA suppression Leukotriene inhibitors montelukast is good (Zafirkulast is not good) Differential Diagnosis in Children: Foreign-body obstruction (get inspiratory versus expiratory films), congenital malformations of the vascular system (e.g., vascular rings and slings) or of the GI and respiratory tracts (e.g., tracheoesophageal fistula), viral URI (see croup,  HYPERLINK \l "rsv" RSV), bronchiolitis, bronchitis (rule out cystic fibrosis, immunodeficiency disease, ciliary dyskinesia syndrome) Differential Diagnosis in Adults COPD, heart failure, multiple small pulmonary emboli occasionally cause wheezing, hypersensitivity pneumonitis (more constitutional symptoms, not wheeze, except in allergic bronchopulmonary aspergillosis), bronchial obstructions (malignancy, aortic aneurysm, endobronchial TB, or sarcoidosis) occasionally present with wheezing, upper airway obstruction due to vocal cord dysfunction (can be diagnosed w/ bronchoscopy) More rare( carcinoid syndrome, Churg-Strauss syndrome, and eosinophilic pneumonias such as tropical eosinophilia and other parasitic infestations like Strongyloides stercoralis (steroids can cause  HYPERLINK "micro.doc" \l "strongyloides" hyperinfection syndrome) Churg-Straus Angiitis ( HYPERLINK \l "churgstrauss" see vasculitides) Hypersensitivity Lung Diseases Hypersensitivity pneumonitis / dust from actinomycetes, fungus, avian proteins Acute onset: cough, dyspnea, fever, chills, myalgias / 4 to 8 hrs Subacute onset: dyspnea on exertion and dry cough over weeks to months Chronic: dyspnea, weight loss, anorexia Complications: chronic hypoxemia, clubbing, pulmonary hypertension, pulmonary fibrosis Diagnosis: CXR may or may not show reticulonodular infiltrates HRCT shows ground-glass infiltrates in lower lobes / may see centrilobular infiltrates as well / chronic disease may have patchy emphysema Labs: IgG present, but not specific; peripheral eosinophilia not a feature; may see lymphopenia and neutrophilia / tissue histology with loose, noncaseating granulomas Treatment: remove from exposure / bronchodilators and antihistamines are not effective; steroids may help in severe cases; try moderate dose then rapid taper Eosinophilic Asthmas CauseBronchial AsthmaPeripheral EosinophiliaSystemic InvolvementPrognosis Acute Eosinophilic Pneumonia?NoneNormal or highNo GoodChronic Eosinophilic Pneumonia? drugs parasitesYesUsually High (can be normal)RareGoodSimple eosinophilic pneumonia (Lofflers)? drugs parasites RareModerateRareExcellentHypereosinophilic syndrome?NoneHighAlwaysFairChurg-Strauss (Allergic Granulomatosis)? drugs?~alwaysHighCommonFair to PoorAllergic Bronchopulmonary AspergillosisAspergillus (usu. fumigatus)~ alwaysHigh No FairEosinophilia myalgiaContaminated L-tryptophanNoneHighUsualGoodTropical eosinophiliaParasitesOccasionalHighOccasionalGood Chronic Obstructive Pulmonary Disease (COPD) Emphysema: abnormal permanent enlargement of the airspaces distal to the terminal bronchioles with destruction of their walls and without obvious fibrosis Risk factors: cigarette smoking, air pollution, hyperresponsive airways,  INCLUDEPICTURE "http://a1412.g.akamai.net/7/1412/430/1153e6d4ae4d85/www.merck.com/pubs/mmanual/images/salpha.gif" \* MERGEFORMATINET 1-Antitrypsin deficiency Classification (not much clinical utility): panacinar emphysema (PAE) increased compliance centrilobular emphysema (CLE) most common form in smokers / affects upper, posterior > bases / decreased compliance distal acinar emphysema (paraseptal or subpleural emphysema) subpleural or along fibrous interlobular septa / rest of the lung often spared, so lung function may be well preserved despite many foci of locally severe disease / often in apices / can cause spontaneous pneumothorax in young persons and may produce giant bullae (bullae = airspaces e" 1 cm, may become huge, rarely large enough to compress lung tissue and severely impair lung function) Findings: barrel chest (increased AP diameter (TLC), but VC drops because RV increases) dyspnea, decreased breath sounds, hyperresonance, pink puffers / tachycardia / decreased I/E ratio / smoking (centroacinar, usually upper lobes) / increased risk for mucoid strain of Pseudomonas (fluoroquinolones for outpatient) / hemoptysis: first rule out lung cancer, but simple mucosal erosion more common Complications acute bronchitis (see below) acute respiratory failure in COPD is defined as an exacerbation accompanied by a PaO2 < 50 mm Hg or a PaCO2 > 50 mm Hg. PaCO2 rarely rises above 80 mm Hg unless patient has received O2 therapy. Mental state ranges from alert, anxious, agitated, and distressed to somnolent, stuporous, or comatose. Cyanosis is usually present unless the patient is receiving O2 therapy. Diaphoresis and a hyperdynamic circulation are typical. Breathing is labored, and the accessory respiratory muscles are in full use. pneumothorax should be suspected in any patient whose pulmonary status suddenly worsens cor pulmonale ( HYPERLINK \l "corpulmonale" see other) Diagnosis CXR: exclude Tb, lung cancer / overdistention of the lungs (low, flat diaphragm) / widening of the retrosternal airspace in lateral view, increase in angle formed by the sternum and diaphragm from acute to e" 90 / heart shadow tends to be long and narrow / excessively rapid tapering of the vascular shadows is a sign of emphysema but may be difficult to identify unless accompanied by obviously hyperlucent lungs / RVH may or may not be apparent / may see prominent hilar vascular shadows / bullae reflect local severe disease (may not correlate with overall disease) / presence of diffuse (acute) infiltrate makes it easier to see changes of emphysema (air spaces and lack of apical vascularity) HRCT: shows all of these things in more detail [HYPERLINK "pics/emphysema-consolidation-airfluid-ct.jpg"pic] PFT: FEV1 and the FEV1/FVC fall progressively as the severity of COPD increases / ABG: usually takes FEV1 < 50% predicted or < 1.5 L in order to cause hypercapnea (chronic CO2 retainer) EKG may show RAD, echo can estimate PAH Treatment: Specific therapy: eliminate risk factors, smoking cessation Drugs: bronchodilators (long-acting inhaled B-agonists or LABAs) anticholinergics (ipratropium; tiotropium) (mostly stays in lungs) corticosteroids (can sometimes have a role; no simple guidelines; current trend is inhaled steroids help QOL/fewer exacerbations for FEV1 < 50%) B-agonists (with no cardiac problems) DO NOT give B-blockers (can cause cor pulmonale) or digitalis (causes problems) antibiotics for acute COPD exacerbations (sometimes prophylactically) Trends: current thinking is to get best QOL (fewer exacerbations, etc.) is to use combination  HYPERLINK "pharm.doc" \l "tiotropium" tiotropium + LABA 1/07; GOLD guidelines for FEV1 < 80%) Immunizations Oxygen Supplementation: maintain O2 saturation above 90% (corresponds to p O2 of 60) / be careful not to give too high oxygen (dont try to correct O2 too rapidly, take several days) / Medicare pays if P02 < 55 on RA Problems with O2 use: removal of respiratory drive in pts with baseline C O2 retention too high O2 messes up VQ mismatch Haldane effect ionized to gaseous form of C O2? Phlebotomy for polycythemia Lung volume reduction surgery: remove bad areas to relieve good areas Pulmonary rehabilitation programs Treatment of  INCLUDEPICTURE "http://a1412.g.akamai.net/7/1412/430/1153e6d4ae4d85/www.merck.com/pubs/mmanual/images/salpha.gif" \* MERGEFORMATINET 1-antitrypsin deficiency (medical and single  HYPERLINK \l "lungtransplant" lung transplant) Treatment of complications Prognosis: death usu. caused by medical complication (acute respiratory failure, severe pneumonia, pneumothorax, cardiac arrhythmia, pulmonary embolism) / survival with severe disease is from several up to 15 yrs Alpha-1-antitrypsin deficiency ( HYPERLINK \l "a1at" see liver disease) specific type of emphysema / panacinar versus basilar Presentation: may present as bronchiectasis Treatment: can give a-1 AT infusions (once weekly; to maintain target level > 80 mg/dL Cystic Fibrosis mutations in cystic fibrosis transmembrane regulator (CFTR) / F508 most common Presentation: bronchiectasis, chronic airway inflammation, pancreatic insufficiency, male infertility (absence of vas deferens) Childhood: H influenzae, S. aureus Adult: Pseudomonas, Aspergillus (50% colonized; occasionally cause disease), Burkholderia (always pathogenic), atypical mycobacteria (usu. colonizers) Diagnosis: sweat chloride test (chloride > 70 meq/L positive; 1-2% false negative) / biopsies and imaging may show chronic tissue changes but not diagnostic Treatment: patients do much better when followed by CF specializing centers Bronchitis Acute bronchitis (infectious) [HYPERLINK "http://content.nejm.org/cgi/content/full/355/20/2125"NEJM] Causes: viral URI:  HYPERLINK "micro.doc" \l "influenzaa" influenza A, parainfluenza, adenovirus,  HYPERLINK "micro.doc" \l "rsv" RSV, rhinovirus, human metapneumonia virus bacterial:  HYPERLINK "micro.doc" \l "mycoplasma" Mycoplasma,  HYPERLINK "micro.doc" \l "bpertussis" B. pertussis,  HYPERLINK "micro.doc" \l "chlamydia" Chlamydia, B. dermatitidis Pathology: hyperemia then desquamation, edema, leukocytic infiltration, production of sticky or mucopurulent exudate / hypertrophy of smooth muscle and secretory epithelium / mucous plugging, resonant breath sounds, VQ mismatch from shunting, periodic exacerbations Presentation: preceded by URI: coryza, malaise, chilliness, slight fever, back and muscle pain, and sore throat / dry cough, nonproductive or mucopurulent sputum (frankly purulent sputum suggests superimposed bacterial infection) / can have burning substernal chest pain (aggravated by coughing) / fever of 38.3 to 38.8 up to 3-5 days (cough may continue for weeks) / persistent fever suggests complicating pneumonia / dyspnea (from airway obstruction), cyanosis, cor pulmonale and edema (late), blue bloaters Findings: scattered rhonchi, wheezing, occasional crackling or moist rales at the bases Diagnosis: influenza assay if indicated sputum culture likely unrevealing or showing underlying pulmonary disease (COPD, etc.) CXR if pneumonia suspected multiplex PCR testing being developed (for major causative bacteria) Treatment: cough suppressants / B2 agonists can be considered with bronchial hyperreactivity and steroids can be considered in patients with persistent cough ABG as needed antibiotics when there is concomitant COPD, purulent sputum, or persistent high fever PO macrolide or tetracycline or ampicillin 250 mg q 6 h trimethoprim-sulfamethoxazole 160/800 mg po bid may be given antivirals if  HYPERLINK "micro.doc" \l "influenzaa" influenza A tests positive or if testing unavailable but during epidemic or clinically suspected or children with severe RSV (no antivirals yet effective for other players 11/06) Acute irritative bronchitis may be caused by various mineral and vegetable dusts; fumes from strong acids, ammonia, certain volatile organic solvents, chlorine, hydrogen sulfide, sulfur dioxide, or bromine; the environmental irritants ozone and nitrogen dioxide; and tobacco or other smoke. Chronic bronchitis definition: chronic productive cough at least 3 months in each of 2 successive yrs for which other causes, such as infection with Mycobacterium tuberculosis, carcinoma of the lung, or chronic heart failure, have been excluded Cough-variant asthma in which the degree of bronchoconstriction is not sufficient to produce overt wheezing, may be caused by allergen inhalation in an atopic person or chronic exposure to an irritant in a person with relatively mild airway hyperreactivity. Management is similar to that of ordinary asthma. Restrictive lung disease decreased VC and TLC extrapulmonary poor mechanics / chronic enlarged tonsils and adenoids in young children pulmonary alveolar or interstitial fibrosis (FEV1/FVC > 90%, leads to cor pulmonale, HYPERLINK "pharm.doc" \l "bleomycin"bleomycin toxicity, gradual progressive dyspnea, cough) Note: overbagging can stop circulation X-ray may appear normal [HYPERLINK "pics/lungs1.jpg"pic] ARDS Mendelssohns syndrome Diffuse Alveolar Damage exudative stage proliferative stage - may follow exudative - honeycomb lung - may only take 10 days UIP - shorter course - fatal DIP - longer course - amenable to steroid treatment - desquamation is actually histiocytes Pneumoconiosis acute silicosis (quartz) CWP, pulmonary tuberculosis talcosis birefringent talc particles CWP dust macules coal nodules palpable Caplans syndrome fibrotic nodules Asbestosis ferruginous body - amphibole fiber (big) / chrysotile fiber (small) / hemosiderin accretions associated with malignant mesothelioma of pleural surface Obstructive Sleep Apnea (OSA) Epidemiology: 18 million Americans / EDS in 4% of men 2% women (30-65) / 82% of men and 93% of women with moderate to severe OSA are undiagnosed / 90% of men and 98% of women with mild to severe OSA and EDS are undiagnosed prevalence comparable to asthma Symptoms: daytime sleepiness (accidents, problems at work, etc.) / stentorian (loud) snoring / personality changes, impotence Mechanism: 87.5% - arousal threshold in NREM sleep / 79.5% - arousal threshold in REM sleep / other causes of REM apnea loss of tone in tongue and pharynx, loss of coordinated intercostal function, relative bradycardia Causes: HTN, change in voice, nasal obstruction, micrognathia, retrognathia, macroglossia (cleft palate), tonsillar hypertrophy, uvulopalatal enlargement/elongation, submucosal infiltration Note: tonsillar hypertrophy is most common cause of OSA in normal children (often misdiagnosed as ADHD) / snoring may increase risk of OSA (not proven) Obesity-hypoventilation syndrome (Pickwickian syndrome): obesity causes decreased compliance of chest wall / O2 decreased all the time (not just when sleeping) (OSA may or may not be concurrently present) / screen for hypothyroid / usefulness of progesterone debated Allergic rhinitis: 40% present (20% incidence in general population) Hypothyroidism: 5% present (decreased response to CO2, deposition of material increases obstruction) Diagnosis: polysomnography > 5 episodes/hour + daytime sleepiness / hypopnea (mild/sub apnea) / 1/07 current trend is to just begin therapy with positive ambulatory nighttime pulse oximetry testing (90% likely to achieve correct diagnosis; recheck in 2 weeks for clinical improvement and then get full sleep study if uncertain) Complications: HTN, LVH and heart failure, dilated cardiomyopathy and CHF, MI nocturnal cardiac disrhythmias (usu. bradycardia), sudden nocturnal death nocturnal pulmonary HTN, early sustained pulmonary HTN and RV failure with diurnal decreased paO2 and increased paCO2 (10% incidence) / Note: rarely causes RV dysfunction without underlying COPD association with renal disorders Treatment: CPAP (continuous positive airway pressure) [80% effective, eliminates mortality: treatment of choice; BIPAP is more expensive, doesnt improve compliance, not shown to be more efficacious] uvulopalatopharyngoplasty, tonsillectomy, other nasal and airway surgeries (40-50% effective), protriptyline 20-30 mg qhs, tracheostomy Central Sleep Apnea (CSA) Presentation: frequent awakenings, daytime sleepiness Causes: defect in respiratory muscle or metabolic control mechanism decreased respiratory drive: sleep onset, hyperventilation (idiopathic, hypoxic, pulmonary edema of CHF, CNS), prolonged circulation time of heart failure [CNS over-corrects before chemoreceptors appreciate signals] upper airway reflex inhibition: esophageal reflux, aspiration, upper airway collapse Diagnosis: polysomnography Treatment: nocturnal supplemental oxygen acidification with acetazolamide CPAP (under investigation, effective in CSA secondary to CHF, may increase paCO2) Bronchiectasis Acquired bronchiectasis Presentation: any age / starts early (childhood), symptomatic later / chronic cough/sputum production or sometimes asymptomatic / worsens over years / coughing boughts occur several times a day / sputum like bronchitis or more multi-layered / hemoptysis from capillary erosion (sometimes bronchial/pulmonary anastomoses) / recurrent fever or pleuritic pain (+/- pneumonia) / wheezing, SOB, etc and cor pulmonale with advanced cases (with bronchitis/emphysema) Specifics: severe pneumonia: Klebsiella, Staphylococci, influenza A virus, fungi, mycobacteria, mycoplasma (rarely) / pneumonia complicating measles, pertussis, or certain adenovirus bronchial obstruction from any cause (foreign body, adenopathy, mucus inspissations, lung tumors) chronic fibrosing lung diseases (e.g., aspiration pneumonia, injurious gases or particles (e.g., silica, talc, or bakelite) AIDS and other immunocompromised (less common cause) Aspergillus fumigatus has more central pattern Associations: RA, Sjgrens, Hashimotos, and UC is unexplained Pathophysiology: may be unilateral or bilateral / lower lobes >> right middle lobe and lingula > others / reduced lung volumes and airflow rates, VQ mismatch, hypoxemia / extensive anastomoses and enlargement of bronchial/pulmonary a. and v. can cause R to L shunt ( PHTN ( cor pulmonale Mechanism: bacterial endotoxins, proteases (bacterial/host), increased elastase, cathepsin G, and neutrophil matrix metalloproteinase (MMP-8), superoxide radicals, immune-complexes / IL-1B, IL-8, TNF-a and NO / depressed  INCLUDEPICTURE "http://a1412.g.akamai.net/7/1412/430/1153e6d4ae4d85/www.merck.com/pubs/mmanual/images/salpha.gif" \* MERGEFORMATINET 1-antitrypsin and antichymotrypsin direct bronchial wall destruction infection, inhalation of noxious chemicals, immunologic, vascular abnormalities interfere with bronchial nutrition mechanical alterations atelectasis or loss of parenchyma with increased traction on airways, leading to bronchial dilation and secondary infection) / Note: post-obstructive decrease in mucociliary clearance (poor ciliary motility) often promotes infection (does not require complete obstruction) Exam: persistent crackles, airflow obstruction (decreased breath sounds, prolonged expiration, or wheezing) / more pronounced in smokers / clubbing in severe, long-standing cases Diagnosis CXR: may show increased bronchovascular markings from peribronchial fibrosis and intrabronchial secretions, crowding from an atelectatic lung, tram lines (parallel lines outlining dilated bronchi due to peribronchial inflammation and fibrosis), areas of honeycombing, or cystic areas with or without fluid levels, but occasionally x-rays are normal HRCT (with or without contrast): dilated airways, indicated by tram lines, by a signet ring appearance with a luminal diameter > 1.5 times that of the adjacent vessel in cross section, or by grapelike clusters in more severely affected areas. These dilated medium-sized bronchi may extend almost to the pleura because of the destruction of lung parenchyma. Thickening of the bronchial walls, obstruction of airways (evidenced by opacification--e.g., from a mucus plug--or by air trapping), and, sometimes, consolidation are other findings. Bronchoscopy: rule out tumor, foreign body, or other localized endobronchial abnormality. Ddx:  HYPERLINK \l "cf" cystic fibrosis, immune deficiencies, bronchitis, mycobacterial, fungal, Mycobacterium avium-intracellulare, Young syndrome (men, sinopulmonary symptoms and infertility), PCD syndromes, immunoglobulin deficiencies (even when total levels of IgG or IgA are normal, some IgG subclass deficiencies have been associated with sinopulmonary infections),  INCLUDEPICTURE "http://a1412.g.akamai.net/7/1412/430/1153e6d4ae4d85/www.merck.com/pubs/mmanual/images/salpha.gif" \* MERGEFORMATINET 1-Antitrypsin ( INCLUDEPICTURE "http://a1412.g.akamai.net/7/1412/430/1153e6d4ae4d85/www.merck.com/pubs/mmanual/images/salpha.gif" \* MERGEFORMATINET 1-antiprotease inhibitor) deficiency, other congenital syndromes, yellow nail syndrome, allergic bronchopulmonary aspergillosis Treatment: treat active infections or underlying disorders / prophylactic or suppressive antimicrobial regimens (talk to pulmonologist) avoid smoking and irritants surgical resection rarely necessary but can be considered Congenital bronchiectasis failure to develop proper bronchi is a rare disease / Mounier-Kuhn syndrome, Williams-Campbell syndrome Kartageners syndrome bronchiectasis, situs inversus and sinusitis / accounts for 50% of a subgroup of primary ciliary dyskinesia (PCD) syndromes (defective mucociliary clearance) / chronic rhinitis, serous otitis media, male sterility, corneal abnormalities, sinus headaches, and a poor sense of smell Young syndrome obstructive azoospermia, chronic sinopulmonary infections, normal spermatogenesis, a dilated epididymal head filled with spermatozoa, and amorphous material without spermatozoa in the region of the corpus / does not have ciliary defect as in PCD Atelectasis usually basilar, acute or chronic Causes: O2, drug, or chemical toxicity; pulmonary edema; the adult or neonatal respiratory distress syndrome, pulmonary embolism, general anesthesia, mechanical ventilation, intraluminal bronchial obstruction, often due to plugs of tenacious bronchial exudate, endobronchial tumors, granulomas, or foreign bodies, bronchial strictures, distortion, or kinking; external bronchial compression by enlarged lymph nodes, a tumor, or an aneurysm; external pulmonary compression by pleural fluid or gas (e.g., due to pleural effusion or pneumothorax); and surfactant deficiency Diffuse microatelectasis (seen with early ARDS) not visible initially on CXR ( progresses to a patchy or diffuse reticular granular pattern, then to a pulmonary edema-like pattern, and finally to bilateral opacification in severe cases Rounded atelectasis (folded lung syndrome) often mistaken for a tumor / "comet tail" complication of asbestos-induced or other pleuropulmonary disease. Ddx: large effusion, pneumothorax Treatment (for acute): CPAP at 5 to 15 cm H2O PEEP bronchoscopy patients with established atelectasis should lie with the affected side uppermost to promote drainage (postural drainage) chest physical therapy encouraged to cough IPPB or an incentive spirometer Aspiration Chemical pneumonitis (aspiration pneumonitis) (Mendelsons syndrome) Presentation: acute dyspnea, tachypnea, tachycardia usu. 4-6 hours after aspiration of (usu.) gastric content (required sizeable aspiration) Findings: cyanosis, bronchospasm, fever, sputum often pink and frothy CXR: infiltrates (one or both (usu.) lower lobes) Treatment: Course: rapid recovery ( < 48hrs) or progression to ARDS or bacterial superinfection / mortality 30-50% Aspiration pneumonia ( HYPERLINK \l "aspirationpneumonia" see other) Mechanical obstruction aspiration of inert fluids or particulate matter children: vegetal (e.g., peanuts) esp. in adults: meat high obstruction is obvious, but more distal can present more insidiously, clues to diagnosis: CXR (taken during exhalation) may show atelectasis or hyperinflation of the affected lung partial obstruction with air trapping causes the cardiac shadow to shift away from the abnormal lung during this phase of respiration recurrent parenchymal infections in the same segment of lung Treatment: extract object, usually by bronchoscopy Lung Abscess Lung abscess: A localized cavity (usu. < 2 cm) with pus, resulting from necrosis of lung tissue, with surrounding pneumonitis putrid (due to anaerobic bacteria) or nonputrid (due to anaerobes or aerobes). Single > multiple (usu. unilateral; S. aureus becoming more common, esp. IVDA; suppurative venous thrombophlebitis due to aerobic or anaerobic bacteria) Causes: aspiration (alcohol, other drugs, CNS disease, general anesthesia, coma, or excessive sedation) usually anaerobes (esp. if periodontal disease) but can be variety of organisms (Klebsiella, Staphylococcus aureus, Actinomyces israelii, B-hemolytic strep, S. milleri (and other aerobic or microaerophilic streptococci), Legionella, or H. influenzae is sometimes complicated by abscess formation) immunocompromised (Nocardia, Cryptococcus, Aspergillus, Phycomycetes, atypical mycobacteria (primarily Mycobacterium avium-intracellulare or M. kansasii), or gram-negative bacilli, blastomycosis, histoplasmosis, coccidioidomycosis) septic pulmonary emboli, secondary infection of pulmonary infarcts, and direct extension of amebic or bacterial abscesses from the liver through the diaphragm into the lower lobe of the lung bronchogenic carcinoma cavitary TB Complications: bronchopleural fistula, ARDS Diagnosis CXR, CT, sputum (usu. only useful if transtracheal aspiration, transthoracic aspiration, or bronchoscopy with a protected brush) Ddx: cavitating bronchogenic carcinoma, bronchiectasis, empyema secondary to a bronchopleural fistula, TB, coccidioidomycosis and other mycotic lung infections, infected pulmonary bulla or air cyst, pulmonary sequestration, silicotic nodule with central necrosis, subphrenic or hepatic (amebic or hydatid) abscess with perforation into bronchus, Wegeners Treatment antibiotics (clindamycin or metronidazole) and/or as per suspected organisms / continue until pneumonitis has resolved and cavity has disappeared, leaving only a small stable residual lesion, a thin-walled cyst, or clear lung fields (usu. requires several weeks or months of treatment, much of which is given oral/outpatient) postural drainage, bronchoscopy and/or surgical drainage as indicated (always drain if empyema suspected) pulmonary resection if resistant to drugs, particularly if bronchogenic carcinoma is suspected / lobectomy versus segmental resection versus pneumonectomy (if really needed; mortality 5-10%) Pleurisy mechanism: underlying lung process (e.g., pneumonia, infarction, TB) / direct entry of infectious agent or irritating substance into the pleural space (e.g., with a ruptured esophagus, amebic empyema, or pancreatic pleurisy) / entry of infectious, noxious agent or neoplastic cells via the bloodstream or lymphatics / parietal pleural injury (e.g., trauma, especially rib fracture, or epidemic pleurodynia [due to coxsackievirus B]) / asbestos-related pleural disease / pleural effusion related to drug ingestion (rarely) Presentation: sudden pain is dominant symptom (usu. only when patient breathes deeply or coughs) / visceral pleura is insensitive (pain from inflammation of the parietal pleura innervated by intercostal nerves; usu. felt over pleuritic site but may be referred to distant regions; irritation of posterior and peripheral portions of the diaphragmatic pleura, supplied by the lower six intercostal nerves, may cause pain referred to the lower chest wall or abdomen and may simulate intra-abdominal disease; irritation of the central portion of the diaphragmatic pleura, innervated by the phrenic nerves, causes pain referred to the neck and shoulder) respiration is usually rapid and shallow / motion of the affected side may be limited / breath sounds may be diminished pleural friction rub, although infrequent, is characteristic sign (varies from a few intermittent sounds that may simulate crackles to a fully developed harsh grating, creaking, or leathery sound synchronous with respiration, heard on inspiration and expiration. Friction sounds due to pleuritis adjacent to the heart (pleuropericardial rub) may vary with the heartbeat as well pleural effusion (usu. occurs along with decrease in pleuritic pain) / larger effusion with all attendant clinical implications Diagnosis: clinical findings and picture (may get relief by pressure on chest wall by mechanical factors) / rule out other causes (many) CXR: cannot show pleurisy but may elucidate any underlying pulmonary infection, process Treatment: treat underlying process (antibiotics, etc) / try to avoid impairing respiration in patient with limited pulmonary function or mental status; encourage deep breathing and cough, but balance with desire to reduce pain with pain medication and/or if appropriate, wrapping chest in elastic bandages to reduce motion / bronchodilators may help Pleural Effusion Pleural fluid normal volume 10-20 mL 50 mL ( visible on lateral decubitus CXR 500 mL ( obscures entire diaphragm Physiology: similar composition to plasma (less protein, < 1.5 g/dL) / fluid enters from the pleural capillaries and exits via parietal pleural stomas and the lymphatics (obstruction of which causes pleural effusion) Note: etiology of an effusion is not established in about 20% of cases (in spite of efforts) CXR: duh. CT scan: lung abscess may be differentiated from an empyema with a bronchopleural fistula and an air-fluid level. Pleural plaques, mesothelioma readily identified / loculated pleural effusions clearly seen with CT MRI is not indicated. Ultrasonography: can identify and localize loculated pleural effusions Bronchoscopy: good VATS: needed to diagnosis pleural-based malignancies Thoracentesis ( HYPERLINK \l "Thoracentesis" see other) Indications: uneven/unilateral, evidence of infection, no cardiac disease, red flags for malignancy, need to evaluate parenchyma If you think you should do it, then do it (you lazy bastard) / what is the highest safe INR? Note: may remove up to 1500 cc without worrying about reexpansion pulmonary edema Visual clear yellow (serous) milky (chylous) blood-tinged (serosanguineous) grossly bloody (sanguineous) translucent or opaque and thick (purulent) LAB send for gram stain, chemical (pH, protein, LD), cell count, culture (bacteria/fungal/AFB), and cytology (the last uses tubes with heparin, 3 U/mL fluid, added) / pH must be sent on ice (pH < 7.2 or WBC > 100,000 = empyema), amylase, eosinophils (rarely in Tb or malignancy) Lights Criteria (exudate must have at least one of following): pleural fluid/serum protein ratio > 0.5, with pleural fluid protein usually > 3.0 g/dL pleural fluid/serum LDH ratio > 0.6 pleural fluid LDH > T! of the upper normal limit for serum Transudates ( HYPERLINK \l "transudates" causes) elevations in microvascular pressure or to decreases in oncotic pressure Exudates ( HYPERLINK \l "exudates" causes) inflammation (pleurisy) with an increased permeability of the pleural surface Glucose < 60 mg/dL ( parapneumonic, malignancy, Tb, hemothorax, Churg-Strauss, paragonimiasis, RA (usu. < 30, will have high RF too) < 40 mg/dL ( tube thoracostomy indicated Pleural fluid pH < 7.00 ( complicated parapneumonic effusion ( tube thoracostomy indicated > 7.20 ( may not need tube thoracostomy Other possible causes: systemic acidosis (normal glucose), esophageal rupture, RA, Tb, malignancy, hemothorax, paragonimiasis, Churg-Strauss, urinothorax (normal glucose) Note: must treat pH sample as ABG (heparinized tube, place in ice, transfer to lab immediately) Hemothorax > 15% of pleural transudates and > 40% of exudates are blood-tinged with RBC counts between 5,000 and 100,000/L (of little diagnostic significance) traumatic tap (Hct < 1%) > cancer, Tb, PE (Hct 1-20%) >> real hemothorax (Hct > 50%) (malignancy, PE, rupture of aortic aneurysm, rupture of vessel associated with spontaneous pneumothorax, coagulation defects) / pleural blood usually does not clot Treatment: water-sealed tube drainage / thoracotomy and decortication Chylothorax (a milky or chylous pleural effusion) traumatic or neoplastic (most often lymphomatous) injury to the thoracic duct (high TG content; sudanophilic fat droplets often seen microscopically; low cholesterol content) Labs: triglycerides > 110 mg/dL (1.24 mmol/L) Treatment: treat underlying cause Cholesterol effusion (chyliform or pseudochylous effusion) rare / golden and iridescent (light-reflecting cholesterol crystals, can be seen microscopically) Labs: high cholesterol up to 1 g/dL [26 mmol/L] / low neutral fat and FA follows long-standing chronic pleural effusion (i.e. Tb pleurisy or RA pleural effusion) cholesterol pleural effusion (not complete diagnosis, must seek cause) Eosinophilic effusions (<10%) often occur when there is air or blood in the pleural space / causes: drug reactions, benign asbestos-related effusions, collagen vascular diseases, pulmonary embolism, parasitic infections (paragonimiasis, echinococcosis, filariasis, and toxocariasis) or idiopathic Conditions Causing Transudates Heart failure most common / right sided 1st, then bilateral Hypoalbuminemia usually bilateral / associated with whole body edema Ascites diaphragmatic defects or lymphatic channels 70% right-sided, 15% left-sided, and 15% bilateral occur in about 5% of patients with cirrhosis and ascites /  HYPERLINK \l "meigs" Meigs syndrome (more exudative, similar mechanism as pleural effusion with peritoneal dialysis, acute Pancreatitis) Myxedema usually transudates, may be exudates Post-parturition small effusions that clear within 1st 24 h Iatrogenic subclavian vein / misplaced feeding tubes (perforated bronchus) PE may be transudate or exudate / rarely large / often bloody Malignancy secondary to decrease drainage from obstructed lymphatics Conditions Causing Exudates PE Pneumonia Fungal Viral Parasitic Neoplasia Mesothelioma Drug-induced RA Acute pancreatitis Post-cardiac Pulmonary embolism ( HYPERLINK \l "pe" see other) 30 to 50% of cases / 80% of PE effusions are exudates (often blood-tinged) / increased permeability of visceral pleura over infarcted lung (1/3 w/out evidence of infarction on CXR) Pleural effusions and pneumonia textbook says bilateral effusions (other than PCP) are almost never from pneumonia, but I have seen a lot of patients with bilateral effusions and pneumonia (in some cases the effusions were probably from another source, but sometimes it appeared as though they were from the infection itself) effusions are not an indicator of severity of infection (unless via compromise of respiratory function) outpouring of serous exudative fluid accompanies acute pleurisy usually bacterial, but small effusions can occur with mycoplasmal and viral pneumonia (virus can cause effusion without evidence of pneumonia) Organisms prone to cause empyema (rather than effusion) are S. pneumo, S. aureus and Klebsiella Specific examples Group A strep ( large, unilateral pleural effusions Pneumococcus ( smaller node infusions H. influenza ( 2/3 have mild-moderate pleural effusions Tularemia ( hemorrhagic effusions (other organisms generally do not do this) Tb ( usu. self-limited ( HYPERLINK "micro.doc" \l "tb" see Tb), many small mature lymphocytes (few mesothelial cells) Empyema Treatment: high doses of IV antibiotics and chest tube drainage (see below) water-sealed tube thoracostomy usually preferable if lined by a thick, organizing, fibrinous exudate or cortex, surgical decortication by is the best way to expand the lung and obliterate the space ( HYPERLINK "pharm.doc" \l "tpa" fibrinolytics only recommended in poor surgical candidates or if surgery must be delayed) decortication for a loculated empyema is best performed within the first 3 to 6 wk of the illness using thoracotomy or VATS (may also be needed for bronchopleural fistula) Chest Tube Indications: empyema, positive gram stain, loculations, pH < 7.10, glucose < 40, LDH > 1000 Course: keep drain until drainage < 50 ml/day Fungal pleurisy - exudate Diagnosis: geographic history, skin and serologic tests, sputum cultures, biopsy may show granulomas, histology of other tissues are useful in establishing a diagnosis Blastomycosis ( ~10% of cases, usually with extensive underlying parenchymal disease Primary coccidioidomycosis ( usually large, unilateral, ~7% of cases, 50% with parenchymal lesion / EM or EN is common / can also occur at a later stage when coccidioidal cavity ruptures (serious complication) rare in primary histoplasmosis and cryptococcosis (occurs with dissemination or massive lung involvement) Metastatic neoplasms most common in > 60 yrs primary: lung >> breast >> any carcinoma / lymphatic obstruction findings: large, cause DOE, small or large amount of blood, mostly exudates / 10% of malignant pleural effusions have slightly to moderately elevated amylase may take 2 or 3 samples to get diagnosis by cytology / pleural biopsy less sensitive (but can be positive when cytology is negative) Diagnosis: pleural biopsy rarely positive / fluid cytology or needle biopsy sometimes positive Hodgkins ( lymphatic obstruction NHL ( pleural infiltration / may be presenting sign Treatment: pleurodesis (using sclerosing agent, asbestos-free talc, doxycycline, tetracycline derivative) to reduce reaccumulation of fluid. Malignant mesothelioma asbestos exposure / 2000 cases/yr / smoking makes worse Presentation: insidious nonpleuritic CP and dyspnea, pleural effusion in 75% of cases CT ( irregular thickening of pleura Diagnosis: cytology may reveal malignant cells not easily differentiated from adenocarcinoma (any unexplained pleural effusion calls for pleuroscopy with biopsy even with negative cytology)/ needle biopsies usually equivocal (often must do VATS) / IF and EM differentiates from adenocarcinoma Pleural fluid: serous or blood-tinged exudate, glucose < 50 mg/dL, pH < 7.2 in ~1/3 Prognosis: horrible (< 2 yrs), poor response to radical surgery, chemotherapy, XRT, or combination therapy Benign fibrous mesothelioma rare solid tumor / CP, dyspnea, fever, HOA (50%) / exudate may be viscid (hyaluronic acid) Diagnosis and cure are by thoracotomy and excision SLE or drug-induced lupus syndromes (HYPERLINK \l "sle"see SLE) Drugs: hydralazine, procainamide, INH, phenytoin, and chlorpromazine produce pleural effusions in up to 40% of patients / usually long usage, symptoms decrease < 10 days after discontinuation Presentation: fever, pleuritic pain, and some systemic manifestations of SLE / rarely with isolated pleural disease / parenchymal lesion usually but not always present / exudative, with neutrophils predominating early and monocytes late Pleural Fluid: glucose > 80 mg/dL, pH is > 7.35, LDH is < 500 IU/L, C3/C4 low, ANA high ( > 1:320 homogeneous or fluid/serum ratio > 1 is very suggestive) / LE cells may be found and are thought to be diagnostic (but very expensive and not really necessary) Note: unlike classic SLE, Ab to histones and ssDNA often occur in the blood Drug-induced pleural effusions (uncommon) Nitrofurantoin occasionally causes acute fever, pulmonary infiltrates, pleural effusion, peripheral eosinophilia / even less often (with long-term use), can cause chronic interstitial pneumonia with fibrosis causing pleural effusions Dantrolene occasionally causes unilateral pleural effusion, blood/pleural fluid eosinophilia (but without parenchymal infiltration Others: dopamine agonists (Bromocriptine),  HYPERLINK "pharm.doc" \l "amiodarone" amiodarone, and IL-2 infrequently cause pleural effusions, usually with pulmonary infiltrates Rheumatoid disease More in males (older with long standing RA) / small to moderate in size / exudates / cholesterol crystals are common Labs: low glucose (< 40 mg/dL), high LDH (> 700 IU/L), low pH (< 7.2), low C3/C4, high RF ( > 1:320) Subdiaphragmatic abscess sympathetic pleural effusion / sterile exudate mostly neutrophils / rarely becomes infected / occur weeks/months after abdominal surgery / Diagnose with US or abdominal CT Acute Pancreatitis ( HYPERLINK \l "pancreatitis" see other) para-ascitic pleural effusion in ~10% of cases exudates / usually small in size / ~60% left, 30% right, 10% bilateral many neutrophils, high amylase Pancreatic pseudocysts may enter mediastinum through aortic/esophageal hiatus and rupture into one/both pleural spaces Labs: very high amylase (up to 100,000 IU/L), even though serum amylase may be normal Abdominal US and CT are useful / must drain pseudocyst as fluid reaccumulates rapidly after thoracentesis Postcardiac injury syndrome Presentation: fever, pleuropericarditis, and parenchymal infiltrates beginning weeks after injury to the pericardium or myocardium occurs in 1% of patients who have had MI, cardiac surgery, blunt chest trauma, pacemaker implantation, or angioplasty generally small, bilateral (50% of cases), often bloody, exudate / glucose and pH are normal Treatment: NSAIDs and (if needed) corticosteroids Uremia generalized serositis, exudative pleural effusion with fibrinous pleurisy grossly bloody, usually with few cells (mononuclear) effusion:serum creatinine < 1 (unlike with urinary tract obstruction and retroperitoneal accumulation of urine) Asbestos exposure produces benign pleural effusion in about 3% of asbestos workers after a latent period ranging from 5 yr to > 30 yr. Patients may be asymptomatic or have chest pain. Effusions are usually unilateral and small to moderate. Pleural plaques, generally without calcification, are common, and about half the patients have evidence of parenchymal disease / exudate, may be blood-tinged, WBC may be as high as 25,000/L, with variable differential, many eosinophils / usually in the lower T! of the thorax AIDS causes pleural effusion (usually an exudate) in < 2% of patients Etiology: parapneumonic effusion, empyema, TB, PCP, Kaposis sarcoma Treatment: treat causative infection 1st then HIV Pleural Fibrosis healed inflammatory reactions Complications: severe fibrosis limits chest wall motion, retracts mediastinum toward affected side, impairs lung function Diagnosis: localized pleural thickening vs. loculated pleural fluid ( may require thoracentesis (if ultrasound/CT inconclusive) Pleural Calcification focal, usually fenestrated, irregular plaques on costal surfaces after intrapleural hemorrhage, infection and exposure (ex. Fibrosis 20 + yrs after asbestos, mostly diaphragmatic pleura, even with low-dose, brief exposure) Pneumothorax Open Tension emergency treatment: needle (MCL/2nd ICS) then tube Spontaneous young, thin males (often smokers) / ventilation, emphysema, Tb, PCP, tumors, central line (1%), needle biopsy, trauma Treatment: < 20%, try O2 and observation 1st then if needed, aspiration, if that doesnt work (get CT surgery consult to) insert chest tube / will have recurrence; requires thorascopy with sapling of blebs and/or mechanical abrasions (almost 100% successful) Traumatic pneumothorax Spontaneous pneumothorax Tension (positive pressure) pneumothorax Induced pneumothorax OTHER CONDITIONS ARDS (adult respiratory distress syndrome) Causes: sepsis, primary bacterial or viral pneumonias, aspiration of gastric contents, direct chest trauma, prolonged or profound shock, burns, fat embolism, near drowning, massive blood transfusion, cardiopulmonary bypass, O2 toxicity, acute hemorrhagic pancreatitis, inhalation of smoke or other toxic gas, and ingestion of certain drugs. Mechanisms: usually develops within 24 to 48 h after the initial injury or illness / extremely low PaO2 often persists despite high concentrations of inspired O2 (FIO2), indicating pulmonary right-to-left shunting through atelectatic and consolidated lung units that are not ventilated / PaO2/FIO2< 200 (regardless of positive end-expiratory pressure), bilateral infiltration on frontal chest x-rays, and PAWP <= 18 mm Hg when measured or no clinical evidence of left atrial hypertension. Diagnosis: Swan-Ganz catheter / pulmonary arterial wedge pressure (PAWP) is low (< 18 mm Hg) in ARDS and high (> 20 mm Hg) in heart failure / pulmonary angiography may be needed to rule out PE / lung biopsy or bronchoscopy-guided bronchoalveolar lavage may be helpful to rule out certain pulmonary conditions (e.g. PCP) Complications: secondary bacterial superinfection: GNR (Klebsiella, Pseudomonas, Proteus) and S. aureus Tension pneumothorax multiple organ system failure lung fibrosis (may resolve later) Prognosis: overall survival 60% with appropriate treatment Treatment: oxygenation prevent complications (above) use of steroids (debated) Goodpastures Progressive pulmonary and renal failure General: men in 20s (60-80%) / in older patients ( men = women Risk factors: infections, inhalation injury, HLA-DRw2, smoking (diffuse alveolar hemorrhage develops in ~100% smokers and 20% of non-smokers) Presentation: severe hemoptysis (80%), dyspnea (up to 70%), and rapidly progressive renal failure. Pulmonary disease can precede renal disease by weeks/months. Findings: active urine sediment (80%), azotemia (50%), hematuria, proteinuria, iron deficiency anemia, positive anti-GBM (90%) CXR (90% sensitivity): progressive, migratory, asymmetric, bilateral, fluffy densities Ddx for pulmonary hemorrhage and renal failure collagen vascular diseases, idiopathic RPGN, essential mixed cryoglobulinemia / microscopic PAN and Wegeners >> Goodpastures sepsis/ARDS ( ATN of kidney Pathology: like  HYPERLINK \l "rpgn" RPGN, linear deposition of IG and complement in basement membrane (lupus and DM glomerulosclerosis do not have anti-GBM) Course: rapidly fatal from pulmonary hemorrhage if untreated Treatment: high-dose steroids, cyclophosphamide, plasmapheresis up to 12 to 18 months Diffuse Alveolar Hemorrhage [HYPERLINK "pics/pulmonaryhemorrhage.jpg"table][ HYPERLINK "pics/pulmonaryhemorrhage-byage.jpg" table] Presentation: may not present with hemoptysis (usu. does occur at some point), +/- anemia small amount pink sputum ( most of the systemic causes minor amount hemoptysis ( infected bronchiectasis (most common) large amount red blood ( erosion of pulmonary artery (high pressure) Causes: Common: bronchitis, bronchiectasis, cancer pneumonia (Tb,  HYPERLINK "micro.doc" \l "pcp" PCP/AIDS, Mycoplasma, Legionella, CMV) any inflammation + bleeding state (low platelets, etc) Autoimmune: MPA, SLE, RA, Goodpastures, Wegeners, alveolar proteinosis Drugs: cytoxic agents, nitrofurantoin, opiates (heroin) Insults: trauma, shock, oxygen toxicity, acid, smoke Note: recurrent hemorrhages can cause ILD Bronchoscopy: usu. takes 50 hrs for appearance of hemosiderin laden macrophages Treatment: respiratory support / intubation / what about methyl-prednisolone 80mg q 8 hrs? bronchial artery embolization (diagnosis and treatment) surgical resection if needed bronchoscopy and chest CT may help diagnose but offer no treatment Occupational Location of Particle Deposition Nose: rhinitis, hay fever (which may be regarded as occupationally related in an agricultural worker), septal perforation in chrome workers, and nasal cancer in furniture workers Trachea and bronchi: bronchoconstriction from an antigen-antibody reaction, e.g., in some forms of occupational asthma; from pharmacologic mechanisms (in byssinosis), in which the deposition of particles causes the mast cells of the airways to produce bronchoconstrictors, such as histamine and slow-reacting substance of anaphylaxis (leukotrienes C4, D4, and E4); or from irritation as a reflex mechanism (e.g., in response to sulfites) bronchitis or mucous gland hypertrophy may be induced by long-continued deposition of particles, which may lead to a minor chronic airflow obstruction lung cancer may result from deposition of asbestos fibers or dusts with adsorbed radon daughters. Lung parenchyma: hypersensitivity pneumonitis (extrinsic allergic alveolitis), an acute granulomatous process affecting the alveoli and respiratory bronchioles Inorganic particles may cause a fibrotic response that is focal and nodular, as in typical silicosis, or diffuse and generalized, as in asbestosis and berylliosis. If particles are inert (e.g., tin oxide), a benign pneumoconiosis without fibrosis develops. Inhalation of certain gases and vapors (e.g., Hg, cadmium, nitrogen dioxide) can cause acute pulmonary edema, acute alveolitis, and bronchiolitis fibrosa obliterans Inorganic Dust Fibrogenic pneumoconioses: silica, coal, asbestos, beryllium / rarely, hard metal and aluminum dust Note: several inert dusts, including iron oxide, barium, and tin, are nonfibrogenic and can produce conditions known as siderosis, baritosis, and stannosis, respectively. The abnormal x-rays in these conditions reflect the radiodense appearance of the deposited materials and do not indicate disease because there are no symptoms or functional impairment. Silicosis Causes: metal mining (lead, hard coal, copper, silver, gold), metal casting, pottery making, and sandstone and granite cutting / exposure of 20 to 30 yr is necessary (< 10 yr when the exposure to dust is extremely high) simple nodular silicosis: no respiratory symptoms and usually no respiratory impairment. They may cough and raise sputum, but these symptoms are due to industrial bronchitis and occur as often in persons with normal CXR conglomerate silicosis: severe shortness of breath, cough, and sputum / nonhypoxemic cor pulmonale eventually causes death PFT: decreased lung volumes and diffusing capacity, airway obstruction, frequently with pulmonary hypertension and, occasionally, mild hypoxemia / CO2 retention unusual Associations: increased risk of developing Tb / positive lung autoantibodies and ANA Diagnosis: characteristic CXR and exposure to free silica simple silicosis: multiple, small, rounded or regular opacities on CXR conglomerate silicosis: opacity > 1 cm in diameter / eggshell calcification in the hilar and mediastinal lymph nodes Ddx: miliary TB, welders siderosis, hemosiderosis, sarcoidosis, and coal workers pneumoconiosis / silicotuberculosis resembles conglomerate silicosis on CXR (sputum culture distinguishes) Treatment: lung transplantation / more aggressive treatment and surveillance for Tb Coal Workers Pneumoconiosis or black lung disease, or anthracosis simple CWP: coal dust is widely distributed throughout the lungs, leading to the development of coal macules around the bronchioles. Later, mild dilation, known as focal-dust emphysema, also occurs; however, it does not extend to the alveoli and is not associated with airflow obstruction. Because coal is relatively nonfibrogenic, distortion of lung architecture and functional impairment are minimal. complicated CWP: 1-2% per year of simple CWP ( progressive massive fibrosis (PMF) opacity e" 1 cm / rarely, develops after exposure has ceased, may progress without further exposure Diagnosis: history (> 20 years exposure), CXR with small rounded opacities in both lung fields for simple CWP or a shadow > 1 cm in diameter on a background of simple CWP for PMF / simple CWP is not associated with respiratory symptoms (cough usu. due to emphysema from smoking, other coincident exposures) Treatment: nonspecific, rarely necessary, mostly futile Caplans syndrome: A coal miner who has or develops RA may develop multiple rounded nodules in the lung over a relatively short time. Such nodules sometimes develop in the absence of simple CWP. Histologically, they resemble rheumatoid nodules but have a peripheral region of more acute inflammation. These nodules represent an immunopathologic response related to the rheumatoid diathesis. Asbestosis diffuse interstitial pneumoconiosis / long-term inhalation of asbestos dust (mining, milling, manufacturing, insulation) / risk of cumulative exposure (smoking adds greatly in combination with asbestosis) Pathology: alveolar and interstitial fibrosis, reduction in lung volumes, compliance (increased stiffness), and gas transfer / uncoated or coated with an iron-protein complex (called asbestos or ferruginous bodies) / diffuse, infiltrates the pleura widely, always with pleural effusion / benign pleural plaques and pleural effusions may develop after asbestos exposure; however, benign pleural mesotheliomas are not related to asbestos exposure. Presentation: insidious onset of exertional dyspnea and reduced exercise tolerance (cough and bronchitis-like symptoms usu. from concomitant smoking or other related-exposure) Diagnosis: history of exposure, CXR, restrictive PFTs and decreased DLco, histology rarely necessary / note: mesothelioma requires biopsy CXR: diffusely distributed, small irregular or linear opacities, usually most prominent in the lower lung fields / often, only minimal changes / diffuse or localized pleural thickening, with or without parenchymal disease, may also be visible HRCT can show pleural fibrosis or pleural plaques Course: progresses (but only for 1-5 yrs) in about 5-12% ( can lead to severe restrictive lung disease Complications: Asbestos pleural effusion exudative pleural effusion 5-20 years after exposure / usu. clear after 3-6 months, 20% develop diffuse pleural fibrosis malignant mesotheliomas (pleural and peritoneal) uncommon / from exposure 15-40 years earlier (even brief, < 12 months) / usu. from crocidolite and/or amosite fibers in asbestos / almost invariably fatal within 2-4 yrs from diagnosis / spread locally by extension and can metastasize widely / bloody effusion, chest wall pain Treatment: prevention / supportive / avoid smoking (makes it worse) Berylliosis Causes: mining and extraction, electronics, chemical plants, manufacture of fluorescent lightbulbs, aerospace industry Presentation: acute or after 10-20 yrs exposure (even if brief at time), can be similar to sarcoid, differs from most pneumoconioses (hypersensitivity disease, occurs in only ~2% of exposed) / dyspnea, cough, weight loss / can also have dermatitis CXR: highly variable, usually diffuse alveolar consolidation / chronic CXR may have diffuse infiltrations, often hilar adenopathy, resembling the pattern seen in sarcoidosis / miliary pattern may occur Diagnosis: clinical and history, often cannot tell from sarcoid without special stains Tissue levels can be measured Treatment: acute can be fatal, but survivors have excellent prognosis / chronic is fairly irreversible / if it does, suspect sarcoid Organic Dusts Occupational asthma usu. after at least 18 mo to 5 yr of exposure; it does not occur within a month of starting work unless sensitization has already occurred Causes: castor bean, grain, proteolytic enzymes used in detergent manufacturing and beer and leather making industries, western red cedar wood, isocyanates, formalin (rarely), antibiotics (e.g., ampicillin, spiramycin), epoxy resins, and tea. (and the lists always is growing) Diagnosis: differentiation from idiopathic asthma generally based on the pattern of symptoms and exposure Treatment: treat asthma / avoid triggers Byssinosis Causes: cotton, flax, and hemp workers / cotton trash (i.e., unprocessed, unpurified cotton), especially those who open bales or work in the card room Presentation: chest tightness develops on the first day of work after a weekend or vacation. In many persons who complain of chest tightness, ventilatory capacity drops during the first work shift. In byssinosisunlike asthma, symptoms/chest tightness lessens with repeated exposure, and usually by the end of the week, the person is symptom-free. With repeated, prolonged exposure over a period of years, chest tightness tends to return and persist through work week or even permanently. Other Chemicals Acute Exposure: irritant gases (chlorine, phosgene, sulfur dioxide, hydrogen sulfide, nitrogen dioxide, ammonia) soluble gases (e.g., chlorine, ammonia) cause mucous membrane irritation of upper tract and distal airways and lung parenchyma only if escape from the gas source is impeded / severe burning and other manifestations of irritation of the eyes, nose, throat, trachea, and major bronchi. Marked cough, hemoptysis, wheezing, retching, and dyspnea are common. Their severity is generally dose-related. After heavy exposure, patchy or confluent alveolar consolidation may be seen on chest x-ray and usually indicates pulmonary edema. Most persons recover fully from a heavy acute exposure / bacterial infections, common during the acute phase, are the most serious complications less soluble gases (e.g., nitrogen dioxide) do not produce the warning signs of upper respiratory tract symptoms and are more likely to cause pulmonary edema, severe bronchiolitis, or both Treatment: proper avoidance/prevention, gas masks, etc. / mechanical ventilation if needed / steroids are often given but few studies Chronic Exposure: chronic bronchitis (confused if patients smokes also) / higher risk of cancer with chronic bis(chloromethyl)ether or certain metalsand in other parts of the body (e.g., liver angiosarcomas after vinyl chloride monomer exposure) Sick Building Syndrome occurs in new, tight buildings, designed to reduce heat loss, have windows that do not open, and usually have heating and cooling ducts that originate from a common source / elevated CO2 is a frequent cause of sick building syndrome / also trucks and other vehicles idling near the air intakes, resulting in excessive exposure to carbon monoxide and diesel fumes (carbon monoxide, nitrogen oxides, various aldehydes, other noxious substances0 Presentation: anxious, hyperventilate, may develop tetany, severe breathlessness. Air-conditioner lung: same organisms that cause  HYPERLINK \l "farmerslung" farmers lung (Thermoactinomyces vulgaris, Micropolyspora faeni). Thermophilic actinomycetes can contaminate humidifiers and piping of air conditioner ducts. Symptoms of air-conditioner lung same as farmers lung (sometimes confused with humidifier fever) Humidifier fever: acute febrile illness usually develops on first workday / fever, muscle aches, mild shortness of breath / amebas, endotoxins, bacteria, and fungi, can cause various types of humidifier fever / usu. resolves once patient no longer exposed / often evidence often points to attacks of mass anxiety or hysteria as cause Interstitial Lung Disease (ILD) Idiopathic:  HYPERLINK \l "ipf" IPF, HYPERLINK \l "uip"UIP,  HYPERLINK "#dip" DIP,  HYPERLINK "#aip" AIP,  HYPERLINK \l "nsip" NSIP (see below) Other ILD: occupational, hypersensitivity, sarcoidosis / also consider IVDA for chronic, diffuse granulomatous disease (repeated embolization of insoluble crystals, filler-material into lungs) CXR: normal in up to 10% of patients (esp. hypersensitivity pneumonitis) HRCT better than CXR in distinguishing airspace disease from ILD / earlier detection and confirmation / better assessment of the extent and distribution of disease / more likely to detect coexisting disease (occult mediastinal adenopathy, carcinoma, emphysema) BAL can sometimes (but often cannot) help narrow Ddx, define stage, and assess progression or response to therapy Treatment: Hypoxemia: supplemental O2 to reduce pulmonary artery pressures Anemia: unlike in garden-variety COPD, some ILD patients have lower Hct due to relative erythropoietin deficiency (< 500 mU/ml). Should erythropoietin be given to these patients? Probably Steroids often helpful in slowing progression of these diseases Idiopathic Pulmonary Fibrosis (IPF) or Cryptogenic Fibrosing Alveolitis most common (50-60%) cause of idiopathic ILD / 50-70 yrs old / note: IPF is a specific disease, not just the term for any ILD of unknown etiology PFT: restrictive pattern Course: slowly progressive Treatment: steroids (equivocal results);  HYPERLINK "pharm.doc" \l "pirfenidone" pirfenidone (under study) Usual Interstitial Pneumonia (UIP) Findings: dyspnea on exertion, nonproductive cough, and velcro-type inspiratory crackles Late ( cor pulmonale, digital clubbing, and cyanosis ECG usually normal (unless pulmonary HTN) CXR: usually diffuse reticular opacities in lower zones / may show diffuse or patchy ground-glass, small cystic lesions (honeycombing), reduced lung volumes, signs of pulmonary hypertension HRCT: ground-glass opacification; patchy, predominantly peripheral, airspace opacities; and a hazy increase in lung density (does not obscure underlying lung parenchyma) / in lower lungs, reticular pattern predominates (thickened interlobular septa and lines) / honeycombing, traction bronchiectasis, and subpleural fibrosis may also occur depending on stage Labs: elevated ESR and hypergammaglobulinemia are common, ANA, RF and circulating immune complexes seen in many patients (may have no connective tissue disease) ABG: hypoxemia (often exaggerated or elicited by exercise) PFT: often restrictive pattern / increased coefficient of retraction / DLCO reduced Pathology: interstitial pneumonia has a classic pattern on lung biopsy (alternating areas of normal lung, interstitial inflammation, fibrosis, and honeycombing) / worst in peripheral subpleural parenchyma / subpleural and paraseptal distribution, patchy character, and temporal heterogeneity are the most helpful features in identifying UIP Note: identical pattern occurs in (RA, SLE, scleroderma, MCTD, diabetes mellitus), asbestosis, radiation injury, and certain drug-induced lung diseases (nitrofurantoin) Diagnosis: usually requires VATS lung biopsy (not enough tissue with transbronchial) / biopsy not necessary when CXR shows extensive honeycombing Course: progressive course; median survival is 4 to 6 yrs Treatment: Empiric prednisone 1.0 mg/kg PO for 3 mo, then tapered over 3 mo to 0.5 mg/kg and given for another 3 mo / maintenance of 0.25 mg/kg for next 6 mo / 2nd line - cyclophosphamide or azathioprine 1 to 2 mg/kg/day / supportive O2 and antibiotics as needed / lung transplantation has been successful / what about Epogen to increase QOL (if patient is anemic)? Desquamative IP or (DIP) General: cigarette smokers in their 30s or 40s / most present with dyspnea Pathology: diffuse and uniform (unlike UIP) / also has numerous macrophages in most of distal airspaces PFT: restrictive pattern with reduced DLCO ABG: hypoxemia CXR: normal in up to 20% of cases / when present, abnormalities less severe than those in IPF / honeycombing usually not as extensive/prominent as in UIP / DIP reaction may occur as part of UIP (people argue) HRCT: patchy, subpleural ground-glass opacities Note: DIP has a better prognosis (survival ~70% after 10 yr) and better response to smoking cessation and steroids than UIP (so its important to make proper diagnosis) Acute IP or (AIP) or Hamman-Rich syndrome rare, fulminant course usually in a previously healthy person / men = women / most > 40 yr (avg. 50 yr range 7-83 yr) Presentation: similar to ARDS / abrupt onset, although prodromal illness, often 7-14 days before presentation, is common / most common symptoms: fever, cough, shortness of breath Pathology: organizing diffuse alveolar damage (nonspecific reaction to several causes of lung injury) / key features: nonspecificity, characteristic temporal phases (acute, organizing, healed), each with different histology Labs: not useful CXR: similar to ARDS / diffuse bilateral airspace opacification CT: bilateral patchy symmetric areas of ground-glass attenuation and sometimes bilateral areas of airspace consolidation / distribution may be predominantly subpleural / mild honeycombing, usually affecting < 10% of the lung, may be seen Diagnosis: when patient has idiopathic ARDS and organizing diffuse alveolar damage confirmed by an open or VATS biopsy Course: most patients have moderate to severe hypoxemia and develop respiratory failure Mortality is > 60%; most patients die within 6 mo of presentation / disease usually does not recur, most substantially or completely recover pulmonary function Treatment: ?steroids / supportive / mechanical ventilation Non-Specific Interstitial Pneumonia (NSIP) Chest CT: may show patchy ground-glass opacities central and peripheral or consolidation central and peripheral / honeycombing is actually a rare finding Diagnosis: biopsy will differentiate from other forms of IP Course: can improve with treatment or progress in spite of treatment / average survival from 3 to ?10 +yrs Treatment: same as UIP? Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RBAIL) current or former smokers Mechanism: inflammatory process affecting the membranous and respiratory bronchioles Presentation: similar to other ILD (cough, dyspnea on exertion) Exam: rales / Labs: no CXR: diffuse, fine reticular or rarely nodular interstitial opacities, usually normal lung volumes / may see bronchial wall thickening, prominence of peribronchovascular interstitium, small regular and irregular opacities, and small peripheral ring shadows HRCT scanning often shows hazy opacities PFT: mixed obstructive-restrictive pattern / can have isolated ! RV Pathology: tan-brown pigmented macrophages are characteristic, bronchioles may be ectatic with mucus stasis, and their walls are mildly thickened, bronchiolar metaplastic epithelium extending into the adjacent alveoli frequently seen. Course: unknown Treatment: smoking cessation important for resolution / steroids reported of benefit Bronchiolitis Obliterans with Organizing Pneumonia (BOOP) 40s or 50s / insidious course / unresponsive to antibiotics Presentation: onset in 2/5 ( flu-like (cough, fever, malaise, fatigue, weight loss) / symptoms last < 2 mo; few have symptoms for > 6 mo before diagnosis Cause: generally unknown; BOOP can be idiopathic or a reaction to various injuries ( HYPERLINK "micro.doc" \l "cryptococcus" Cryptococcosis, Wegeners, lymphoma,  HYPERLINK \l "hypersensitivitypneumonitis" hypersensitivity pneumonitis, eosinophilic pneumonia) Mechanism: foci of organizing pneumonia develops and fibrous granulation tissue obstructs bronchioles and alveolar ducts (an interstitial lung disease) Labs: nonspecific, 50% with ! WBC (without ! eosinophils), initial ESR often high PFT: restrictive >> obstructive (20%) >> normal / ! TLC, ! DLCO / resting/exercise hypoxemia common / in contrast to similarly named entities, constrictive bronchiolitis and obliterative bronchiolitis, which cause ! FEV1/FVC and ! RV CXR: bilateral (rarely unilateral), diffuse alveolar opacities with normal lung volumes / can see a peripheral distribution (similar to chronic eosinophilic pneumonia) / recurrent/migratory opacities are common / rarely, irregular linear or nodular interstitial opacities or honeycombing seen at presentation / pleural effusion is uncommon HRCT: patchy airspace consolidation, ground-glass opacities, small nodular opacities, bronchial wall thickening and dilation / opacities more in periphery , lower lobes Note: CT can show much more extensive disease than predicted by CXR Lung biopsy: excessive proliferation of granulation tissue within small airways and alveolar ducts, with chronic inflammation in the surrounding alveoli Treatment: steroids successful in 2/3 Lymphocytic Interstitial pneumonitis (LIP) Adults (rare) / children (more common) / associated with  HYPERLINK \l "pbc" PBC, Sjogrens, various lymphoproliferative Dz, gammopathies, myasthenia gravis, CTD, chronic active hepatitis, EBV, HIV, HTLV-1 Pathology: cause unknown / polyclonal gammopathy / infiltrates on alveolar septa (occasionally bronchi and vessels) are polyclonal (B/T cells, plasma cells) [unlike monoclonal lymphoma] / hypogammaglobulinemia (in children) Findings: serum protein abnormality (up to 75%), Sjgrens (25%), first symptom in up to 50% of infants and children with HIV) Presentation: cough and dyspnea (slowly progressive over months/years), +/- crackles / weight loss, fever, arthralgias, and pleuritic chest pain / hepatosplenomegaly, arthritis, and lymphadenopathy CXR: basilar linear or nodular interstitial opacities (late --> fibrosis with honeycombing (loss of lung parenchyma) / HRCT may establish extent, define hilar anatomy, identify pleural involvement ABG: can have marked hypoxemia PFTs: reduced TLC and DLCO with preserved airflow BAL: increased lymphocytes Diagnosis: demonstration of an interstitial infiltrate, formation of germinal centers, and multinucleated giant cells with noncaseating granulomas Course: pulmonary disease precedes or follows diagnosis / spontaneous resolution or after treatment, progression to lymphoma, or development of pulmonary fibrosis (respiratory failure) Treatment: steroids or other are under investigation Histiocytoses granulomatous lesions may occur in many organs (esp. lungs and bones) / etiology unknown / progressive proliferation of histiocytes and infiltration with eosinophilic granulocytes, then fibrotic phase with little cellular infiltration / varying degrees of granulomatosis, fibrosis, and honeycombing / histiocytosis X bodies, seen on EM, are characteristic and may be seen within histiocytes or alveolar macrophages from BAL fluid Letterer-Siwe disease systemic disease that occurs before age 3 yr. Untreated, it is usually fatal. Skin, lymph nodes, bone, liver, and spleen are frequently affected. Pneumothorax is a common complication. Hand-Schller-Christian multifocal disease that most often begins in early childhood but can appear in late middle age. The lungs and bones are most commonly affected, although other organs may be affected. A triad of bone defects, exophthalmos, and diabetes insipidus occurs rarely. Tissue biopsy, usually performed on skin or bone lesions, is required to confirm the diagnosis. Multisystem disease should be treated with systemic chemotherapy, which includes vinblastine or etoposide. Eosinophilic Granuloma (Langerhans Cell Granulomatosis) (pulmonary histiocytosis X) General: rare, smoking-related diffuse lung disease / 20 to 40 yrs / men Pathology: peribronchiolar inflammation with aggregates of Langerhans cells, lymphocytes, plasma cells, neutrophils, and eosinophils. Presentation: asymptomatic (16%) or persistent or rapidly progressive (most) Common: cough, dyspnea, chest pain, weight loss, fever,  HYPERLINK \l "ptx" PTX (25%) Rare: hemoptysis and diabetes insipidus Diagnosis: Exam: usually normal Labs: not helpful CXR: vary; ill-defined or stellate nodules (2 to 10 mm), small reticulonodular infiltrates in bases, upper zone or apical cysts or honeycombing, preservation of lung volume, and sparing of the costophrenic angle is considered highly specific for eosinophilic granuloma HRCT (nodules and thin-walled cysts) differentiates from other fibrosing lung diseases PFTs: markedly reduced DLCO / lung volumes normal or reduced with variable restrictive, obstructive, and decreased exercise capacity Ddx: miliary Tb (no cysts), PCP (no nodules), alpha-1-antitrypsin (lower lungs) Treatment: smoking cessation (33% improve, most have progressive interstitial disease, 10% mortality from respiratory complications) Idiopathic pulmonary hemosiderosis rare disease of unknown etiology characterized by episodes of hemoptysis, hemorrhage into the lung, pulmonary infiltration, and secondary iron-deficiency anemia / young children >> adults Ddx: must be distinguished from Goodpastures, pulmonary hemorrhage in SLE or Wegeners Pathology: diffuse infiltration with hemosiderin-containing macrophages is characteristic, although hemosiderin deposition occurs in many other disorders / may get pulmonary capillaritis (neutrophilic infiltration of alveolar septa) Treatment is symptomatic and supportive (death often from massive pulmonary hemorrhage) Course: pulmonary hemorrhages are most often mild and continuous but can be severe. Blood in interstitial spaces leads to pulmonary fibrosis. Patients may live for several years, developing pulmonary fibrosis and insufficiency with chronic secondary anemia. Pulmonary alveolar proteinosis (PAP) [ HYPERLINK "http://www.nejm.org/content/2001/0344/0003/0212.asp" NEJM] 20 to 60 yrs / previously healthy or 2o inorganic dusts / chronic PCP infection, hematologic malignancies, myeloproliferative diseases, or immunosuppression Pathology: limited to the lungs (diffuse or local) / basal, posterior >> anterior segments / alveoli filled with amorphous PAS-positive granules (serum and nonserum proteins) / alveolar lining and interstitial cells are normal / pleura and mediastinum unaffected / lipid concentration in the alveolar spaces is high, possibly because of abnormal clearance of alveolar phospholipids. Presentation: asymptomatic to severe / often gradually progressive exertional dyspnea and cough (usually unproductive) / extrapulmonary symptoms unusual / patients who smoke usu. produce sputum (not diagnostic) Rales: fine inspiratory crackles over affected areas / big rales and persistent fever usually minimal / when present ( think 2o pneumonia (Nocardia, Mycobacteria, Aspergillus, Cryptococcus sp) Anemia uncommon ( think diffuse alveolar hemorrhage Complications: interstitial fibrosis (rare) / secondary infections (usu. S. aureus) Diagnosis: lung biopsy or bronchoscopy with segmental BAL (special staining and characteristic findings by LM or EM) CXR: butterfly pattern of opacities resembling that in pulmonary edema / normal heart, normal hilar lymph nodes [HYPERLINK "pics/alveolarproteinosis-cxr.jpg"pic] HRCT: ground-glass opacification and thickened intralobular structures and septa in typical polygonal shapes (crazy-paving) PFT: VC, RV, functional residual capacity, TLC, and single-breath DLCO are usually slightly reduced (from decreased lung volumes) Obstructive pulmonary disease is not a feature Labs: polycythemia, hypergammaglobulinemia, increased LDH, increased A-a gradient (intrapulmonary R-L shunt) Treatment: indicated only with significant symptoms and hypoxemia / general anesthesia ( lungs are lavaged one at a time with 3 to 5 days between lavages most effective is whole-lung lavage via a double-lumen endotracheal tube, with repeated cycles of filling and emptying one lung, using 1 to 2 L of warmed 0.9% NaCl / Some require only one lavage (others require lavage q 6 to 12 mo for many years) Investigational: potassium iodide and proteolytic enzymes (trypsin, streptokinase-streptodornase) steroids unsuccessful and may increase possibility of secondary infection / lung transplant has been used for (fibrosis still can recur) / G-CSF has been used in some patients Course: condition may progress, remain stable, or clear spontaneously / disability common (respiratory insufficiency), death is rare with treatment Hypersensitivity pneumonitis (extrinsic allergic alveolitis) diffuse interstitial granulomatous lung disease allergy to organic dusts or simple chemicals Etiology/Pathogenesis: foreign animal or vegetable protein > simple chemicals (with a lot of exposure) mostly  HYPERLINK \l "typefour" type IV or delayed-type hypersensitivity reaction (some features of  HYPERLINK \l "typethree" type III) only after weeks to months of exposure chronic progressive parenchymal disease may result from continuous or frequent low-level exposure to the antigen history of allergic disease (e.g., asthma, hay fever) is uncommon and is not a predisposing factor Pathology: diffuse granulomatous interstitial pneumonitis characteristic but not definitive or specific lymphocyte and plasma cell infiltrates occur along airways and in thickened alveolar septa single, nonnecrotizing granulomas randomly scattered in the parenchyma fibrosis depends on the stage of the disease (usually mild) bronchiolitis in ~50% of patients with farmers lung Presentation (3 sub-forms): Acute: fever, chills, cough, dyspnea +/- anorexia, nausea, vomiting in previous sensitized person (4-8 h post-reexposure) / +/- rales, (-) wheezing / symptoms improve within hours after stopping exposure, complete recovery days/weeks. Subacute: cough, dyspnea over days to weeks can lead to hospitalization Chronic: progressive exertional dyspnea, productive cough, fatigue, weight loss over months/years (can progress to respiratory failure) Diagnosis: exposure (challenge), clinical, CXR, PFT / can test for Ab to suspected agents but not necessary (can have present but untelling Ig) / last resort is lung biopsy (differentiate from ILD) / BAL might differentiate from  HYPERLINK \l "sarcoidosis" sarcoid / can differentiate from infective pneumonias by diagnosing the infection (serology, culture, PCR) / asthma and allergic bronchopulmonary aspergillosis have obstructive PFTs and eosinophilia CXR: range from normal to diffuse interstitial fibrosis / bilateral patchy or nodular infiltrates (usu. upper lobes) increased interstitial markings or picture of mild edema / usu. does not have hilar lymphadenopathy or effusions HRCT: may help evaluate extent of disease but no pathognomic findings PFT: restrictive pattern with ! lung volumes, a ! DLco, abnormal VQ, hypoxemia / airway obstruction unusual in acute disease but may develop in chronic disease / (-) eosinophilia Ddx: autoimmune (Hamman-Rich syndrome, IPF, UIP, Wegeners, LAM, C-S), eosinophilic pneumonia, BOOP, psittacosis, viral pneumonia, other infective Prevention and Treatment stop exposure / acute disease usually self-limiting dust control / protective masks / cleaning of wet ventilation systems steroids may help in severe acute/subacute cases but have not been shown to alter eventual outcome in chronic disease / prednisone 60 mg/d for 1-2 wk then tapered over the next 2 wks to 20 mg/d, followed by weekly decrements of 2.5 mg until off / antibiotics only if superimposed infection bronchodilators and antihistamines not shown to help Farmers lung repeated inhalation of dusts from hay containing thermophilic actinomycetes / worse in rainy season / delayed type hypersensitivity Atypical farmers lung (pulmonary mycotoxicosis) fever, chills, cough occurring within hours of massive exposure to moldy silage (e.g., when uncapping a silo) / (+) pulmonary infiltrates Note: different from silo fillers disease (toxic oxides of nitrogen given off by fresh silage) Organic dust toxic syndrome (e.g., grain fever) transient fever, muscle aches +/- respiratory symptoms / no sensitization after exposure / ?endotoxin Humidifier fever contaminated heating, cooling, and humidifying / ?endotoxin Eosinophilic Pneumonias (pulmonary infiltrates with eosinophilia (PIE) Causes: parasites (e.g., roundworms, Toxocara larvae, filariae), drugs (e.g., penicillin, aminosalicylic acid, hydralazine, nitrofurantoin, chlorpropamide, sulfonamides, thiazides, TCAs), chemical sensitizers (e.g., nickel carbonyl inhaled as a vapor), and fungi (e.g., Aspergillus fumigatus, which causes allergic bronchopulmonary aspergillosis). Most eosinophilic pneumonias, however, are of unknown etiology, although a hypersensitivity mechanism is suspected. Eosinophilia suggests a type I hypersensitivity reaction; other features of the syndrome (vasculitis, round cell infiltrates) suggest type III and possibly type IV reactions. eosinophilic pneumonias associated with bronchial asthma (more common) extrinsic bronchial asthma with the PIE syndrome, often is allergic bronchopulmonary aspergillosis intrinsic bronchial asthma with the PIE syndrome (chronic eosinophilic pneumonia), characteristic peripheral infiltrates on CXR allergic granulomatosis ( HYPERLINK \l "churgstrauss" Churg-Strauss syndrome) or simple eosinophilic pneumonia (Lfflers syndrome) eosinophilic pneumonias NOT associated with asthma Acute eosinophilic pneumonia, a distinct entity of unknown cause, results in acute fever, severe hypoxemia, diffuse pulmonary infiltrates, and > 25% eosinophils in bronchoalveolar lavage fluid; it resolves promptly and completely with corticosteroid therapy eosinophilia-myalgia syndrome is associated with ingestion of large doses of contaminated L-tryptophan used as a dietary supplement. Pulmonary infiltrates occasionally occur along with the expected features of myalgia, muscle weakness, skin rash, and soft tissue induration resembling scleroderma hypereosinophilic syndrome are persistent eosinophilia > 1500 eosinophils/mm3 for more than 6 mo, lack of evidence for other known causes of eosinophilia, and systemic involvement of the heart, liver, spleen, CNS, or lungs. The heart is commonly affected. Fever, weight loss, and anemia are common. Thromboembolic disease, arterial more commonly than venous, occurs often. Presentation: mild or life threatening Lfflers syndrome may include low-grade fever, minimal (if any) respiratory symptoms, and prompt recovery other forms of the PIE syndrome may produce fever and symptoms of bronchial asthma, including cough, wheezing, and dyspnea at rest chronic eosinophilic pneumonia is often progressive and life threatening (if not treated Diagnosis: parasite workup based on geography and travel / A.. fumigatus may be present in the sputum / complete drug history Labs: marked blood eosinophilia (between 20-40% and higher) is usually striking CXR: rapidly developing and disappearing infiltrates in various lobes (migratory infiltrates) / chronic EP described as photographic negative of pulmonary edema. Ddx:  HYPERLINK \l "tb" TB,  HYPERLINK \l "sarcoidosis" sarcoidosis,  HYPERLINK \l "hodgkinsdisease" Hodgkins disease and other lymphoproliferative disorders,  HYPERLINK \l "eosinophilicgranuloma" eosinophilic granuloma of lung,  HYPERLINK \l "dip" desquamative interstitial pneumonitis, and collagen vascular disorders Note: hypersensitivity pneumonitis and Wegeners are not commonly associated with eosinophilia Treatment: may be self-limited and benign, requiring no treatment / if severe, steroids usu. dramatically effective; in acute eosinophilic pneumonia and idiopathic chronic eosinophilic pneumonia (may be lifesaving) / when bronchial asthma is present, usual asthma therapy is indicated / appropriate vermifuges should be used for parasite Aspergillus allergic reaction / not same as invasive aspergillosis ( HYPERLINK \l "invasiveaspergillosis" see below) Causes: rarer organisms, such as Penicillium, Candida, Curvularia, or Helminthosporium sp, may cause identical syndromes more accurately termed allergic bronchopulmonary mycoses. Mechanism: types I, III (and possibly type IV) hypersensitivity reactions Pathology: alveoli full of eosinophils / granulomatous interstitial pneumonitis / proximal bronchiectasis develops in advanced cases / fibrosis can lead to severe, irreversible airway obstruction Presentation: exacerbation of bronchial asthma, intermittent low-grade fever and systemic symptoms. Radiology CXR (serial) show migratory opacities/shadows and/or atelectasis Chest CT may show bronchiectasis in proximal airways Sputum same as typical asthma with Curschmanns spirals (mucoid casts), Charcot-Leyden crystals (eosinophilic debris), mucus, and eosinophils but may also have A. fumigatus mycelia; sputum culture may or may not be positive Labs: peripheral eosinophil count usually > 1000/L and IgE and IgE to A. fumigatus may be very high Diagnosis: extrinsic (atopic, allergic) asthma (usually long-standing), pulmonary infiltrates, sputum and blood eosinophilia, and hypersensitivity to Aspergillus or another relevant fungus as shown by a wheal and flare skin test, precipitating antibodies in the serum, and high levels of total and specific IgE. The presence of these features makes the diagnosis very likely / unlike hypersensitivity pneumonitis wherein PFTs show restrictive rather than obstructive pattern and eosinophilia is rare Bronchocentric granulomatis Usually targets small airways sparing adjacent pulmonary vasculature; may result in association with allergic aspergillosis or other infections such as Tb, histoplasmosis, blastomycosis, mucormycosis Invasive aspergillosis usually occurs as a serious opportunistic pneumonia in immunosuppressed patients / in old cavitary disease (e.g., TB) or, rarely, in rheumatoid spondylitis due to colonization within cystic airspaces of the upper lobes Treatment: antiasthmatic drugs (theophylline, sympathomimetics) usually successful in allowing expectoration of the mucus plugs and the Aspergillus with them prednisone as for hypersensitivity pneumonitis (may require long-term treatment, to prevent progressive, irreversible disease / success for maintenance therapy with inhaled corticosteroids is not established immunotherapy and fungicidal or fungistatic drugs are not recommended Note: sustained fall in serum IgE is sign of successful treatment and favorable prognosis / spirometry and CXR periodically to avoid silent progression Lung Transplantation population at highest risk for pneumonia early (first 2 weeks): GNR (Enterobacteriaceae), pseudomonas, S. aureus, aspergillus, candida middle (1 to 6 months): primary or reactivation of CMV (hard to distinguish from acute rejection; CMV may be cause of rejection and BOOP) / RSV causes post-transplant pneumonitis late (> 6 months): Pneumocystis, nocardia, listeria, other fungi, intracellular pathogens / any transplant patient at risk for EBV-associated lymphomas Treatment: pre-transplant cultures often guide antibiotics / CMV and PCP prophylaxis Neurology  HYPERLINK \l "cnsinjury" CNS injury  HYPERLINK \l "cva" CVA,  HYPERLINK \l "cnstrauma" trauma,  HYPERLINK \l "ich" ICH,  HYPERLINK \l "cnsvasculitis" vasculitis  HYPERLINK \l "cnsinfection" CNS infection  HYPERLINK \l "cnsmalformations" CNS malformations  HYPERLINK \l "cnsneoplasms" CNS tumors  HYPERLINK \l "headaches" Headaches  HYPERLINK \l "seizures" Seizures  HYPERLINK \l "dementia" Dementia Encephalitis HYPERLINK "ddx.doc" \l "delirium"Delirium  HYPERLINK \l "icp" Intracranial Pressure  HYPERLINK \l "nph" NPH,  HYPERLINK \l "pseudotumor" pseudotumor cerebri  HYPERLINK \l "neuropathies" Peripheral Neuropathies  HYPERLINK \l "neurological" Degenerative Neurological Disease  HYPERLINK \l "alzheimers" Alzheimers,  HYPERLINK \l "picks" Picks,  HYPERLINK \l "huntingtons" Huntingtons,  HYPERLINK \l "parkinsons" Parkinsons  HYPERLINK \l "msa" Multiple System Atrophy  HYPERLINK \l "motor" Motor Neuron Disease  HYPERLINK \l "als" ALS,  HYPERLINK \l "werdnig" WHD,  HYPERLINK \l "kugelberg" KWS  HYPERLINK \l "demyelinating" Primary Demyelinating  HYPERLINK \l "ms" MS,  HYPERLINK \l "adem" ADEM,  HYPERLINK \l "ahem" AHEM,  HYPERLINK \l "gbs" GBS  HYPERLINK \l "demyelinatingsystemic" Systemic Demyelinating CPM, MB,  HYPERLINK \l "pml" PML  HYPERLINK \l "myopathy" Myopathy  HYPERLINK \l "myopathycongenital" Congenital,  HYPERLINK \l "myopathymitochondrial" Mitochondrial  HYPERLINK \l "myopathyinflammatory" Inflammatory ( HYPERLINK \l "mg" Myasthenia Gravis,  HYPERLINK \l "lamberteaton" Lambert Eaton,  HYPERLINK \l "pmr" PMR)  HYPERLINK \l "muscular" Muscular Dystrophies ( HYPERLINK \l "duchenne" Duchenne,  HYPERLINK \l "beckers" Becker,  HYPERLINK \l "emery" ED, others) [ HYPERLINK \l "neuroexam" neuro exam] [ HYPERLINK \l "neuroradiology" neuroradiology] [ HYPERLINK \l "anatomicdiagnosis" anatomic diagnosis] [low back pain] Neuro Exam Mental status Cranial Nerves Motor proximal weakness implies muscle or spinal cord, distal is everything else / spasticity implies corticospinal / cogwheel implies Parkinsons or PD-like / paratonic (Gegenhalten, pushing against) implies metabolic, degenerative or drug effect Gait/Station Romberg positive (vestibular or position sense, not cerebellar) when unsteady only with eyes closed and feet together (must be steady with eyes open, of course) ataxia ( cerebellum apraxia ( delayed initial step (wide-based !  HYPERLINK \l "nph" NPH and frontal lobe; loss of arm swing and shuffling gait !  HYPERLINK \l "parkinsons" PD) Reflexes briskness more important than amplitude / Hoffmans (common to have bilateral, symmetrical) / Babinski (always abnormal in adult) / increased with cerebral, brainstem and spinal cord disease (except in anterior horn such as  HYPERLINK \l "als" ALS, which is rare), decreased with nerve or never root, variable with muscle and cerebellum Sensory vibration lost first with neuropathy, myelopathy and brain stem / position sense lost first only with cerebral pathology (double simultaneous stimulation testing for extinction phenomenon most effective but not pathognomonic for cerebral disease) Neck rigidity, bruits Anatomic Diagnosis Cerebral (encephalopathy, right or left cerebral dysfunction) aphasia/apraxia, dementia, seizures, homonymous hemianopia / sterognosis, graphesthesia, tactile localization, 2-point discrimination most often cerebral or high cervical cord Brainstem/cerebellum Spinal cord (myelopathy) Spinal root (radiculopathy) pain, localized weakness, decreased reflexes, sometimes numbness Nerve (neuropathy) can be small (pain, temp) or large (position, vibration) fibers / reflexes decreased NMJ (MG, Eaton-Lambert) Muscle (myopathy) usually proximal and head flexion Meningeal Note: spinal cord lesions are infrequently vascular, neuropathies unlikely due to tumor unless paraneoplastic / non-localizing findings often misinterpreted include: hemiparesis, dysarthria, dysphagia, hemisensory loss Neuroradiology Tools  HYPERLINK \l "cnsmri" MRI  HYPERLINK \l "cnsct" CT  HYPERLINK \l "cnsultrasound" Ultrasound  HYPERLINK \l "transcranialdoppler" Transcranial doppler  HYPERLINK \l "cerebralangiography" Cerebral Angiography  HYPERLINK \l "eeg" EEG MRI tidbits T1 spinal fluid is dark tumor ( dark edema ( white w/ contrast T2 spinal fluid is white [there is no contrast with T2] Diffusion weighted ( distinguishes new from old stroke Note: must order additional study of posterior fossa to look at cerebellum and hindbrain structures on MRI (normal MRI will not do this) / only commonly variable ventricle is occipital horn Caution: risk of NSF in renal failure patients ( HYPERLINK \l "nsf" see other) CT scan non-contrast brain scan is good for CVA unless 1) < 5mm lesion, < 12 hrs old, brainstem contrast CT actually worse for evaluation of ICH because vasculature can appear like bleeding Ultrasound Good for evaluation of carotid arteries Transcranial doppler Cerebral Angiography Gold standard EEG Status epilepticus vs. metabolic encephalopathy 3 spike and wave ( absence seizures Cranial Nerves CN palsies by themselves do not indicated brainstem disease / limb ataxia is not only cerebellar disease, but also brainstem (cerebellar peduncles), severe position sense loss and cerebral disease (infrequently) impaired dysdiadochokinesia (rapid alternating movements) implicates motor, pyramidal, extrapyramidal, cerebellar and is most often early finding of hemiparesis Oculomotor CN III [HYPERLINK "pics/fn-oculomotor.jpg"pic] Sympathetic pathway Hypothalamus ( C8-T2 ( superior cervical ganglion ( sweating (one path) and Mullers muscles (eyelids) and dilator pupillae / because pathway splits (can have Horners without anydrosis) Parasympathetic pathway Retina ( optic n. ( chiasm ( tract ( pretectum ( Edinger-Wesphal ( CN III ( ciliary ganglion ( sphincter pupillae Pupil in coma Metabolic/diencephalic ( 2-3 mm reactive Pretectum ( 5-6 mm, round, NR Midbrain ( 4-5 mm, irregular, NR Pons ( pinpoint, reactive Uncal herniation ( ipsilateral, fixed dilated from CN III compression Narcotic overdose ( pinpoint, reactive Barbiturate overdose ( 4 mm, NR Note: if entire CN III destroyed, pupil will be dilated (loss of parasympathetics), if eye is down and out, eyelid closed, and pupil not constricted, consider partial CN III damage (e.g. diabetic neuropathy) Neuroanatomy of gaze Horizontal gaze ( Left eye is left PPRF to left 6th and contralateral right MLF and right 3rd / MLF lesion is an INO (internuclear opthalmoplegia) / left PPRF produces left lateral gaze, lesion causes deviation to right Upward gaze ( pretectum and posterior commisure Downward gaze ( riMLF Pupil ( afferent pupillary defect (APD) ( implies optic nerve problem (symmetric APD may be normal variation) Visual Defects Optic nerve central scotoma, decreased visual acuity, unilateral altitudinal hemianopia Optic chiasm in pituitary tumor, central scotoma (one or both) precedes bitemporal hemianopia / it may be as subtle as a color problem, also use pinhole to correct acuity Optic tract contralateral homonymous hemianopia (often affecting macula) / incongruent VF defect (uncommon) also implies optic tract lesion Optic radiations - homonymous hemianopia or quadrantanopsia, contralateral Occipital - homonymous hemianopia or quadrantanopsia, contralateral / homonymous scotomata / bilateral altitudinal hemianopia / temporal crescent (monocular, contralateral and just about the only unilateral VF defect seen with occipital lesions (otherwise its the optic n.) Nystagmus (see  HYPERLINK \l "vertigo" vertigo) mostly of central origin (brainstem) vs. toxic effect Others: direction fixed seen with CN VIII (contralateral nystagmus with rotary element identical in all directions of gaze), BPPV and congenital nystagmus Diencephalic syndrome Most common hyperalert, euphoria, FTT (anorexia in children, obesity in adults) Less common vomit, nystagmus, optic atrophy, polyuria (less common) Spasmus Nutans early childhood (1st year) / nystagmus, head nodding / complete recovery Nervous System Neoplasia childhood tumors of CNS medulloblastoma - homer-Wright rosettes ependymoma - perivascular pseudorosettes choroid plexus papilloma and carcinoma craniopharyngiomas ( HYPERLINK \l "craniopharyngioma" children) Adults (supratentorial) metastases > glioblastoma multiforme > meningioma > pituitary Presentation: 30% with headaches (dull/steady, worse in morning, exacerbated by coughing), nausea, vomiting, focal neurological defects, seizures / symptoms are progressive over time Diagnosis: focal CNS findings, seizures, lethargy / CT and MRI with contrast Treatment: radiation therapy [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/15/1527" NEJM] or tumor excision / almost all anaplastic astrocytomas and gliomas recur Brain metastases 25% of cancer patients die with intracranial mets Presentation: similar to primary CNS tumor / 3-8% involve leptomeninges / multifocal signs (cranial nerve palsies, extremity weakness, paresthesias, loss of DTRs Diagnosis: CT or MRI / CSF samplings (at least 3) to diagnose leptomeningeal involvement Treatment: resection or radiotherapy / others depending on specific cancers bronchogenic carcinoma > breast cancer > melanoma > renal cell carcinoma > colon Specific CNS Tumors Astrocytomas -protoplasmic vs. gemistocytic (may be aggressive) Astrocytoma - NO vascular proliferation / NO necrosis Anaplastic astrocytoma - vascular proliferation but NO necrosis Glioblastoma multiforme - necrosis with or without pseudopallisading Pilocytic astrocytoma compact areas (rosenthal fibers) / loose areas (eosinophilic granular bodies and stellate astrocytes) Pleomorphic xanthroastrocytoma Subependymal giant cell astrocytoma Desmoplastic astrocytoma of infancy Meningioma meningothelial whorl / syncytial, fibrous, transitional (may have psammoma bodies) Schwannoma (Neurilemmoma) antoni A (nuclear palisading) / antoni B MRI better than CT (shows tissue better and evaluates spinal canal involvement) Neurofibroma may accompany von Recklinghausens oligodendroglioma - artifactual fried egg appearance anaplastic oligodendroglioma myxopapillary ependymoma - occurs in cauda equina subependymoma colloid cyst of 3rd ventricle gangliocytoma ganglioglioma - plus neoplastic glial cells central neurocytoma - in foramen of Monroe germinoma - most frequent pineal tumor pineocytoma pineoblastoma Dementia Incidence: 1% by 60 yrs / 5% by 65 yrs / 20% by 80 yrs / 50% by 85 yrs Ddx: 1st Alzheimers (70%), 2nd Alcoholism, 3rd Vascular (10%) Neurological:  HYPERLINK \l "alzheimers" Alzheimers,  HYPERLINK \l "picks" Picks,  HYPERLINK \l "lewybody" Lewy Body,  HYPERLINK \l "parkinsons" Parkinsons,  HYPERLINK \l "als" ALS,  HYPERLINK \l "huntingtons" Huntingtons,  HYPERLINK \l "cjd" CJD,  HYPERLINK \l "nph" NPH,  HYPERLINK \l "ms" MS Drugs: analgesics, diuretics, anticholinergics, antihypertensives, psychotropic, sedative-hypnotics Others:  HYPERLINK \l "meningitis" infectious (HIV, neurosyphilis, lyme), toxic/metabolic ( HYPERLINK \l "hypothyroid" hypothyroid,  HYPERLINK \l "wilsons" Wilsons,  HYPERLINK \l "b12" B12 deficiency, etc),  HYPERLINK \l "cnsneoplasia" intracranial tumors, paraneoplastic syndromes Work-Up History Use of medication (analgesic, anticholinergic, psychotropic, sedative-hypnotic) Distinguish from depression (depression usually has poor effort in answering questions whereas dementia has good effort but incorrect answers) Reversible causes generally do not present with constellation of findings (aphasia, apraxia, aculculia, agnosia) Hypothyroid causes depression, irritability, mental slowing Psychiatric, myelopathic and/or neuropathic changes of B12 deficiency may occur in absence of anemia; low B12 levels also may have no clinical manifestations HIV-dementia (20% of HIV patients) often shows psychomotor slowing and focal neurological signs, but dementia is rarely the sole presentation  HYPERLINK \l "cnsvasculitis" Cerebral vasculitis presents with progressive cognitive decline or based on area of involvement Testing Mini-mental status exam Labs: CBC, urinalysis, TSH, B12, folate, RPR + non-contrast head CT [~10% yield] HIV, Apo E testing (utility debated) CSF reserved for atypical cases Imaging ( infarction, neoplasm, extracerebral fluid, HYPERLINK \l "icp"hydrocephalus CXR MRI if motor dysfunction (rigidity, abnormal reflexes, asymmetry) [can diagnosis some ischemic changes missed by CT] EEG toxic/metabolic, subclinical seizures, Creutzfeldt-Jakob Neuropsychological testing impaired verbal memory and category naming is suggestive Physical exam: frontal release signs (rooting reflex, Myersons sign, palmomental reflex, bilateral grasp reflex) Vascular Dementia Urinary dysfunction, gait disturbance / can have Parkinsonian motor features of CVA Periventricular white-matter lesions are non-specific (can occur in normal aging) Vitamin Deficiencies (causing dementia) Thiamine ( HYPERLINK \l "thiamine" see other) Wernickes horizontal nystagmus, opthalmoplegia, cerebellar ataxia, encephalopathy (psychoses), orthostatic hypotension Treatment: IV thiamine (with glucose otherwise can cause metabolic neuronal death) Korsakoffs confabulation, confusion, memory loss (irreversible) Vitamin B12 ( HYPERLINK \l "b12" see other) subacute combined degeneration (ascending first, then descending track demyelination) Folate ( HYPERLINK \l "folate" see other) deficiency early in gestation causes neural tube defects Niacin ( HYPERLINK \l "niacin" see other) dermatitis, diarrhea, dementia - degeneration of cortical and BG neurons (rare) Metabolic Disturbances Hypoglycemia - loss of pyramidal hippocampal neurons and cortical III-IV Hyperglycemia - hyperosmolar coma (type 2) or diabetic ketoacidosis (type 1) Hepatic Encephalopathy seizures, rigidity, asterixis (flapping tremor, hyperreflexia) Alzheimers 11 cells / edema / symptoms may resolve only 48-72 hrs after normalization of BUN (although symptoms may not correlate to BUN) / give  HYPERLINK "pharm.doc" \l "lactulose" lactulose +/-  HYPERLINK "pharm.doc" \l "flagyl" flagyl Toxic Disorders Carbon monoxide Headache, nausea, confusion Mechanism: heme unable to let go of CO molecules, so heme cannot function properly to deliver O2 to body tissues Pathology: bilateral globus pallidus necrosis (medial) Diagnosis: venous or arterial carboxyhemoglobin levels Treatment: 100% FiO2 (hyperbaric if possible) to displace CO from heme Methanol bilateral putamen and claustrum necrosis (lateral) / retinal ganglion cell death Chronic ethanol ataxia, gait disturbance, nystagmus / degeneration of cerebellar vermis Rhabdomyolysis ( HYPERLINK \l "rhabdomyolysis" see other) Serotonin syndrome ( HYPERLINK \l "serotonin" see other) Fetal alcohol syndrome Marchiafava-Bignami acute necrosis/dementia due to cheap red wine Radiation injury pattern of vasogenic and coagulative necrosis Lead cortical cell death (demyelination) in children peripheral neuropathy in adults (wrist and foot drop) Degenerative Neurological Diseases Alzheimers (dementia Alzheimers type or DAT) 70% of dementia / 4 million in US / 15% familial (apoE e4) / survival 8-10 yrs Presentation: aphasia, agnosia (visual-processing), apraxia (disorder of skilled movement, tools use), personality changes (passivity, stubbornness, hostility, paranoia), delusions (up to 50%, early onset predicts rapid deterioration), depression/anxiety (40%), hallucinations (25%) Motor ( rigidity and postural instability mimicking Parkinsonism occurs in 30%, usually progresses more rapidly (early extrapyramidal signs suggests atypical variant or other neurological disease) Pathology: decreased ACh activity (with increased butyrylcholinesterase activity) / neuritic plaques (A,B amyloid, Congo Red, Maltese cross birefringence / neurofibrillary tangles (paired helical fragments of hyperphosphorylated tau protein, intracellular) / Hirano bodies (granulovacuolar degeneration) / loss of cholinergic neurons in NB Meynert, loss of serotonergic and dopaminergic neurons in brainstem amyloid deposits in CNS vasculature also Diagnosis: PET with fluorodeoxyglucose (FDG-PET) (93% sensitivity, 76% specificity), MRI only rules out other things (does not diagnose DAT), MMSE and other functional testing Ddx ( HYPERLINK \l "dementia" see dementia): depression, multi-infarct dementia, other neurodegenerative dementia (see below),  HYPERLINK \l "hypothyroidism" hypothyroidism, drugs,  HYPERLINK \l "b12" B12 deficiency,  HYPERLINK \l "nph" NPH, alcoholism, HIV, syphilis Treatment: Cholinesterase inhibitors (ChEIs) ( HYPERLINK "pharm.doc" \l "aricept" donepezil, rivastigmine, galantamine) improve cognitive function and global clinical state  HYPERLINK "pharm.doc" \l "risperidone" risperidone reduces psychotic symptoms and aggressive behavior (recent studies 10/6 suggest side-effects may outweigh benefits; but Risperdal has been generally shown to be the most tolerated) SSRI for depression BZ for insomnia  HYPERLINK "http://www.alz.org" www.alz.org DAT Lewy Body Variant More rapid / early onset of extrapyramidal signs (rigidity or tremor) Frontotemporal Degeneration (FTD) Picks disease much less common than DAT (1:20) / earlier onset than DAT / course from 2-10+ yrs Presentation: disinhibited behavior / +/- cognitive impairment on testing / aphasia and personality changes usually precede memory impairment (opposite of DAT) Radiology: atrophy of frontal/temporal lobes (sparing of posterior 1/3 of superior temporal gyrus) / can be asymmetric / left > right in 60% of cases Pathology: classified into three type A, B, C / pick cells (chromatolytic or ballooned neurons) / Pick bodies (argyrophilic, tau-positive inclusions) Other FTDs: Primary progressive aphasia (usually without dementia) Semantic dementia Frontal lobe dementia Corticobasal ganglionic degeneration FTD with parkinsonism linked to chromosome 17 Huntingtons Chorea General: onset 35-40 yrs / severe progressive atrophy of caudate and putamen / non-progressive reduction in brain weight in all grades Genetics: short arm of chromosome 4 / CAG triplet repeat / shows anticipation Molecular: loss of medium spiny GABAergic, sparing of large aspiny cholinergics in striatum Presentation: small writhing movements (athetosis) > choreoform jerking movements Radiology: caudate atrophy on CT scan (very reliable finding) Labs: triplet repeat test can rule out disease Parkinsons Disease General: 500,000 in US Presentation: 1) bradykinia 2) slow thinking 3) rigidity 4) loss of balance 5) tremor 30% get dementia (atrophy of brain stem and cortex) can cause low back pain, leg pain that is often confused with other entities (treatment is more PD meds) central and/or peripheral autonomic insufficiency (see treatment for  HYPERLINK \l "shydragers" Shy-Dragers) gait is shuffling, festinating (versus apractic gait of NPH) may have small handwriting (micrographia) Pathology: depigmentation of substantia nigra (pars compacta) and locus ceruleus / Lewy bodies (also in 10% of normal population) Molecular: MPTP converted to toxic MPP+ by MAO-B (inhibited by seligiline and smoking) Treatment: L-dopa/carbi-dopa ( HYPERLINK "pharm.doc" \l "synemet" Synemet): benefits are immediate, do not stop abruptly to avoid risk of  HYPERLINK \l "nms" NMS) Artane and Cogentin: can help restore balance of Ach activity psychosis secondary to PD medication seems to respond best to atypical antipsychotics Comtan blocks COMT Diffuse Lewy Body Disease Hallucinations (more visual), delusions, ?signs of parkinsonism / antipsychotics may actually worsen underlying disease Parkinsonism-dementia form of ALS that occurs in Guam and Japan / no amyloid accumulation Parkinsonism-like syndromes Post-Encephalitic Parkinsonism neurofibrillary tangles / Lewy bodies rare Striatonigral Degeneration no Lewy bodies / pigmental putamenal atrophy (form of MSA) / does not respond to L-dopa Progressive Supranuclear Palsy (PSP) akinesia, opthalmoparesis, dementia / globose type of neurofibrillary tangle Hallervorden-Spatz disease childhood dystonic syndrome / discoloration of globus pallidus and pars reticulata / axonal spheroids Multiple System Atrophy Spinocerebellar ataxia type 1 (olivopontocerebellar atrophy) most common form of MSA / ataxia, rigidity, oculomotor / CAG triplet expansion / AD Shy-Dragers syndrome nigral disease (Parkinsonism), ANS symptoms (neuronal degeneration) Treatment: stop BP meds, increase dietary salt , waist-high compression stockings, fludrocortisone 0.1 to 0.5 mg qd, increase water intake, small but frequent meals, avoid excessive heat, avoid Valsalva maneuver, elevate head of bed, correcting anemia / in some cases, L-dopa/carbi-dopa may actually worsen ANS symptoms Friedreichs ataxia most common inherited progressive ataxia / AR / onset before 20s / GAA repeats / loss of frataxin function / Symptoms: cardiomyopathy (arrhythmias, EKG changes), skeletal deformities, DM Acute cerebellar ataxia viral infection, brief duration / less than of cases show increased WBCs in CSF Other Atypical Dementias Creutzfeldt-Jakob Disease (CJD) General: prions from infected tissue (cannibalism, cow brains, corneal transplants) / familial form exists / other prion diseases include Gerstmann-Straussler-Scheinker syndrome Incidence: 1 in 167,000 (maybe growing) Presentation: personality changes (irritability), somatic sensations, dementia, motor signs (myoclonus, Parkinsons-like, etc) Diagnosis: brain biopsy only definitive method EEG: slowing and periodic sharp complexes are diagnostic, but may be absent early on Course: rapidly progressive over 1-2 years; no treatment Dialysis encephalopathy syndrome aluminum-containing phosphate binding gels used in dialysis / usually fatal Corticobasilar ganglionic degeneration Parkinsonism, apraxia (alien hand syndrome) Progressive subcortical gliosis Personality changes, inappropriate behavior Progressive supranuclear palsy Parkinsonism, opthalmoplegia, psychomotor slowing Cerebellar degeneration Family history (AD), ataxia, psychomotor slowing, emotional lability Olivopontocerebellar atrophy Family history (AD or AR), ataxia, eye-movement disorders, executive dysfunction Motor Neuron Disease Amyotrophic lateral sclerosis (ALS) (Lou Gehrigs Disease) [ HYPERLINK "http://content.nejm.org/cgi/content/full/344/22/1688?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1688&journalcode=nejm" NEJM] Affects motor neurons of cortex, brainstem, spinal cord Presentation: asymmetrical, slowly progressive / may present with fasciculations Upper motor neuron: spasticity, increased DTRs, (+) Babinski Lower motor neuron: fasciculations, loss of DTRs, flaccid paralysis, muscle weakness, muscle atrophy, (-) Babinski Diagnosis: combination of U and L motor neuron findings in 3 or more extremities (after ruling out other considerations) EMG would show widespread denervation, fibrillation potentials with preserved nerve conduction velocity, normal sensory Ddx: spondylotic cervical myopathy, syringomyelia, neoplasms, demyelinating diseases, benign fasciculations, polio, hypothyroidism, hyperparathyroidism, dysproteinemia, lymphoma, heavy metal poisoning, post-radiation effects, Guillain-Barr syndrome Course: almost always progresses to respiratory failure/death Sporadic 60s, more males, 2-7 yr course / variants include progressive muscular atrophy, progressive bulbar palsy, primary lateral sclerosis Familial 10% of cases / eosinophilic inclusions in anterior horn cells / degeneration of posterior columns / onset in lower limbs with SOD-1 mutations Treatment: primarily supportive  HYPERLINK "pharm.doc" \l "Riluzole" Riluzole interferes with glutamate release (100 mg qd shown to prolongs life-expectancy 20%; even more in patients with bulbar onset) IGF-1 studies mixed (may not be approved?) Zonaflex relaxes muscles (increases speed, decreases pain) Spinal muscular atrophy (SMA) Degeneration of anterior horn cells of spinal cord MRI may show severe atrophy of entire muscles / may have intermediate form with preservation of adductor longus or mild form with fatty infiltration and increased intermuscular fat planes MRI of lower extremities for adjuvant in diagnosis and follow-up assessment Werdnig-Hoffman disease (infantile spinal muscular atrophy) progressive degeneration of anterior horn cells / pathognomic groups of large type I fibers floppy baby, frog position, hypotonia, weakness, decreased DTRs, tongue fasciculations / fatal < 2 yrs (recurrent respiratory infections) Kugelberg-Welander syndrome proximal muscle weakness after initial normal development / slow or no progression over years Other Motor Disease Tourettes ( HYPERLINK "http://www.utmed.com/psychiatry" see psyc) onset < 15 yrs / 1st clonazepam/clonidine, 2nd haloperidol, 3rd pimozide Benign Essential Tremor Intention tremor, may have cogwheel-like rigidity / may have finger to nose but without other cerebellar abnormalities / thought to be overactivity of sympathetics Treatment: B-blockers (propranolol) 1st line or ?mysoline, Klonopin, or Neurontin Restless Leg Syndrome Causes: idiopathic or anemia or renal insufficiency Exam: normal reflexes, motor / possible mild sensory loss Treatment: DA agonists ( HYPERLINK "pharm.doc" \l "pramipexole" pramipexole, pergolide, ropinirole) act directly / BZ or opioids provide indirect relief Idiopathic Dystonia Writers cramp Stiff Person Syndrome or Stiff Man Syndrome rare CNS, systemic disorder / rigidity of truncal and proximal limb muscles with intermittent superimposed spasms / anti-GAD65 or glutamic acid decarboxylase antibodies (same antibodies found in type I DM, associated with autoimmune syndromes) / Ab are produced intrathecally resulting in low GABA levels / sometimes alleviated by high doses of diazepam (some try plasma exchange and IVIG) Primary demyelinating diseases acute perivascular myelinoclasis Acute disseminated encephalomyelitis (ADEM) children / 3-21 days after infection or immunization / 15% mortality cellular immunity (NO Abs in CSF) Acute necrotizing hemorrhagic leukoencephalopathy (AHEM) (Weston-Hurst) hyperacute / rapidly fatal / Abs? / resembles EAE animal model Guillain-Barr syndrome acute inflammatory demyelinating polyradiculoneuropathy following Campylobacter jejuni (20-40%), respiratory infection, vaccination Presentation: distal then proximal (ascending paralysis) / paresis, paralysis, dysesthesia (50% facial diplegia, autonomic nerve abnormalities, CNS abnormalities) / may have chronic form Ddx:  HYPERLINK \l "mg" myasthenia gravis,  HYPERLINK \l "ms" multiple sclerosis,  HYPERLINK \l "cidp" CIDP,  HYPERLINK \l "als" ALS,  HYPERLINK "micro.doc" \l "polio" polio,  HYPERLINK \l "porphyria" porphyria, heavy metals,  HYPERLINK "micro.doc" \l "botulism" botulism, transverse myelitis, diptheric neuropathy, tick paralysis, lyme disease, HIV, meningitis Diagnosis:  HYPERLINK \l "emg" EMG shows diffuse demyelination (nonuniform slowing and conduction block) / CSF protein > 55 with little or no WBC / antibodies in CSF (anti-ganglioside Abs up to 50%) / EAN / MRI with normal or subtle enhancement of nerve roots Treatment: always admit to ICU and intubate for FVC < 15-20 ml/kg or MIP < 30 cmH2O or MEP < 40 cmH2O (30% require intubation) plasma exchange 200-250 mL plasma/kg body weight over 7 days IVIG 0.4 g/kg body weight daily for 5 days steroids have NOT been shown to be of benefit DVT prophylaxis and intense PT Course: 5% mortality Multiple Sclerosis (MS) Epidemiology: 20s and 30s / female:male 2:1 / 1 in 2000 / 2nd most common non-traumatic disabling neurological disease of young adults / associated with temperate climates Genetics: HLA DR2, B3, B7 (viral trigger?) / general population ( 0.1%, parent, uncle, aunt ( 5% / sibling ( 2% Mechanism: T-cells attacking white matter Pathology: irregular, patchy distribution / chronic, active plaques vs. shadow plaques (relapse, remit) / lesions occur in brain and spinal cord Presentation: limb weakness, paresthesias,  HYPERLINK \l "opticneuritis" optic neuritis, diplopia, urinary retention, vertigo / symptoms can be transient (days) or chronic / other findings include spasticity, incoordination, partial or complete paralysis / chronic cognitive dysfunction may occur / may present as isolated optic neuritis, transverse myelitis, brain stemcerebellar syndrome Diagnosis: 4% with both negative CSF and MRI / LP only needed in some cases (can make diagnosis based on clinical and MRI) CSF abnormal > 80% / mild lymphocytosis ( > 5 and usu. < 20) / mild protein elevation < 100 / IgG and oligoclonal bands > 90% (during flares) / can measure MBP to follow disease activity MRI abnormal > 80% / T2 hyperintense lesions in white matter, T1 contrast reveals active lesions / should find some periventricular lesions [HYPERLINK "pics/multiplesclerosis.gif"pic] (usu. enhancing, older lesions may appear as black holes) EEG: evoked potentials (not really necessary) abnormal (60-80%), may help find other areas of involvement Ddx [HYPERLINK "pics/msddx.gif"table]: B12 deficiency, neoplastic, paraneoplastic, infectious, autoimmune vasculitis, monophasic demyelinating syndrome (which then does not progress to MS),  HYPERLINK \l "stiffperson" stiff person syndrome Treatment: current strategy is to treat earlier and aggressively High-dose steroids used for acute attacks / 1 g day for 5 days (less effective later on in course) then slow taper over 2-3 weeks IFN reduces time between attacks (30%) / can exacerbate symptoms transiently IFN-1b (Betaseron) IFN-1a (Avonex, Rebif) given once a week Glatiramer (Copaxone) daily SC injection / synthetic amino acid combination Treat complications: Baclofen to reduce spasticity Anti-cholinergics for bladder storage problems Bethanechol for bladder emptying problems TCAs or tegretol for dysesthesias ( ~peripheral neuropathy-like issues) Course: 30% benign / 50% progress within 10 yrs / 40% classical relapsing-remitting / 30% chronic progressive with superimposed attacks / pregnancy often helps, but 6-9 months post-partum increased risk poor prognostic indicators: > 2 exacerbations/yr, motor/cerebellar involvement, older age at onset (> 40), residual motor/cerebellar deficits 6 months s/p attack, moderate disability by 5 yrs good prognostic indicators: initial attack is optic neuritis or pure sensory Primary Multiple Sclerosis Fatigue self-management strategies - managing time differently, adjusting activities, naps, minimize heat (cool beverages, cool showers), exercise program 1st  HYPERLINK "pharm.doc" \l "amantadine" amantadine 100 mg bid (morning and noon) mechanism unclear 2nd  HYPERLINK "pharm.doc" \l "pemoline" pemoline may cause irritability, anxiety and need LFTs checked q 2 wks 3rd methylphenidate and dextroamphetamine potential for abuse SSRI have been used successfully (even without any underlying mood disorders) Non-classic Multiple Sclerosis Acute (Marburg) rapid course less than 10 months / no evidence of antecedent infection Neuromyelitis optica (Devic) under 10 or over 60 / blindness and paraplegia / more common in Japan Diffuse cerebral sclerosis (Schilders disease) sporadic, diffuse / variant of MS occurring in children Concentric sclerosis (Balo) very rare, occurs in children / death in 3-5 yrs Demyelinating disorders associated with systemic disease central pontine myelinosis  HYPERLINK \l "marchiafava" Marchiafava-Bignami - cheap red wine PML from HYPERLINK "micro.doc" \l "jc"JC virus Note: blood-nerve-barrier is less effective in dorsal roots and dorsal and autonomic ganglia Peripheral Neuropathies Hereditary motor and sensory (CMT), sensory and ANS, tomaculous, giant axonal, amyloid neuropathy Acquired DM, paraneoplastic, systemic inflammatory, drug-induced, infection, carpal tunnel Predominantly sensory multiple mononeuropathy: sarcoidosis, malignancy, retroviruses, leprosy, hepatitis, lyme, CIDP Work-up Basic: CXR, TSH, FBS/A1C, Other HIV, Hep Panel, VDRL ANA, Ro, La SPEP, cryoglobulins Anti-MAG ( CIDP (can show up in CSF) Anti-Hu ( 80% sensitivity with paraneoplastic neuropathies Anti-GD1b/Anti-GQ1b EMG can distinguish congenital neuropathy from other forms 4 typical reasons to get EMG diagnose neuropathy (versus myopathy, other) characterize axonal versus demyelinating define extent rule out other forms of neuropathy in differential diffuse demyelination: markedly slow sensory nerve conduction velocities and conduction block on nerve conduction studies Note: examination of flexor hallucis brevis muscle may establish motor involvement which is not otherwise apparent (in larger muscles) MRI Congenital neuropathy can be minimal for a long time and then cause joint deformity later on (even beginning at an older age) / other types of neuropathy typically do not cause joint deformity Charcot-Marie-Tooth most common congenital neuropathy / slow progression over years Presentation: numbness without prickling or tingling, symmetric weakness on dorsiflexion of feet (steppage gait), asymptomatic weakness of hands, and pes cavus with hammer toes / has primary demyelinating form CMT Ia (resembles CIDP) Labs: may have increased CK (non-specific) Diagnosis: EMG (r/o other motor disease), can also do DNA testing for involved genes (commercially available tests) CIDP Labs: anti-MAG (can show up in CSF) Acquired neuropathy DM ( HYPERLINK \l "dm" see other) symmetric, ANS, focal, multi-focal, axonal and demyelinating usually distal occurs first (longer nerves) cranial and autonomic tends to be more asymmetric and reversible than the distal Inflammatory, dysglobulinemic plasma cell dyscrasias or Castlemans disease Drug-induced amiodarone, chloroquine Leukodystrophies Krabbes uremic, carcinomatous, small cell carcinoma of lung, leukemias Vasculitides PAN, RA, SLE,  HYPERLINK \l "Sjogrens" Sjogrens, Wegeners Infections HIV, HCV, HBV, HTLV-1, syphilis, lyme, leprosy Carpal Tunnel Syndrome Presentation: numbness/pain in fingers/hands, usually worse w/ wrist flexion (caused by involvement of median nerve) / also very common is compression of lateral femoral cutaneous nerve (from recent wt gain or other), causing numbness in lateral, upper thighs Causes: can be caused by repetitive trauma/overuse, but also can come from any inflammatory process in wrist (with tissue deposition) such as diabetes, hypothyroidism, RA, amyloidosis Physical exam: Tinels (tap on palm just distal to flexor retinaculum, elicits numbness/pain if positive), Phalens (bend wrists and hold backs of hands together for 1 minute, to check for numbness/pain) Diagnosis: can get EMG to confirm diagnosis, evaluate degree of nerve involvement Treatment: splint wrists at night, reduce causative activity, surgery if medical management fails DeQuervrains tenosynovitis focal wrist pain on radial aspect of hand due to inflammation of tendon sheath of abductor pollicis longus / should not have positive Tinel sign or median nerve involvement Treatment: conservative to intra-sheath steroid injection Spinal Cord Injury Note: increased threshold, low amplitude of compound muscle action potentials, and elongated latency correlated with degree of motor weakness Spinal cord infarction T4 and L1 are most vulnerable (boundary zones) / aortic aneurysms, atherosclerosis Spinal cord injury fracture is tender to palpation / brisk reflexes below lesion Treatment: NSGY consult, methylprednisolone may be helpful within 8 hrs / vertebral Cervical C6 upper arm, shoulder / index finger and thumb / biceps and brachioradialis C7 arm and forearm / middle finger / triceps Lumbar sciatic pain in both S1 and L5 / Treatment: NSAIDS and rest or surgery if not better in 2-4 weeks and/or radiography reveals nerve root compression L5-S1 (70%) outer aspect of foot / ankle tendon reflex / atrophy of gastrocnemus L4-L5 (25%) outer aspect of leg and dorsum of foot / great toe weakness / foot drop Extramedullary lesions Causes: metastatic (breast, prostate, lungs) primary (meningioma, neurofibroma) hematoma (warfarin) infection (Tb, many others) Cauda equina syndrome loss of sphincter control / numbness in buttocks/back of thighs / weakness, paralysis of dorsiflexion (L4) and toes (L4/5) and plantar flexion (S1) Diagnosis: plain films, bone scan, MRI (depends on situation) Treatment: steroids, urgent neurosurgery consult if cord compromised, urgent radiation-oncology consult if due to tumor effect Prognosis: 10% of patients with paraplegia from neoplasm recover ability to walk Intramedullary lesions Causes: astrocytoma, ependymoma, syringomyelia, vascular infarcts, plaque demyelination (MS) Syringomyelia central canal / loss of pain/temperature bilaterally, sparing of pinprick and proprioception / sacral sparing differentiates from extramedullary Outer spinal injury ipsilateral weakness / contralateral loss of pain/temperature below lesion Myopathy  HYPERLINK \l "myopathycongenital" Congenital  HYPERLINK \l "muscular" Muscular Dystrophies  HYPERLINK \l "duchenne" Duchenne,  HYPERLINK \l "beckers" Becker,  HYPERLINK \l "emery" ED, others Metabolic  HYPERLINK \l "mcardles" McArdles, Type VII  HYPERLINK \l "myopathymitochondrial" Mitochondrial  HYPERLINK \l "myopathyinflammatory" Inflammatory  HYPERLINK \l "polymyositismuscle" polymyositis,  HYPERLINK \l "mg" MG,  HYPERLINK \l "ibm" IBM,  HYPERLINK \l "emf" EMF,  HYPERLINK \l "rhabdomyolysis" rhabdomyolysis  HYPERLINK \l "myopathyother" Other causes of myopathy hypothyroid/hyperthyroid hyper PTH HYPERLINK \l "conns"Conns polyneuropathy of DM steroid myopathy vitamin D deficiency uremic polyneuropathy Myopathy of systemic disease: heart, lungs, liver Drug-induced myopathy: many Muscular Dystrophies histologic myopathic changes group atrophy and type grouping / central nuclear migration / hypertrophy / fiber type predominance / split fibers, basophilic fibers, target fibers, interstitial changes (fibrosis) Duchenne muscular dystrophy XLR / altered dystrophin protein / progressive debilitation until early death (20s) Beckers muscular dystrophy milder form Emery-Dreifuss myopathy early onset / shoulders, calves, heart atrophy Autosomal dominant dystrophies AD / atrophy of face, shoulders (but not deltoid), calves / slowly progressive, prolonged survival Myotonic dystrophy and non-dystonic myotonias cranial changes, cataracts, small testes, endocrine disturbances (diabetes) / central nuclei / may develop slowly progressive respiratory failure (abnormal sleep study may be earliest indicator) Congenital muscular dystrophy same as HYPERLINK \l "_werdnig"floppy baby? neonatal hypotonia Bethlem muscular dystrophy defective collagen 6 / contractures Late-onset muscular dystrophies Oculopharyngeal dystrophy late onset / opthalmoplegia and dysphagia / rimmed vacuoles Facioscapularhumeral dystrophy Congenital myopathies Nemaline myopathy intracytoplasmic rods / variable inheritance Centronuclear myopathy selective hypertrophy of type I fibers Central core disease AD / type one fibers devoid of mitochondrial enzymes centrally / predisposes to malignant hyperpyrexia Mitochondrial myopathies Oculocraniosomatic syndrome rare AD inheritance / called Kearns-Sayre syndrome if onset in childhood Mechanism: myotonia (prolongation of muscle contraction) Presentation: progressive external opthalmoplegia that is symmetric and develops over many years, ptosis and masseter wasting produce characteristic facial appearance, proximal muscle weakness, myotonia (cant let go of doorknobs) Complications: diabetes, retinitis pigmentosa, cataracts, frontal balding, testicular atrophy, epilepsy, hypothyroidism, cardiomyopathy, and heart block Carnitine deficiency limb girdle myopathy presenting in 2nd decade Glycogen storage diseases (see  HYPERLINK \l "mcardles" McArdles) Inflammatory myopathies Prevalence of Antibodies Anti Jo-1 (20-30%) Anti-Mi-2 (8%, 20% of DM) Histone (17%) U1-RNP (12%) Ro (10%) Pm-Scl (8%) Polymyositis ( HYPERLINK \l "polymyositis" see other) proximal, painful muscle weakness / autoimmune, ANA / biopsy NOT always conclusive Myasthenia Gravis 1 in 7500 / women: 20-30s, men: 50-60s Associations: hyperthyroidism (3-8%) and thymomas (~10-15%) Presentation: weakness and fatigue / early: cranial, facial (ptosis, diplopia, dysarthria, nasal speech) / later: generalized (85%) / proximal limb weakness (may be asymmetrical) Diagnosis: AChE inhibitor (IV edrophonium) test / repetitive nerve stimulation gives decremental response / ACh receptor antibodies (80%) / thoracic CT or MR to detect thymoma Treatment: Mild ( AChE inhibitors (stigmines) Severe ( prednisone, plasmapheresis, Cyclosporin A, Immuran, Cellcept Younger pts ( remove thymus to decrease production of anti-ACh antibodies Older pts ( thymus often removed prophylactively / always remove if a tumor is present Note: current thought is to remove thymus automatically in anyone from puberty to 55 yrs Lambert-Eaton cranial nerves (ptosis, diplopia) (70%), bulbar (dysphagia, dysarthria), proximal lower limbs (mostly), other muscles (some) Mechanism: IgG against voltage-gated calcium channel receptors at NMJ prevents ACh release; generally, this is a paraneoplastic syndrome / ~50% of cases have associated cancer (usu. small cell carcinoma of lung); may allow earlier detection of cancer, but cancer is less likely in patients < 40 yrs Diagnosis: EMG readily distinguishes from MG as well as PM Treatment: pyridostigmine, guanidine, diaminopyridine, plasmapheresis, immunosuppressive therapy (maybe) Inclusion body myositis progressive, painless weakness (distal) Mechanism: CD8 T-cells involved / exact sequence of events unclear (could be response to primary degeneration of muscle) Genetics: 2-3 fold prevalence of DR1 Pathology: enzyme tests suggest neurogenic picture / rimmed vacuoles containing amyloid (ability to eliminate amyloid is lost), mononuclear cell invasion of nonnecrotic muscle fibers and/or 15-18 nm tubulofilaments by EM Malignancy: relative risk 2.4 (no particular type) Treatment: try steroids because they occasionally help, but not generally / some are trying IVIG sporadic (SIBM) most common inflammatory myopathy in over 50 population / males 2-3x females / more in Caucasians / painless proximal muscle weakness, progresses over yrs, distal involvement in 50% (predominant in 30%) / has characteristic, often asymmetrical pattern that is clinically distinguishable (if you grab the textbook) / CK normal in 20% (usu. does not exceed 12 x normal) / EMG atypical in 30% (i.e. may look like neuropathy or seem normal) hereditary (HIBM) 20s to 30s / AR and AD forms / slowly progressive / early involvement of distal muscles / absence of inflammation on biopsy Eosinophilic Fasciitis (Schulman syndrome) great prognosis Presentation: edema of lower extremities and taut skin, flexion contractures / no primary muscle involvement (can extend from fascia to muscle) Acute (short prodrome) ( low-grade fever, myalgias, and fatigue, thickening of subcutaneous tissues ensues, sparing of face, pitting edema Over weeks ( limited ROM in small joints and large joints (less) Complications (uncommon): untreated could lead to ?compartment syndrome, a lot of unnecessary echocardiograms, aplastic anemia, amegakaryocytic or idiopathic thrombocytopenia, some report delayed lymphoproliferative disorders Diagnosis: can get MRI to localize involvement (must get fat saturation study) Labs: eosinophilia, elevated ESR, and hypergammaglobulinemia Treatment: often improves spontaneously, but resolution faster with steroids / relapses infrequent / can use serum aldolase to follow improvement Eosinophilic Myositis (worse prognosis) rare disease, more in men, 30 to 60 years, half with intense exertion prior to the onset Presentation: low-grade fever, transient maculopapular rash, muscle pains, and cramps and weakness of the extremities +/- paresthesias / can have predominance of fasciitis, myositis, peripheral neuropathy or combination Note: severity peripheral eosinophilia correlates with level of tissue inflammation Complications: Diffuse fasciitis Proximal muscle weakness and elevated CK (+/- neuropathy) CNS: neurocognitive deficits and peripheral neuropathy (neurotoxins? MBP?) / can occur 1 to 23 months after onset / less likely to respond to therapy CVS: heart block, arrhythmias, and pulmonary infiltrates, resulting in death Esophageal motility Diagnosis: history, organ involvement, serologic studies Labs: serum CK (can be normal with EF, usu. normal or minimal elevation with EMS), RF may be present (unlike eosinophilic fasciitis), ESR often moderately elevated (similar to others) EMG: myopathic pattern with eosinophilic myositis (less common with EF), may show axonal or demyelinative lesions Biopsy: muscle Bx can aid in the diagnosis of eosinophilic myositis / tissue biopsy shows infiltrates of vessels and connective tissues with everything but eosinophils (similar to toxic oil syndrome from rapeseed oil) Ddx: PAN, RA, allergic granulomatosis, hypersensitivity vasculitis, scleroderma, or parasitic infections Treatment: high-dose prednisone at 1 mg/kg/d +/- cytoxic agents Eosinophilia-myalgia syndrome and toxic oil syndrome Presentation: insidious onset of fatigue, myalgias, peripheral eosinophilia associated with the chronic ingestion of L-tryptophan or oil products containing bad things like certain aniline derivatives / mostly in white women Polymyalgia rheumatica (PMR) 1 in 133 of > 50 yrs population (peak 80-90 yrs) / women > men 2:1 / not a true myopathy and no joint erosions (synovitis, bursitis and not so much actual joints), can have swelling of joints/bursa [HYPERLINK "pics/pmr-hands.jpg"pic] / 15-20% have  HYPERLINK \l "gca" giant cell arteritis (r/o if any symptoms present) Presentation: acute onset ( < 2 wks) of severe myalgias (shoulder > pelvis, neck > torso, proximal arms, thighs) / morning stiffness > 30 mins / 1/3 have fever, malaise, fatigue, anorexia, weight loss Ddx: RA, PM, fibromyalgia, malignancies, RS3PE, infections, depression Labs: ESR normal to elevated (> 40) / usu. normal CK and EMG / biopsy normal (not usually performed) Treatment: NSAIDS or low-dose steroids (15-20 mg/d) usually rapidly effective (different treatment regimen from GCA) RS3PE seronegative, symmetric synovitis with pitting edema / acute onset bilateral, diffuse, symmetric swelling of wrists/hands with marked, pitting edema of dorsum of hands > feet / persistently seronegative for RF / responds rapidly to small doses of steroids Other Causes of Myopathy (~weakness) Hypothyroidism ( HYPERLINK \l "hypothyroidism" see endocrine) cramps, pain, stiffness / proximal muscle weakness (33%), muscle enlargement / elevated CK Hyperthyroidism ( HYPERLINK \l "hyperthyroidism" see endocrine) proximal muscle weakness and atrophy / brisk reflexes / bulbar/proximal or generalized pattern / decreased CK Hyperparathyroidism ( HYPERLINK \l "hyperpth" see endocrine) CK normal or elevated / proximal muscle weakness, wasting, brisk reflexes / Ca and PO4 do not correlate with disease / may be primary or secondary to renal failure Polyneuropathy of Diabetes Mellitus (see endocrine) Hyperaldosteronism (Conns) ( HYPERLINK \l "conns" see endocrine) Addisons  HYPERLINK \l "acromegaly" Acromegaly Excess steroid (exogenous or Cushings) normal CK / EMG unremarkable / hyperglycemia? Vitamin D deficiency Uremic polyneuropathy?  HYPERLINK "micro.doc" \l "botulism" Botulism dilated pupils / repetitive nerve stimulation gives incremental response Myopathy of Systemic Disease (lung, heart, liver) Non-dystrophic myopathies (Channelopathies) Sodium channel disease (hyperkalemic periodic paralysis, paramyotonia congenital) and chloride channel disease (Thompsens, Beckers) Treatment: quinine, procainamide, phenytoin Metabolic myopathies Disorders of carbohydrate and lipid metabolism Chronic Drug-Induced Myopathy Causes: HMGCoA reductase or  HYPERLINK "pharm.doc" \l "statins" statins (< 1%, lovastatin is worst, risk increased with elevated drug levels via  HYPERLINK "pharm.doc" \l "p450" P450 interactions), gemfibrozil, nicotinic acid, clofibrate (more than statins), alcohol, aminocaproic acid, procainamide, zidovudine, L-tryptophan, colchicine Rhabdomyolysis (pigment-induced ATN) Causes: Drugs: alcohol, cocaine, amphetamines, LSD, heroin, PCP Medications: diuretics, narcotics, barbiturates, anesthetics (halothane), Succinylcholine, Aminocaproic acid, terbutaline, quinine, TCAs, phenothiazides, theophylline, steroids) Prolonged immobility (including surgery), strenuous exercise, seizures, crush injury, malignant hyperthermia, heat stroke Electrolytes: hypokalemia, hypophosphatemia, hyperosmolar states, hyperglycemia, hypernatremia Infections (viral): Coxsackie, Echo, Influenza, Measles, Infections (bacterial): Clostridium, Staphylococcus, Legionella, Typhoid, Tularemia Toxins Mechanism: ARF from myoglobin damaging renal tubules and causing tubular obstruction and all exacerbated by hypovolemia from fluid sequestration into necrotic muscle Complications (in addition to renal failure): hypercalcemia may occur 2-3 weeks after acute muscle injury as deposited calcium dissociates from deposited CaPO4 salts Labs: muscle breakdown directly causes elevated CK, ! uric acid, ! K, ! PO4; low Ca results from binding to PO4 and low vitamin D levels; Cr may rise more than BUN (unlike prerenal); (+) anion gap acidosis; UA shows (+) blood (! hemosiderin), myoglobinuria without RBC s on exam (unless there is an additional reason for RBCs) Treatment: aggressive fluid resuscitation, hydration (as much as tolerated by cardiopulmonary status, e.g. 200 cc/hr NS; diuretics may worsen situation) / alkalinization of urine not proven to prevent tubular damage from rhabdomyolysis and pigmenturia and may increase risk of  HYPERLINK \l "hypocalcemia" hypocalcemia 9/06 Neuroleptic malignant syndrome (NMS) Mechanism: effect of using anti-dopamine agents or sudden withdrawal dopaminergic agent (Parkinsons patients who abruptly stop levodopa) Usual drugs: haldol, thiothixine but also prochlorperazine, promethazine, droperidol, and metoclopramide Note: can occur any time during treatment (doesnt matter how long theyve been on it) / not result of overdose (serum levels of drug do not correlate with NMS) Risk factors: prominent psychomotor agitation, higher doses, increased dose in short time (< 5 days), IV administration, organic brain abnormalities (infection, encephalitis, AIDS, tumors, etc.), dehydration, history of increased CK with neuroleptics / Note: NMS less common with atypical antipsychotics than typical Presentation: altered mental status (confusion, delirium, stupor, coma) motor symptoms (rigidity, tremor, akinesia, bradykinesia, dystonia, mutism, dysarthria, involuntary movements) hyperthermia (38 to 41oc) autonomic instability (respiratory irregularities, incontinence, cardiac arrhythmias, labile blood pressure) Ddx: non-NMS drug effect, encephalitis, other neurological condition, mood disorder with catatonia Labs: ! WBC (10-40K), elevated CK , ! LDH, ! AST, ! ALT, ! alk phos, hypocalcemia (sequestration in muscle), ! pH Course: usually evolves over 24 to 72 hours (rarely, slower onset over a few days may occur), usually lasts 7-10 days / usually MS changes 1st then rigidity ~fever ~ANS findings Complications: renal failure (from  HYPERLINK \l "rhabdomyolysis" rhabdomyolysis),  HYPERLINK \l "dvt" DVT (stasis, hypercoagulable state), multiple system failure (respiratory, cardiac, SZ, DIC), residual catatonia may last weeks to months Treatment: supportive (needs ICU, IV fluid, temp, alkalinize urine, DVT prophylaxis) pharmacologic (believed to reduce duration by a few days)  HYPERLINK "pharm.doc" \l "bromocriptine" bromocriptine central dopamine agonist / only PO (titrate up to 60mg/d) / dose-limiting hypotension, psychosis, nausea  HYPERLINK "pharm.doc" \l "dantrolene" dantrolene skeletal muscle relaxation by inhibition of Ca release from SR / PO (50-200 mg/d) or IV (2-10 mg/kg/d) / hepatotoxicity (esp. > 10 mg/kg/d) can give either alone or give IV dantrolene followed by PO bromocriptine / must continue treatment at least 10 days after resolution of episode (and then slowly taper off treatment)Other agents used: amantadine, apomorphine (not available in U.S.), PO or IV  HYPERLINK "pharm.doc" \l "levodopa" levodopa, IV  HYPERLINK "pharm.doc" \l "clonidine" clonidine (for BP control)  HYPERLINK "pathology.doc" \l "ect" ECT useful in refractory cases (consider if no improvement after 48 hrs of supportive/pharmacotherapy) / also good for ALC or residual psychosis following NMS episode Note: must distinguish whether caused by stopping neuroleptic or dopaminergic agent (must restart comparable agent following day) or starting/changing neuroleptic (must discontinue offending agent) Recurrence: 40% risk on rechallenge (much lower if you wait longer before restarting), concomitant lithium increases risk Malignant hyperthermia Inhalational anesthetics: halothane, isoflurane, sevoflurane, and desflurane depolarizing muscle relaxants: succinylcholine Note: it is safe to use thiopental, etomidate, and propofol Presentation: masseter spasm often earliest indicator, then tachypnea, tachycardia, increasing end-tidal carbon dioxide levels and acidosis then hyperthermia and cyanosis, rigidity, rhabdomyolysis Note: can pre-screen with halothane-caffeine contracture test in vitro Treatment: stop offending agent, supportive measures Neuroleptic-induced heat stroke More in elderly and young / impaired sweating / risk increased by concomitant use of anticholinergics (Cogentin) / can produce seizures Treatment: supportive, rapid cooling, fluids Acute lethal catatonia Presentation: posturing, waxy flexibility (cerea flexibilitas), hyperactivity preceded by behavioral changes in weeks leading up to motor deficits, which then may progress to hyperthermia, akinesia, and rigidity and death from respiratory and circulatory failure Treatment: electroconvulsive therapy (ECT) Serotonin syndrome Causes: SSRI, amphetamines, cocaine, dextromethorphan, meperidine, TCA, tramadol, MAO Presentation: mental status changes, neuromuscular (tremor, rigidity, seizures + shivering, ataxia, hyperreflexia, myoclonus, ankle clonus), autonomic dysfunction (flushing, labile, HTN, fever, though not as high as NMS, salivation, tachycardia), gastrointestinal dysfunction (nausea, vomiting, diarrhea) Complications: CV collapse, lactic acidosis, multiorgan failure, coma, death are all rare but possible outcomes Labs: WBC, CK, LFT variably elevated Course: recovery in 1-7 days after drug stopped / usually no sequelae Treatment: can give SSRI antagonists, cyproheptadine, chlorpromazine Central anticholinergic syndrome Presentation: altered mental status +/- hyperthermia, decreased sweating, mydriasis, dry mouth, and urinary retention Treatment: physostigmine (and supportive measures) CNS injury  HYPERLINK \l "cva" CVA  HYPERLINK \l "ich" intracranial hemorrhage  HYPERLINK \l "venoussinusthrombosis" venous sinus thrombosis  HYPERLINK \l "cnsvasculitis" CNS vasculitis Cerebrovascular Accident (CVA, stroke)  HYPERLINK \l "carotidstenosis" Carotid/vertebral artery disease (10-15%) Cardiac emboli (25-30%) Intracardiac thrombus or mass MI (anterior wall, septum, akinetic segment), cardiomyopathy, arrhythmias (Afib), cardiac myxoma Valvular rheumatic heart disease, bacterial endocarditis, non-bacterial endocarditis (Libman-Sacks, carcinoma), mitral valve prolapse, prosthetic valve Intracranial (40-50%) Vasculitides Primary CNS vasculitis systemic vasculitis (PAN, allergic angiitis), CTD (RA, scleroderma, Sjgrens), Wegeners, Behets, GCA, Takayasus,  HYPERLINK \l "lymphomatoidgranulomatosis" lymphomatoid granulomatosis Hypersensitivity vasculitis (serum sickness, drug-induced, cutaneous) Infectious vasculitis (lyme, meningitis, Tb, AIDS, opthalmic zoster, HBV) Sub-arachnoid hemorrhage or vasospasm Hematologic Hemoglobinopathies (sickle cell, HbSC) Hyperviscosity syndromes (polycythemia, thrombocytosis, leukocytosis, macroglobulinemia, multiple myeloma) Hypercoagulable states (carcinoma, pregnancy, puerperium, protein C/S deficiency, antiphospholipid antibodies) Drug-related: street drugs (cocaine, amphetamines, lysergic acid, PCP, meth, heroin, pentazocine), alcohol, OCPs Other: lipohyalinosis, fibromuscular dysplasia, arterial dissection, homocystinuria, migraine, moyamoya, other embolic (HYPERLINK \l "fatembolism"cholesterol, fat, bone, air) Types of Stroke ( HYPERLINK \l "cvasyndromes" see specific syndromes) MCA: contralateral hemiparesis (hemiplegia), hemianesthesia, homonymous hemianopsia dominant ( aphasia, nondominant ( apraxia, neglect Lacunar (often MCA territory, internal capsule): pure motor or sensory stroke, dysarthria-clumsy hand syndrome, ataxic hemiparesis ACA: leg paresis PCA: homonymous hemianopsia Basilar: coma, apnea, cranial nerve palsies TIA: any of above < 24 hrs Note: only bilateral hemispheric and basilar (RAS) strokes cause loss of consciousness! Aphasia Suggests left hemisphere lesion (most people, even left-handed have language on left) Wernickes from left inferior MCA fluid but meaningless speech / hemiparesis mild or absent Brocas from left superior MCA impaired speech / hemiparesis, hemisensory loss is common Ddx: brain tumor, hematoma (all kinds), abscess, endocarditis, MS, metabolic (ex. hypoglycemia), neurosyphilis Work-Up: CT without contrast (faster to get and good for r/o herniation, bleed) MRI CBC, glucose, coagulation, lipid, ESR, VDRL EKG and echo Vascular: carotid ultrasound, MRA or CT angiography / transcranial doppler or MRA Hypercoagulable work-up if relevant Treatment: Thrombolysis (tPA) < 3 hrs (see  HYPERLINK "pharm.doc" \l "thrombolysis" contraindications); does no higher than 0.9mg/kg over 60 mins / RF for ICH older age, female, black, h/o CVA, HTN > 140/100 Consider anti-platelets if no hemorrhage ASA has been shown to have slight reduction in mortality and risk of recurrence (plavix may be more effective but slightly higher cost and GI bleed risk) Consider heparin if no hemorrhage no studies (as of 2001) show mortality increase with heparin for acute CVA (some neurologists use it in specific circumstances) maintain cerebral perfusion (so-called ischemia penumbra): do not overtreat HTN (SBP goal should be 160 to ?) watch for signs of progression/herniation Long-term Treat underlying cause (carotid stenosis, Afib, etc) Carotid Stenosis NASCET ( in patients with TIA/CVA and ipsilateral carotid artery stenosis > 70%, a carotid endarterectomy reduced stroke rate from 26% to 9% over 2 years ACAS ( 11% to 5% over 5 years if > 60% stenosis TIA (Transient Ischemic Attacks) 4 to 20% will have stroke within next 90 days / 50% within 48 hrs / ABCD score used to help risk stratify / Age > 60 = 1, BP > 140/90 = 1, (unilateral weakness = 2; speech only = 1), (duration > 60 mins = 2; 10-59 mins = 1), diabetes = 1 Specific Stroke Syndromes Lateral medullary syndrome of Wallenberg - vertebral artery or PICA Clinical: loss of pain and temperature to ipsilateral face (descending spinal tract and nucleus of 5th CN) and contralateral body (spinothalamic tract), ipsilateral ataxia (cerebellar peduncle), ipsilateral Horners (descending sympathetic fibers), ipsilateral weakness of the palate and vocal cords (nuclei of 9th and 10th CN) / may present with nausea, vomiting, vertigo from involvement of vestibular system Mediobasal mesencephalic syndrome of Weber infarction of one cerebral peduncle / ipsilateral 3rd nerve palsy and contralateral hemiplegia [HYPERLINK "pics/eye-cn3palsy.jpg"pic] Millard-Gubler syndrome basilar artery damage to pons (left corticospinal tract proximal to decussation in medulla) 6th and 7th CN affected ( impaired lateral gaze, diplopia, facial weakness (all ipsilateral) [ HYPERLINK "pics/eye-cn6palsy.jpg" pic] contralateral hemiplegia mid basilar artery occlusion causes same thing only 5th CN ipsilateral and contralateral hemiplegia Hypertension Lenticulostriate arteries ( basal ganglia, pons, cerebellum, lacunes (small focal areas, lacunar infarcts) Clinical scenarios: motor hemiplegia, pure sensory stroke, ataxic-hemiparesis syndromes, clumsy hand dysarthria (base of pons or internal capsule) Charcot-Bouchard aneurysm aneurysms of lenticulostriate arteries Binswangers disease arteriolosclerotic encephalopathy Multi-infarct dementia second leading cause of dementia / step-wise progression (hemiparesis, extensor plantar response, pseudobulbar palsy) / hypoglycemia, vasculitis, infection, compression Venous and dural sinus thromboses infectious origin, hemorrhagic, often fatal Malformation berry aneurysms (80% single), AVMs (most common congenital, supratentorial) Perinatal cerebrovascular disease Germinal matrix hemorrhage post-hemorrhagic hydrocephalus, sub-ependymal cysts / small blue cell vessels, blood in ventricles Periventricular leukomalacia white matter infarct multicystic encephalomalacia ischemic lesions of grey matter pontosubicular karyorhexis (hyperoxemia) CNS infection Meningitis ( HYPERLINK \l "meningitis" see other) Brain Abscess Immunocompetent (from oral spread): peptostreptococcus > fusobacterium, bacteroides Immunocompetent: zygomyces, staphylococcus (possibly from bacteremia) glucose normal / increased risk with R-L shunt from congenital cardiac defect (blood skips alveolar macrophages in lungs) Evolution of brain abscess: early cerebritis (3 to 5 d), late cerebritis (5 to 14 d), early encapsulization (14 d, late encapsulization (weeks to months) early ( normal or hypodense lesions on noncontrast CT / ill-defined enhancing lesions on contrast CT late ( ring-enhancing on contrast CT Drugs that penetrate CSF: Empyema may lead to superior saggital sinus thrombosis Congenital rubella, CMV Vasculitis mucor, aspergillus Amoebiasis N. fowleri, Acanthamoeba, Leptomyxid amoebae CNS malformations lissencephaly (agyria) agenesis of corpus callosum (batwing X-ray) Arnold-Chiari small posterior fossa / herniation of vermis into foramen magnum, hydrocephalus, lumbar myelomeningocoele syringomyelia soft cavitation of central canal, loss of pain/temperature bilaterally in upper extremities (light touch preserved) Dandy-Walker enlarged posterior fossa / absent cerebellar vermis, cyst protruding from 4th ventricle CNS trauma - accidents 4th most common COD in all ages fractures diastatic, comminuted, ring contusions plaque jaune CSF leak (from basilar skull fracture) CT ( air-fluid levels, opacification of paranasal sinuses, intracranial air Radioisotope cisternography or HRCT with water-soluble contrast (metrizamide cisternography) are the gold standards Epidural hematoma middle meningeal, skull fracture, lucid interval, progressive hemiparesis/obtundation and blown pupil from herniation CT: lens-shaped convex hyperdensity Treatment: emergent neurosurgical evacuation Subdural hematoma Causes: bridging veins, head trauma, blood dyscrasias, elderly, alcoholics, child abuse (shaken baby) Presentation: headache, change in mental status, contralateral hemiparesis or other focal CT: crescent-shaped concave hyperdensity Treatment: neurosurgical evacuation if symptomatic / avoid anticoagulation Venous Sinus Thrombosis Presentation: headache (often acute, thunderclap), papilledema ( HYPERLINK \l "icp" increased ICP), focal neurologic symptoms, seizures, and mental status changes Note: important to distinguish from arterial thrombosis/hemorrhage because of different clinical implications Ddx: may need to do LP prior to MRI if subarachnoid hemorrhage in Ddx Diagnosis: CT with contrast only 20% sensitivity / MRI with MR venography is gold standard Treatment: heparin for cerebral venous thrombosis and cerebral sinus thrombosis (even with hemorrhagic lesions) because it can open vessels and reduce edema and ICP. Then target INR 2.0 to 3.0 with warfarin for e" 6 mos. / catheter-guided thrombolysis in severe cases / lateral or transverse sinus thrombosis may require more aggressive treatments and/or stents Prognosis: with proper treatment, 70% recover fully, 20% with sequelae, 10% mortality < 30 days Intracranial Hemorrhage avoid lowering BP with known cerebral ischemia, but if necessary, a reasonable goal would be to reduce a diastolic > 120-130 mm Hg by no more than 20% in the first 24 h / Nitroprusside increases ICP by cerebral vasodilation / 1 in 5 will be related to warfarin use Subarachnoid hemorrhage (SAH) Accounts for 4% of patients presenting to ER with severe headache / 1 in 10,000 / females:males 2:1 / 50s and 60s Causes: ruptured cerebral aneurysm (APKD, fibromuscular dysplasia, Marfans, Ehlers-Danlos type IV, AVM, coarctation of aorta, stroke, trauma) / Presentation: sudden-onset, intensely painful, often with neck stiffness (other meningeal signs), fever, N/V, fluctuating level of consciousness / may be heralded by milder sentinel headaches / can cause seizure from cortical irritation Diagnosis: CT without contrast (contrast can irritate cortex causing seizures) 95% sensitive if e" 12 hrs and d" 24 hrs LP may reveal frank RBC s or xanthochromia (100% sensitive e" 12 hrs) or elevated ICP / presence of bilirubin distinguishes xanthochromia from traumatic LP 4-vessel MRA is done later and can detect aneurysms e" 5 mm Angiography has 80-90% success in finding (if negative, can repeat in 1 to 6 weeks) ECG (QT prolongation with deep, wide inverted T waves) (25-100% of cases) Treatment: prevent ICP by raising head of bed, limiting IVF, treating HTN / can give nimodipine (60 mg q 4 x 21 days) and Dilantin / neurosurgery or interventional radiology / for patients with worsening neurological deficits ( triple-H (hypertension (CVP 8-12), hypervolemia, hemodilution (Hct 30) Course: hydrocephalus occurs in 15-20% cerebral vasospasm occurs 3 to 12 days after in ~ 1/3 (detected by transcranial Doppler) rebleeding more with aneurysm, same or other aneurysms extension into parenchyma (more with AVM) LV dysfunction // from cardiac stun of catecholamine release/response // these changes usually resolve Parenchymal hemorrhage Hypertension, tumor, amyloid angiopathy (elderly) Lethargy and headache / focal motor and sensory Dx: same as SAH Rx: similar to SAH Seizure Disorders  HYPERLINK \l "absence" absence,  HYPERLINK \l "status" status epilepticus,  HYPERLINK \l "febrileseizures" febrile seizures,  HYPERLINK \l "alcoholicseizures" alcoholic seizures HYPERLINK "pharm.doc" \l "seizure"Seizure Pharmacology partial (simple or complex) ( 2o generalized Note: both types of partial seizures may generalize Differential: CVA (CNS hypoperfusion) or syncope (may have a few spasms prior to passing out) Work up: CBC, electrolytes, calcium, glucose, ABGs, LFTs, renal panel, RPR, ESR and toxicity screen / EEG, CT, MRI Simple-partial can have postictal focal deficit lasting 1-2 days (Todds paralysis) Complex-partial (50% or more) EEG: unilateral or bilateral spikes over temporal lobes (70-80%) Stereotyped automatisms (frequent) / altered mental status, consciousness or responsiveness, confusion, emotional reactions, dj vu, feelings of detachment, hallucinations / postictal confusion common Frequency: every day or every few weeks, months Treatment:  HYPERLINK "pharm.doc" \l "dilantin" Dilantin,  HYPERLINK "pharm.doc" \l "tegretol" Tegretol, VPA Jacksonian seizure rhythmic twitching marches proximally to entire limb Generalized (absence, tonic, myoclonic, atonic, GTC) GTC or generalized tonic-clonic almost always under a minute During seizure: loss of consciousness, neck/back extension then 1-2 minutes of clonic movements / cyanosis, incontinence Labs: CPK may be elevated, serum prolactin usually elevated afterwards Treatment: VPA, Dilantin, tegretol Ataxic several minutes Akinetic brief (type of myoclonic SZ) Specific Types of Seizures Absence seizures Begin in childhood, often subside before adulthood, often familial EEG: characteristic 3 Hz S + SWC during one second hyperventilation can precipitate absence seizures usually have 10s to 100s per day / last 5-10 seconds / amnesia before and after Treatment: HYPERLINK "pharm.doc" \l "ethosuximide"ethosuximide or  HYPERLINK "pharm.doc" \l "vpa" VPA Status Epilepticus repetitive seizures without return to baseline > 30 mins / anticonvulsant/alcohol withdrawal, other drug abuse, noncompliance with seizure meds, metabolic, infection, trauma / 20% mortality / all too easy to miss in ICU with patients on ventilator, either actively sedated or with baseline low-consciousness from underlying disease Treatment: same as seizure but faster and may need to intubate / IV Ativan, load Dilantin, try phenobarbital if that fails / also consider IV sedative like midazolam or pentobarbital Ictal bradycardia syndrome epileptic discharges profoundly disrupt normal cardiac rhythm, resulting in cardiogenic syncope during the seizure Diagnosis: ambulatory EEG/ECG monitoring Treatment: cardiac pacemaker + antiepileptics Juvenile Myoclonic Epilepsy 10% of epilepsy / presents usually at 15-16 yrs Treatment: VPA, Lamictal, others under study Course: this type of seizure disorder rarely remits spontaneously Febrile seizures Peak 6 months to 3 years (maximum 3 months to 5 years) / cause developmental delay Treatment: phenobarbital, ACTH / ?treat underlying cause of fever + Tylenol Infantile spasms (Salaam attacks) < 2 yrs / poor long term neurological outcome (developmental delay) / massive flexor spasms / no loss of consciousness / occur in clusters upon awakening EEG: hypsarrhythmias Treatment: respond to ACTH (unclear if helpful in long term outcome?) Lennox-Gastaut frequent, mixed, generalized refractory to treatment (try a ketogenic diet) Alcoholic Seizures (and Alcoholic Withdrawal) Tremulousness Withdrawal seizures Alcoholic hallucinosis Delirium Tremens (DTs) 2-4 days after cessation / lasts a few days / mortality 5% Treatment: supportive measures long-acting benzodiazepines for 42-78 hrs B12, thiamine (give thiamine before glucose to avoid acute Wernicke encephalopathy Headaches Red flags: change in pattern, progression, first severe or worst ever, abrupt onset, awakening from sleep, symptoms > 1 hr, onset at age < 5 yrs or > 50 yrs, in setting of other serious medical disease, altered consciousness (ICH), triggered by exertion/valsalva Primary (90%) tension > migraine >> cluster Depression HA often the first sign of depression / treat with TCA (SSRIs thought less effective with this type of depression/HA) HTN usually diastolic > 115 in order to cause HA Other  HYPERLINK \l "meningitis" meningitis, trauma ( HYPERLINK \l "cva" CVA,  HYPERLINK \l "ich" ICH), venous sinus thrombosis, drug side effect,  HYPERLINK \l "glaucoma" glaucoma Migraine Headaches Incidence in US (15-20%), familial (70-80%) / major undiagnosed problem Presentation: pulsatile, throbbing, unilateral (usually) / duration 1-2 days nausea (90%), vomiting (60%), diarrhea (15%), photophobia (80%), phonophobia, light-headed (70%), vertigo (30%), paresthesia (30%), scalp tenderness (70%), visual (40%, 10% fortification spectrum), seizure (4%), confused (4%), syncope (10%), may have cranial autonomic features (tearing or nasal congestion) migraine aura without headache (20% migraneurs and 40% of aura positives) fortification spectrum central scotoma, migrating scotoma with peripheral scintillation, colored Note: migraine often wakes people from sleep (dont think such HA automatically implies brain tumor) Inciting factors: certain smells, foods (10% can identify), stress, falling barometric pressure Mechanism (proposed): dysfunction of central neurogenic regulation / vascular reactivity / serotonin? / dorsal raphe nucleus / wave of 20-30% hypoperfusion progressing occipito-frontally, usually not crossing midline at 2-3 mm/min, lasting 4-6 hrs / prevention: type 2 antagonists / abortion: type 1 agonists Complications: possible cause of lipid abnormalities and early CVA Menstrual migraines occur during menses and are often refractory to therapy / Amerge (naratriptan) seems to be most effective (1 mg bid 2-3 days prior to menses and a week after) / pregnancy and menopause may produce remission Vertebrobasilar migraines (hemiplegic, ophthalmic) more rare / post-HA confusion up to 5 days Transformed migraines low grade HA that just doesnt go away (many days) / Treat same as other migraines / toradol IM Mixed headache syndrome chronic tension headaches and periodic migraines Treatment: (see prevention below) ( any one agent should have > 60% efficacy Triptans newer triptans (Maxalt, Zomig) are very effective, but very expensive ($20/pill) caffeine, ergot, butalbital (this is addictive) Other: biofeedback / acetominophen/dichloralphenazone/isometheptene (2 then 1 or 2 caps an hour later) / ergotamine + caffeine or triptan / rapid acting NSAIDS taken in large doses and repeated a few hours later (meclofenamate, naproxen, ibuprofen) / steroids may provide relief / prochlorperazine IV (sedation may help) / butalbital + ASA or Tylenol (often overused) / metoclopramide (Reglan) given 20 mins before vasoconstrictive agents and NSAIDS to control nausea / consider prevention with several episodes per month Prevention: B-blockers 1st line / failure does not preclude trying a different B-blocker Tricyclic antidepressants 1st line Anti-epileptics 1st/2nd line Topamax et al Divalproex (HYPERLINK "psycdrug.doc" \l "vpa"VPA) low doses and titrate upward Tegretol ?Gabapentin (Neurontin) NSAIDS can be given for several weeks and are often effective for prevention / toradol (IM) can often abort refractory migraine Calcium channel blockers 2nd line may take 6-8 weeks for effective control Methysergide ? 3rd line may cause retroperitoneal fibrosis Botulinum toxin type A injections into forehead muscle / studies ongoing Tension Headaches Pathology: muscle spasms and/or central neurogenic regulation Ddx: analgesic and caffeine withdrawal headaches Presentation: tightness and pressure in entire head / may have associated tightness/spasm in neck and shoulders / may also have nausea and photophobia (non-specific) Treatment: biofeedback/relaxation/physical therapy / tricyclics +/-  HYPERLINK "pharm.doc" \l "nsaids" NSAIDs (amitriptyline, doxepin for increased sedation, cyclobenzaprine for sedation/muscle relaxation / 10-20 mg q hs up to 100 mg) /  HYPERLINK "pharm.doc" \l "ssri" SSRIs are less effective directly but may work indirectly by treating causative depression / muscle relaxants (chlorzoxazone, orphenadrine) / carisoprodol (muscle relaxant/sedative which is metabolized to meprobamate, can cause dependency) / aspirin/caffeine/orphenadrine combination (may cause rebound headache) / analgesics such as codeine, propoxyphene, oxycodone, hydrocodone frequently overused but may be the only effective means of relief Cluster Headaches men 8x > women / usually younger men Pathology: hypothalamus involved? Ddx: sinusitis, trigeminal neuralgia Presentation: less than 3 hrs duration (usu. 20 mins to 2 hours) / intensely painful, unilateral, in or behind eye (maybe of cases, pain is somewhere else such as ipsilateral suboccipital area), often occur more at night, can be precipitated by alcohol or vasodilating drugs / patients will usually pace to try to get relief (unlike migraine) / parasympathetic overactivity ( 20% with Horners-like syndrome (ipsilateral tearing and conjunctival injection > miosis, ptosis, cheek edema) Treatment: 100% O2 at 7-8 L/min given only 10 min/h (50% effective) verapamil 40-60 mg/d for several days, then tapered / prednisone given at the same time at 40-60 mg/d for several days, then tapered / lithium 300-900 mg/d / ?methysergide 4-8 mg/d / prednisone and methysergide work within 2-3 days, while verapamil and lithium work slowly Others: NSAIDS / clonidine / ergotamine, SC sumatriptan or DHE may shorten attacks / under investigation: surgery, IV histamine Cough Headaches 4:1 male to female / 25% with structural anomalies like Arnold-Chiari Headache from Viral Illness EBV, influenza, adenovirus, cold Post lumbar puncture bifrontal, occurs 1-2 days after LP / lasts 3-4 days Trigeminal Neuralgia (Tic Douleureux) This condition really sucks / irritation of trigeminal (or other) nerve that causes misfiring and sharp pain sensation (in spells) Treatment: Acute pain: tegretol 1st, baclofen 2nd, other (acupuncture) 3rd Prevention: Trileptal If medical treatment fails, can do surgery (for young patients, usu. successful) and radiofrequency ablation (for older patients) / these measures usu. work for 1-5 yrs ICP (Intracranial Pressure) Causes: NPH, PC, ACM, Chiari I, tonsillar herniation, intracranial AVM, sinus venous thrombosis Cushing s triad  bradycardia, hypertension, breathing changes e" 30 mmHg demands intervention 37.5 mmHg causes ischemic damage 60 mmHg is fatal Treatment: mannitol, steroids, carbonic anhydrase inhibitor decreases CSF production (treats ICP) (watch HCO3 levels) vasogenic edema (white matter) cytotoxic edema (gray matter) swelling of cells from hypoxia / hypoosmolality / Reyes syndrome interstitial edema transudation of CSF from ventricles from hydrocephalus Normal Pressure Hydrocephalus (NPH) Dementia, incontinence, ataxia / usually ( gait 1st, incontinence 2nd, dementia 3rd  HYPERLINK \l "alzheimers" DAT pathology seen in S! apraxia ( delayed initial step, wide-based ( HYPERLINK \l "parkinsons" PD has more shuffling gate) NPH can also have bradykinesia and bradyphrenia (slow thought) Ddx: heavy metal poisoning, chronic ETOH Diagnosis: radioisotope diffusion studies in CSF and Miller-Fisher test (removal of 30 mL CSF improves gait) Treatment: decision of when to shunt is a (difficult) clinical decision / Miller-Fisher test is best predictor of successful treatment with VP shunting (works in T!) / VP shunting has 40% complication rate (meningitis, shunt malfunction, subdural hematoma) /  HYPERLINK "pharm.doc" \l "synemet" carbidopa/levodopa helps some patients who do not receive VP shunt Pseudotumor Cerebri benign, idiopathic increase in ICP / young, obese females Presentation: headache, visual disturbance Findings: papilledema, may have palsy of CN VI Causes: tetracycline,  HYPERLINK \l "vitamina" vitamin A overdose, idiopathic Note: if sudden onset (r/o saggital sinus thrombosis) MRI: normal or small ventricles Treatment: usually self-limited, can use steroids, reduce pressure with spinal taps, osmotic diuretics, oral glycerol?, surgery (rarely) Arnold-Chiari Malformation communicating hydrocephalus Chiari I positive Babinski, cerebellar signs (eye signs), spasticity / usually presents at young age (may present at older age occasionally) Tonsillar herniation Durets hemorrhages in mid-brain, pons and respiratory arrest (medulla) Intracranial AVMs convulsions, increased ICP / often present with high-output congestive heart failure Miscellaneous Neurological Problems Chronic Pain Treatment: TCAs, effexor, avoid narcotics Transient Global Amnesia Migraine vs. vascular / 25% recur once, 3% chronic / no treatment other than possibly anti-platelet agents if you like the vascular hypothesis Concussion [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/2/166" NEJM] clinical state resembles transient global amnesia / concussion does not cause a loss of autobiographical information (this is more c/w hysteria or malingering); concussion-related amnesiacs do not confabulate Observation: at least 2 hours, up to overnight in hospital [HYPERLINK "pics/concussion-management.jpg"table] Imaging: decide whether to obtain CT [HYPERLINK "pics/concussion.jpg"table] post-concussion syndrome: headache (90%), dizziness, trouble concentrating in days-weeks-years following [ HYPERLINK "pics/postconcussionsyndrome.jpg" table] Vertigo key point is to r/o brainstem/cerebellar stroke Lasting > 24 hrs Vestibular Neuritis peaks 1st day / resolves from week to months / 50% observe viral illness Romberg ( usu. fall or tilt toward side of lesion / can often be distinguished from stroke by associated nystagmus (pure vertical almost always means stroke, whereas horizontal and torsional can be both / nystagmus usu. remains in same direction when gaze changes and is suppressed by visual fixation) Stroke of Brainstem may remain for days, usually improves within week of infarct / improvement for several months thereafter / can mimic vestibular neuritis by occurring without other symptoms of vertebrobasilar ischemia (diplopia, reduced vision, dysarthria, dysphagia, focal defects) / Romberg is variable Multiple Sclerosis ( HYPERLINK \l "ms" see other) can present with vertigo Lasting Hours or minutes Menieres isolated, severe vertigo (may have reduced hearing, tinnitus, pressure) followed by several days of dizziness / audiogram shows low frequency pure-tone hearing loss that fluctuates in severity Treatment: low salt diet, acetazolamide / antihistamines, anti-emetics, benzodiazepines may help with acute attacks / surgical decompression may be necessary in extreme cases TIA of vertebrobasilar system Migraine headaches Seizures (rarely, tornado epilepsy from focal Sz of temporal lobe) Perilymph fistula (s/p otologic surgery) Lasting Seconds BPPV (benign paroxysmal positional vertigo) from debris in semicircular canal Findings: nystagmus or dizziness when quickly moved from sitting to lying position with head turned to one side (Nylens maneuver) / there should be no hearing loss, brainstem, cerebellar, or cranial nerve signs except N/V with severe episodes Note: similar to vestibular neuritis, nystagmus is mostly unidirectional (horizontal or rotary) and does not change with direction of gaze; if vertical or changing with gaze ( think stroke Differential: hypothyroidism, AG or Lasix toxicity, stroke, trauma, Menieres labyrinthitis,  HYPERLINK \l "acousticneuroma" acoustic neuroma Treatment: Eppley maneuver (takes just a few minutes, patient learns to repeat at home) / fixation on near object sometimes stops episodes CNS tumors Glial Cell Tumors Astrocytoma I Anaplastic astrocytoma II Glioblastoma multiforme III butterfly glioma (spreads across midline) < 1 yr survival Treatment: radiation therapy with  HYPERLINK "pharm.doc" \l "temozolomide" temozolomide Oligodendrogliomas adults, slow, frontal lobes, calcifications Ependymomas children, 4th ventricles, increased ICP Infratentorial more in children Cystic cerebellar astrocytomas Ependymomas Medulloblastoma vermis in kids, hemispheres in adults Meningioma resection can be curative +/- radiation 30% of systemic CNS cancer spreads to lung, breast, melanoma, kidney, colon Increased ICP: N/V, headache (worse in am, diffuse), bilateral papilledema, personality changes, coma, generalized seizures, focal signs (sensory/motor) Ddx: bleed, neurodegenerative disease, abscess, AVM, meningitis, encephalitis, congenital hydrocephalus, toxic state Diagnosis: CT/MRI - MRI with gallidium is best for astrocytoma type I Treatment: +/- resection, +/- radiation, +/- chemotherapy, +/- steroids, +/- shunting Acoustic neuromas (CN VIII) usually presents with unilateral tinnitus, progressive hearing loss, not vertigo Spinal Tumors Mets from lung, breast, prostate Multiple myeloma, lymphoma Meningioma, neurofibromatomas Astrocytomas, ependymomas Presentation: dumbbell tumors ( nerve root pain Diagnosis: plain film, CT with myelography, MRI Ddx: cervical spondylopathy/myelopathy, acute cervical disc protrusion, spinal angioma, acute transverse myelitis Treatment: resection (if wont produce instability), radiation CNS aneurysms Hunt & ? I ( mannitol, Dilantin / IV & V ( ventriculostomy (1st), surgery (2nd) Diagnosis: CT / 4 vessel angio Epidural Hematoma Middle meningeal artery / honeymoon period / unilateral dilated pupil (herniation), bilateral/fixed/dilated (impending respiratory failure, death) Treatment: burr hole, then craniotomy Subdural Hematoma Elderly, anticoagulation / Presentation: headache, drowsy (not so much seizures and papilledema) Spondylosis more cervical (C6 and C7) / protrusions of bone Presentation: progressive, glove-like distribution / limited neck extension, diminished reflexes Ddx: rheumatoid arthritis, ankylosing spondylitis, cervical rib, scalene anticus, carpal tunnel syndrome, ulnar nerve palsy, Pancoast tumor, primary CNS tumor of brachial plexus Diagnosis: plain film shows canal < 10 mm, decreased normal cervical lordosis / MRI for discs / CT for bones Treatment: neck immobilization, cervical traction, muscle relaxants / 95% improve without surgery (osteophyte resorption) / surgery: anterior cervical disc fusion, laminectomy (decompression) with progressive spondylotic myelopathy (may still recur) Disc Protrusion more lumbar (L5 and S1) / nerve root compression Presentation: radiating pain (sciatica), pain with straight leg raise (ipsilateral and contralateral), pain with direct palpation of nerve root, decreased ankle reflex, weakness of dorsiflexion Treatment: elective laminectomy for chronic pain / urgent laminectomy for foot drop and cauda equina syndrome (urinary retention, perineal numbness, bilateral sciatica) / Opinion: laminectomy is often only a temporizing procedure that may hasten spinal immobility Psychiatric Panic Attacks Incidence: 3% over lifetime Note: among postmenopausal women, panic attacks are relatively common, and may be an independent risk factor for heart disease and stroke. Ddx: thyrotoxicosis, hypoglycemia, pheochromocytoma, MVP (arrhythmia) Treatment: acute ( benzodiazepines, long-term ( TCA, SSRI Anorexia < 75% expected body weight / should be hospitalized / complications of refeedings (heart failure, abnormal LFT, low Mg and PO4 (so avoid TCAs with possibility of prolonged QT), no psychiatric medication has yet been shown completely effective in this disorder 1/07 Ophthalmology Inflammatory Conditions Conjunctivitis Discharge [HYPERLINK "pics/eye-conjunctivitis.jpg"pic][HYPERLINK "pics/eye-conjunctivitis1.jpg"pic] Viral [HYPERLINK "pics/eye-viralconjunctivitis.jpg"pic] (HSV, adenovirus, others) Bacterial [ HYPERLINK "pics/eye-bacterialconjunctivitis.jpg" pic][ HYPERLINK "pics/eye-bacterialconjunctivitis1.jpg" pic] (Neisseria, others) Other Endopthalmitis [HYPERLINK "pics/eye-endophthalmitis.jpg"pic] hypopyon (pus in anterior chamber) [HYPERLINK "pics/hypopyon.gif"pic] Episcleritis RA, IBD Iritis Pain, no discharge IBD, Reiters Keratitis Causes: vitamin A deficiency (most common worldwide), chlamydia, trachoma, virus (HSV [HYPERLINK "pics/eye-keratitis-hsv.jpg"pic], adenovirus [HYPERLINK "pics/eye-keratitis-adenovirus.jpg"pic])contact lens wear (more in US) Presentation: greater visual loss, pain, photophobia, discharge / distinguish from less severe/dangerous keratoconjunctivitis / may develop hypopyon Diagnosis: slit-lamp exam, corneal scrapings Treatment: empiric topical fluoroquinolones +/- aminoglycosides / may need subconjunctival (injected) antibiotics / consider fungus with failure to improve [HYPERLINK "pics/eye-keratitis-aspergillus.jpg"pic] Keratoconjunctivitis more superficial infection Retinitis Etiology: infectious (e.g. CMV [HYPERLINK "pics/eye-cmvretinitis.jpg"pic],  HYPERLINK "micro.doc" \l "candida" candida [HYPERLINK "pics/eye-candidaretinitis.jpg"pic]), mitochondrial myopathies, autoimmune (e.g.  HYPERLINK "path.doc" \l "behcets" Behets), other HSV retinitis 30% recurrence / branching, dendritic form Retinitis pigmentosa Abetalipoproteinemia, neuronal ceroid lipofuscinosis, Ushers Uveitis Presentation: abrupt onset of pain, photophobia / may have iritis, iridocyclitis (constriction of pupil increases pain) / may have hypopyon [HYPERLINK "pics/eye-hypopyon-uveitis.jpg"pic] Causes: Sarcoidosis, Stills disease, Reiters, Ankylosing spondylitis, Behets, IBD, HSV, Tb, leprosy, onchocerciasis / most cases are idiopathic Diagnosis: slit-lamp exam shows keratic precipitates Treatment: topical steroids, mydriatics (decreases pain but also reduces formation of synechiae) Scleritis Pain, recurs Treatment: steroids subconjunctival Diseases Involving Retina Macular degeneration Most common cause of blindness in whites > 50 yrs / loss of central vision (peripheral vision often spared) / may see druzen (yellow clumps or deposits which coalesce over time) around maculae on retinal exam / most common form is dry, non-exudative (in exudative form, neovascularization is prominent and begins in choroid plexus going under retinal pigment epithelium leading to blurred vision) Treatment: laser therapy,  HYPERLINK "pharm.doc" \l "Bevacizumab" bevacizumab (direct intravitreal injection) / antioxidants (multivitamins) may slow progression (unproven) Diabetic Retinopathy Most common cause of blindness in 20-60 population Mechanism: macular edema, neovascularization Presentation: decreased vision, ocular pain, photophobia, circumcorneal redness - ? Retinal findings: flame nerve layer blot and dot deeper cotton-wool spot microinfarct of nerve fiber layer (soft lesions) microaneurysms/hard exudates (lipid, protein material) chronic disease - lose vision but dont go blind proliferative disease lose vision & go blind can get huge bleed Treatment: can do laser surgery to create scar in peripheral retina and save central vision / if patient has a lot of bleeding ( vitrectomy and endolaser Branch or Central Retinal Vein Occlusion (CRVO) widespread hemorrhages and edema (wavy, distinct pattern seen on retina) [ HYPERLINK "pics/retinalveinocclusion1.jpg" pic][HYPERLINK "pics/eye-crvo.jpg"pic][HYPERLINK "pics/eye-crvo1.jpg"pic][HYPERLINK "pics/eye-cvro2.jpg"pic] / usually due to thrombus / painless / non-ischemic vs. ischemic (worse prognosis) Central Retinal Artery Occlusion (CRAO) sudden onset, total loss of vision / usu. embolization (may be preceded by amaurosis fugax) Findings: cherry red spot (there is slightly less edema in the macula allowing the well-perfused choroid to show through creating a small red dot) [HYPERLINK "pics/eye-crao.jpg"pic][HYPERLINK "pics/eye-crao1.jpg"pic][HYPERLINK "pics/eye-crao2.jpg"pic] / boxcar pattern (stasis in retinal vessels) Treatment: emergent optho consult, can try things like external ocular pressure (?helps allow flow around occlusion), give carbon dioxide/oxygen mixture to induce vasodilation Optic Neuritis Vision impaired, ocular movement usually painful, early on retina appears normal patient sees nothing, doctor sees nothing / most likely due to attack of  HYPERLINK \l "ms" MS Retinal Vasculitis Bacterial: endocarditis, Tb, Syphilis, Lyme, Bartonella, Whipple's Viral: VZV, HSV (1 or 2), CMV, EBV, Rubella, Rubeola, Mumps, Coxsackievirus B4, Rift Valley fever virus, HIV, HTLV Fungus: candida, cryptococcus Parasite: malaria, toxoplasma Presentation: decreased visual acuity, cloudy vision, decreased color perception, photopsias, floaters Findings: vascular sheathing, vessel attenuation, vessel occlusion, optic disc and macular edema, optic nerve pallor, cystoid bodies, cotton wool spots, hemorrhages, Roth spots [ HYPERLINK "pics/eye-rothspots.jpg" pic], and central scotomata / often an accompanying vitritis Acute retinal necrosis (HSV, VZV) Big Time!! vasoocclusive arteritis/phlebitis of retinal/choroid vessels and confluent necrotizing retinitis (+/- peripheral retina/vitreous) Treatment: empiric acyclovir, systemic corticosteroids, and even antithrombotic therapy / get an ophthalmology consult Ocular Trauma Corneal abrasion Do NOT use anesthetics with corneal abrasion (slows healing) Red, tearing, pain, photophobia, decreased visual acuity, small pupil (ciliary spasm, aching pain) Treatment: cyclopentolate 1-2% / homatropine 2-5% / scopolamine 0.25% Topical antibiotics / pressure patch 24-48 hrs / oral analgesic Hyphema = trauma blood can cause increased IOP, often have 2nd bleeding day 2-5 Treatment: dilate pupil to prevent adhesions of lens and iris / topical steroids? RTC with changes in vision / early: wash out blood / late: forms a dumbbell-shaped clot, must maintain outflow and wait for clot to dissolve Other Ocular Conditions Actinic keratosis [HYPERLINK "pics/eye-actinickeratosis.jpg"pic] Arcus junenilis [HYPERLINK "pics/eye-arcusjunenilis.jpg"pic] Chalazion [HYPERLINK "pics/eye-chalazion.jpg"pic][HYPERLINK "pics/eye-chalazion1.jpg"pic][HYPERLINK "pics/eye-chalazion2.jpg"pic] Dermoid [HYPERLINK "pics/eye-dermoid.jpg"pic] Gerontoxon [HYPERLINK "pics/eye-gerontoxon.jpg"pic] Glaucoma Screening PMH, FH, visual acuity, IOP exam [15-20 normal, 22 mm HG is worrisome] Few early symptoms of 1o open angle glaucoma (OAG) (only diagnosed by eye exam) Cup: small, pale / vertical cup-disc ratio changes Neural rim: wide, symmetrical, orange-red / color and width of neural rim changes / asymmetry between eyes Early: S! disc surface / cup extends to rim (always abnormal) Narrow angle glaucoma (closed angle glaucoma) Findings: intense pain, mid-dilated pupil, blurred vision, light reflex broken up, eye may appear red, nausea, vomiting Treatment:  HYPERLINK "pharm.doc" \l "pilocarpine" pilocarpine 2% gtts q 15 mins (constrict pupil) /  HYPERLINK "pharm.doc" \l "diamox" acetazolamide 500 mg PO or IV (reduces production) / oral glycerine or isosorbide 1 cc/kg (osmotic agents to reduce pressure) / surgical correction Congenital glaucoma (1 in 10,000) presents with tearing (more likely congenital obstruction of nasolacrimal duct, Rx with little probe) Chronic (open angle glaucoma) (OAG) incidence of 1.5 million (?most common type of glaucoma) Hordeolum (stye) [HYPERLINK "pics/eye-hordeolum.jpg"pic][HYPERLINK "pics/eye-hordeolum1.jpg"pic] pain, swelling, discomfort / very common / acute inflammatory process usu. limited to 5-7 days, 50% resolve with medical management in < 6 wks Ddx: acute chalazion Treatment: initially, medical (warm compresses, eyelid hygiene, topical anti-inflammatories and possibly/probably concomitant topical antibiotic therapy; oral if severe), but if not improving or severe, consult ophthalmologist for possible surgical incision and curettage under topical anesthesia / may need to treat accompanying blepharitis or meibomianitis Hyperemia [HYPERLINK "pics/eye-hyperemia.jpg"pic] Presbycusis most common cause of sensorineural hearing loss in elderly / damage over time (> 2000 Hz) Ddx: Menieres, chronic otitis media (both unilateral) / rule out cerumen impaction Pterygium chronic irritation (like wind/dust) causes damage to cornea [HYPERLINK "pics/eye-pterygium.jpg"pic][HYPERLINK "pics/eye-pterygium1.jpg"pic] Treatment: removal/radiation Other Notes Papilledema HTN/increased ICP Ddx for red eye includes acute NAG vs. Adenovirus (with pre-auricular LAD with pink eye) Pain ( think cornea or bacteria > viral Steroids contraindicated in HSV, fungus, increased IOP (25% with 1-2 wks use), cataracts (long term use) Eye findings linked with medical diseases angioid streaks on fundusPseudoxanthomatous elasticumangioid streaks on fundusPagets diseaseKayser-Fleicher ringsWilsons DiseaseBlue scleraOsteogenesis imperfectacholesterolemiaArcus sinilus?hemochromatosis Female [HYPERLINK "ddx.doc" \l "postmenopausalbleeding"postmenopausal bleeding] [ HYPERLINK "ddx.doc" \l "amenorrhea" amenorrhea] [ HYPERLINK \l "obstetrics" obstetrics]  HYPERLINK \l "femaleinfection" Infections  HYPERLINK \l "bv" BV, chlamydia, Trichomonas,  HYPERLINK \l "pid" PID  HYPERLINK \l "breast" Female Breast  HYPERLINK \l "breastca" Breast Cancer ( HYPERLINK \l "breastcancerscreening" screening)  HYPERLINK \l "vulva" Vulva,  HYPERLINK \l "vagina" Vagina  HYPERLINK \l "cervix" Cervix  HYPERLINK \l "cin" CIN,  HYPERLINK \l "cervicalca" cervical Ca  HYPERLINK \l "endometrium" Endometrium  HYPERLINK \l "endometriumfxn" functional disorders,  HYPERLINK \l "endometriosis" endometriosis,  HYPERLINK \l "endometrialneoplasia" neoplasia,  HYPERLINK \l "endometriummesenchymal" mesenchymal tumors, HYPERLINK \l "_gestationalca"gestational trophoblastic  HYPERLINK \l "fallopiantube" Fallopian tube  HYPERLINK \l "ovary" Ovary HYPERLINK \l "follicularcysts"follicular cysts, HYPERLINK \l "pcos"PCOS,  HYPERLINK \l "ovarianca" ovarian tumors  HYPERLINK \l "ovarianepithelial" epithelial/ HYPERLINK \l "ovariangermcell" germ cell  HYPERLINK \l "femaleother" Other   HYPERLINK \l "incontinence" incontinence,  HYPERLINK \l "femalehealthmaintenance" womens health maintenance,  HYPERLINK \l "menopause" menopause,  HYPERLINK \l "pmof" PMOF Disorders of Sexual Development Gonadal dysgenesis (Turners syndrome) 1 in 2500-10,000 live female births / 45,X / not familial, is not related to the mothers age Ovaries fail to develop (bilateral streaks of connective tissue, no germ cells) Estrogen deficiency ( sexual infantilism (no 2o sexual characteristics) and !LH/FSH Somatic abnormalities Short stature (48 to 58 in), short, webbed neck, epicanthal folds, low-set ears, a shield- chest with widely spaced nipples, cubitus valgus (wide carrying angle), and renal and cardiac abnormalities (coarctation of aorta) Treatment: estrogen to promote secondary sexual characteristics (cyclic E/P can cause regular menstruation, but not fertility) / removal of streak ovaries: can have sex chromosome mosaicism (some cells have Y chromosome, can lead to gonadal tumors) Testicular feminization syndrome genetic males 46,XY with normal female external genitalia (raised as girls) Mechanism: resistance of target tissues to androgens Findings: external genitals female by default / no internal female organs (vagina ends in blind pouch) / endogenous E stimulates normal breast development at puberty Diagnosis: usu. when menarche fails to occur or testes felt in abdomen Treatment: remove testes, which have malignant potential / give supplemental E to maintain female secondary sex characteristics Resistant ovary syndrome ovaries cannot respond to gonadotropins (can result from autoimmune destruction of ovaries or other conditions) Hypogonadotropic hypogonadism Panhypopituitarism causes primary or secondary amenorrhea (depending on time of onset) / from destructive lesions in HPA regions Isolated gonadotropin deficiency usu. from defective GnRH production, Kallmans is a specific form associated with anosmia) Delayed menarche Consider if no periods by age 16 / sometimes delay runs in family / one can prescribe E for 6 months or so even prior to making diagnosis in order to assist sexual/psychological development Hypothalamic amenorrhea (psychogenic, functional, and idiopathic) most common nonphysiologic secondary amenorrhea / LH/FSH is low or normal Treatment: if GnRH is infused in pulsatile fashion, this may correct all problems Malnutrition/Anorexia Menstruation often ceases below critical body weight Exercise (common in serious athletes) ? Hypothyroidism Post-pill amenorrhea delay > 6 months since stopping pill / only occurs in 1% / must r/o other causes Primary ovarian failure (premature menopause) similar to normal menopause but < 40 yrs / some cases have auto-Abs ovarian function declines, estrogen levels decrease with compensatory !LH/FSH Ovarian tumors (e.g. granulosa-theca cell tumors) may inhibit normal menstrual cycles with excessive E Hyperprolactinemia ( HYPERLINK \l "prolactinoma" see other) excess prolactin is a very common cause of secondary amenorrhea Androgen excess syndromes Polycystic Ovary Syndrome (PCOS or Stein-Leventhal) chronic lack of ovulation, androgen excess, obesity / unknown etiology 3%-7% of reproductive-age women Mechanism: ovary ( excess androgenic steroids (esp. androstenedione, converted to estrone) increased estrone has (+) feedback on LH and (-) on FSH increased LH ( hyperplasia of ovarian theca/stroma ( increased androgen production lack of follicle maturation from decreased FSH and ovarian androstenedione Note: obesity may increase sex hormone levels by decreasing SHBG and increases peripheral conversion of androstenedione Pathology: ovaries enlarged with thickened capsules and many small follicular cysts Theories: HPA axis, with constant LH vs. excess ovarian secretion of androgen vs. adrenal abnormalities Presentation: infertility and menstrual abnormalities ( HYPERLINK "ddx.doc" \l "amenorrhea" amenorrhea or  HYPERLINK "ddx.doc" \l "oligomenorrhea" oligomenorrhea) from chronic anovulation / prolonged, noncyclic, unopposed E may cause functional bleeding and increase risk of endometrial Ca androgen excess ( oily skin, acne, hirsutism obesity in 40% insulin resistance // 30% of girls with PCOS have glucose intolerance; 10% chance of diabetes Labs: ! LH to FSH ratio (~2) (LH elevated while FSH low-normal) testosterone and androstenedione usually elevated (adrenal androgens, DHEA and DHEA-S, are found less often) estrone usually high, estradiol normal Treatment of androgen excess: use trial and error vs. testing for suppression of androgen levels / usually takes 3-6 months to see improvement in hirsutism oral contraceptives (E-P) decrease androgen levels by negative feedback on LH and increased hepatic production of SHBG (although sometimes not high enough levels)  HYPERLINK "pharm.doc" \l "spironolactone" spironolactone decreases ovarian and adrenal synthesis of androgens and inhibits androgen binding to receptors in hair follicles and other target tissues / 100 mg QD or BID often effective steroids decrease adrenal androgen production by suppressing ACTH (may also lower ovarian androgen secretion, although the mechanism is unknown / 0.5 mg dexamethasone q HS (because ACTH peaks in early morning)  HYPERLINK "pharm.doc" \l "metformin" metformin (effective in , mechanism thought to be related to finding that hyperinsulinemia synergizes with LH to increase thecal androgen production and decrease sex hormone-binding globulin) / treatment with metformin can lead to clinical improvement, even in adolescents without overt diabetes mellitus Infertility Clomiphene citrate stimulates LH/FSH production / given 5th to 9th day following P-induced menstruation / 80% effective Human menopausal gonadotropin has both FSH and LH bioactivity / injected daily until increasing serum E and u/s confirm follicle maturation / hCG then injected to induce ovulation / this therapy increases risk of multiple gestation GnRH (given IV or SC in pulses q 90-120 mins may induce ovulation without causing ovarian hyperstimulation MPA to prevent endometrial CA / 10 mg MPA for 10 days q 1-3 months Androgen-producing ovarian tumors are rare Arrhenoblastoma is most common type ( HYPERLINK \l "arrhenoblastoma" see ovarian tumors) Hyperthecosis (of the ovary) probably represents severe form PCOS / try meds, but oophorectomy may be necessary Adrenal tumors adenomas or carcinomas may produce excess androgens (+ or cortisol) Diagnosis: high levels of adrenal androgens (urinary 17-ketosteroids, serum DHEA) that cannot be suppressed by dexamethasone suggest Labs: 24-hr urinary 17-ketosteroid level > 50-100 mg strongly suggestive Congenital adrenal hyperplasia ( HYPERLINK \l "cah" see other) Idiopathic hirsutism poorly understood but common / mild hirsutism and sometimes acne, menstrual irregularities Labs: T high-normal or slightly elevated, or elevated T (with decreased SHBG) and adrenal androgens Ovaries are otherwise normal Treatment: E-P combinations, steroids, spironolactone (1st choice), ?metformin sometimes decrease the androgen levels and symptoms psammoma bodies epithelial inclusion cysts serous ovarian tumor papillary carcinoma of thyroid meningioma key point candida and tuberculosis are NOT sexually transmitted Infections of Female Genital Tract Peri-genital Chancroid ( HYPERLINK \l "chancroid" see other) LGV ( HYPERLINK \l "lgv" see other) Molluscum contagiosum ( HYPERLINK "micro.doc" \l "molluscum" see micro) unclassified poxvirus Insects:  HYPERLINK "micro.doc" \l "scabies" scabies, crab lice Vulva Yeast infections (vulvovaginal) common / not an STD / white patches Risk Factors: antibiotic use, DM, obesity, oral contraceptives, pregnancy HSV-1, HSV-2 (vulvovaginal) ground-glass nuclei or eosinophilic intranuclear inclusions (cowdry A) / fatal infection of neonate Bartholins cyst abscess associated with gonorrhea Condyloma acuminatum [ HYPERLINK "pics/condylomata.jpg" pic][ HYPERLINK "http://dermis.net/dermisroot/en/14295/diagnose.htm" dermis] STD / koilocytosis / HPV 6, 11 / no atypical mitoses Extramammary Pagets Disease 20% have underlying adenocarcinoma / velvety-red lesions / local excision if no mets / high recurrence Vulvar intraepithelial neoplasia (VIN) peaks in 50s 60s / HPV-16 predominates (80-90%), lesions in younger women usually more aggressive Presentation: pruritis, vulvodynia Diagnosis: multiple punch biopsies Treatment: wide local excision or laser vaporization Follow-up: colposcopy ever 3 months (then every 6 months after 2 years) precursor to squamous carcinoma (10%) Vulvar Cancer 5% of gynecological malignancies / epidermoid (85-90%), malignant melanoma (5-10%), basal cell carcinoma (2-3%), sarcomas (<1%), fibrous histiocytomas associated with diabetes, hypertension, obesity, vulvar dystrophies, granulomatous PID Staging: I - lower 1/3 II - lower 2/3 III- over 2/3 / 25% with positive nodes will have none on physical exam / 5 yr survival with 1 node (90%), 2 nodes (75%), 3 nodes (15%) Treatment: surgical resection +/- radiation / lymphadenectomy not helpful for melanoma or required for  HYPERLINK \l "bcc" BCC Squamous cell carcinoma most common carcinoma of vulva / usually > 60 yrs / HPV 16 / 5 yr survival 75% Vagina Vaginal Infections Bacterial Vaginitis Organisms: Gardnerella vaginalis, Ureaplasma hominis > Chlamydia, N. gonorrhea Diagnosis: 3 of 4 criteria: increased vaginal discharge (fishy odor when mixed with 10% KOH), pH > 4.5, clue cells on wet mount [ HYPERLINK "pics/cluecells.jpg" pic] Ddx: bacterial (40%) > candida (30%) > T. vaginalis / chemical irritants, HSV Treatment: oral or vaginal metronidazole or clindamycin N. Gonorrhea ( HYPERLINK "micro.doc" \l "ngonorrhea" see micro) Chlamydia trachomatis most common STD in W. hemisphere / 20% asymptomatic / infects glandular epithelia / may cause PID and infertility / treat partner / Treatment: azythromycin, doxycycline Trichomonas vaginalis (HYPERLINK "micro.doc" \l "trichomonas"see micro) 25% asymptomatic / variable pruritis / strawberry mucosa, frothy, purulent discharge / pear-shaped wobbling flagellated organisms + epithelial cells / fishy odor (w/ or w/out addition of 10% KOH) Treatment: 500 mg metronidazole PO bid x 7 days / must treat partner, no intercourse during Rx Candida vaginitis Lower pH, more itching, fungal elements on KOH Vaginal Neoplasia Vaginal intraepithelial neoplasia (VIN) Peaks in 40s / diagnosed with colposcopy and acetic acid/biopsy Treatment: CO2 laser or topical 5-FU if not-invasive Squamous cell carcinoma Peak in 50s (mean age 55) / most common carcinoma of vagina Presentation: discharge, bleeding, pruritis Spread by direct extension into bladder, rectum and lymphatics (upper 1/3 ( iliac nodes, lower 2/3 ( inguinal nodes) Stage I and II upper 1/3 ( surgical resection Stage III and IV and lower 2/3 ( radiation alone (palliative surgery) Adenocarcinoma clear cell carcinoma / fetal DES exposure causes adenosis / subset become CA / young women / Treatment: surgery and radiation Cervix Cervical Infection PID (pelvic inflammatory disease) Criteria: all 3 present: (1) lower abdominal tenderness (2) CMT (cervical motion tenderness) (3) adnexal tenderness at least 1 of these: temperature > 38 C / WBC > 10.5 / positive culdocentesis / mass on exam or ultrasound / evidence of GC or chlamydia in endocervix Risk factors: young female, recent menses, multiple partners et al Diagnosis: Non-clotted blood ( ectopic pregnancy Clotted ( from vessel? or recently ruptured ectopic? Differential: ovarian torsion, ovarian cysts, fibroids, endometriosis, appendicitis, bowel disease, ectopic pregnancy Organisms: C. trachomatis (25-45%) / N. gonorrhea (10-40%) / anaerobes (Bacteroides, C. perfringens) (30-60%) / aerobes (Staph, Strep, E. Coli) (30-65%) / Mycoplasma sp. (2-10%) Treatment: different opinions from OB/GYN vs. ID people Ceftriaxone 250 mg IM x 1 and doxycycline 100 mg bid x 14d (follow-up 48 hrs) / treat partner, consider in-patient treatment cefotetan 2 g IV q 12 hrs or cefoxitin plus doxycycline / alternative: Unasyn + doxy, cipro + doxy, ofloxacin, metronidazole with abscess (TOA) (more likely anaerobic; bacteroides): Unasyn, clindamycin, gentamicin Complications: peritonitis, GI obstruction, bacteremia, infertility (ectopic pregnancy later on) Cervical Neoplasia Endocervical polyp most common cervical growth / inflammatory cause / may bleed Cervical Intraepithelial Neoplasia (CIN) vaccine available! Incidence: 6th leading COD in women / 5000 deaths/yr Risk factors: early start, many partners, history of STD, smoking / also an AIDS-defining illness caused HPV 16,18,31,33 (integration, replication vs. episomal (HPV 6, 11) more common in anterior / Schiller test (dysplastic ECs do not stain for glycogen) Clinical Staging: physical exam, CXR, IVP, barium enema, cystoscopy Bethesda system Atypical squamous cells of undetermined significance (ASCUS) 10-15% will have significant lesions on colposcopy (80% of them will resolve with repeat PAP in 4-6 months Squamous intraepithelial lesions (SIL) low grade: CIN I (30% or progress in 7 yrs) and HPV changes high grade: CIN II (4 yrs to progress) and CIN III Squamous cell carcinoma 20% of CIN III progress to invasive carcinoma by 10yrs Treatment: cryotherapy, laser therapy / loop electrosurgical excision procedure (LEEP) for endocervical lesions Prevention: anti HPV vaccine (effective if given prior to sexual activity) Invasive squamous cell carcinoma (cervical cancer) cervical cancers are 90% large cell (keratinizing or non-keratinizing) and 10% small cell / remainder are adenocarcinoma and rarely (sarcoma/lymphoma) Presentation: post-coital bleeding, abnormal vaginal bleeding, watery discharge, pelvic pain/pressure, rectal or urinary problems microinvasive SCC refers to <3 mm invasion, no blood vessels, no mets invasive SCC is the most common cervical cancer / may be fungating, ulcerating, infiltrative Treatment: cone biopsy for microinvasive/desire for fertility / others require (simple or radical) hysterectomy / radiation (external beam or intracavitary radiation) can be curative or palliative (pain/bleeding) / chemotherapy is only minimally effective with cisplatin (+/- doxorubicin, bleomycin) Prognosis: 5 yr survival for IIIA (50%) / death from ureteral obstruction, pyelonephritis, renal failure Endometrium Endometrial Inflammatory acute endometritis associated with delivery or abortion chronic endometritis non-specific abortion, PID, IUD, pregnancy / plasma cells / may be asymptomatic / culture for chlamydia and gonococci chronic endometritis specific mycoplasm subacute focal inflammation (SFI) / lymphocytes, NO germinal centers, NO plasma cells tuberculosis infertility / systemic infection / superficial endometrial granulomas Functional Disorders of Endometrium estrogen withdrawal bleeding and anovulation 1st cause of dysfunctional uterine bleeding / asynchronous / proliferative pattern / fibrin thrombi inadequate luteal phase luteal phase defect / premature menses / infertility / >2 day lag in endometrium endometrial polyp (benign) abnormal uterine bleeding / associated with tamoxifen use hyperplastic polyp: originate in basalis, may have squamous metaplasia functional polyp: least common / glandular and respond to hormones atrophic polyp: post-menopausal / regressive polyp Endometrial Neoplasia Endometriosis ectopic endometrial glands / chocolate cysts / 1st - ovaries (associated w/ endometrioid carcinoma) / 2nd recto-vaginal septum / reproductive age / dysmenorrhea, menometrorrhagia, dyspareunia, infertility / pathogenesis: retrograde menstruation, implantation, coelomic metaplasia, lymphatic, hematogenous dissemination Endometrial hyperplasia simple: dilated glands, abundant stroma complex: crowded architecture, epithelium may be stratified, reduced stroma atypical simple or complex: 25% progress to carcinoma other endometrial CA usually has worse prognosis adenosquamous, clear cell carcinoma, squamous carcinoma, papillary serous carcinoma Endometrial Adenocarcinoma most common invasive neoplasm of female genital tract / 75% of endometrial CA 70% before age of 50 / peak 60 yrs Presentation: HYPERLINK "ddx.doc" \l "postmenopausalbleeding"post-menopausal bleeding (90%), abnormal Pap (30%), bone pain Note: if endometrial biopsy (90% sensitivity) negative, proceed with hysteroscopy Risk factors: unopposed estrogen, obesity, nulliparity, low parity, anovulation, menopause > 50 yrs / diabetes, hypertension, breast/ HYPERLINK \l "ovariantumors" ovarian cancer, family history of endometrial cancer Type I pre and peri-menopausal, low grade, hyperplastic, secretory, responds to HRT, whites Type II post- menopausal, high grade, serous clear cell, progressive, does not respond to HRT, blacks endometrioid: most common / adenocarcinoma / may have squamous differentiation Method of Spread: direct extension, lymphatic (most), direct, peritoneal seeding, hematologic dissemination Treatment: TAH/BSO with surgical staging +/- postoperative radiation, hormonal therapy, single-agent chemotherapy / hormonal therapy for advanced/recurrent Prognosis: histological grade is the most important factor, then depth of myometrial invasion (> 1/3 worse), then histological type / pelvic node mets, tumor volume, involvement of cervix/adnexa, positive peritoneal washings Overall 5 yr survival is 65% / stage I (73%), stage II (56%), stage III (32%), stage IV(10%) / 75% of recurrence in first 2 yrs, 85% in first 3 yrs FIGO Grading I - III / increases with solid component / FIGO Staging I IV is most common / abdominal abscesses is most common COD Follow-up: every 3 months for 2 yrs, then every 6 months for 3 yrs, then once yr Mesenchymal Tumors of Endometrium Leiomyoma most common uterine neoplasm / SMC / blacks > white / usually multiple / hyaline fibrosis / apoplectic leiomyoma: pregnancy, progestins / hemorrhage, edema, myxoid changes, mitoses apoplectic and marantic: hemorrhagic degeneration/necrosis due to hormonal effects Treatment: OCPs, NSAIDS, surgery Malignant Mixed-Mullerian Tumor (MMMT) poor prognosis 1st uterine sarcoma / associated with pelvic radiation / homologous or heterologous (muscle, cartilage, bone, fat) / rapid spread, poor prognosis for both types Leiomyosarcoma 2nd uterine sarcoma / mitotic and cellular atypical / not arising from leiomyoma Treatment: only proven treatment is surgical Gestational Trophoblastic Tumors Complete hydatidiform mole (CHM) homozygous 46 XX (started as one paternal X / RF: young/old, Asian, FH, infertility, smoking large edematous villi (grapes of wrath) / Symptoms: vaginal bleeding, preeclampsia, uterine enlargement, high hCG complications: DIC, infection, choriocarcinoma (2%) Partial hydatidiform mole (PHM) fetal tissue often present / triploidy (69XXY) results from dispermy / RFs same as CHM w/out maternal age, ace / milder symptoms / does NOT lead to choriocarcinoma Choriocarcinoma poor prognosis mole, abortion, normal pregnancy / no chorionic villi / Treatment: chemotherapy Placental site trophoblastic tumor (PSTT) rare / intermediate trophoblast deeply invades myometrium Miscellaneous Endometrial stromal tumors stromal nodule: benign low-grade endometrial stromal sarcoma: responds to progestins high-grade endometrial stromal sarcoma: very poor prognosis Adenomyosis diffuse glands in inner myometrium / posterior wall Fallopian Tube Fallopian Tube Infection Acute salpingitis TORCH / abortion (Strep, Staph, coliform, anaerobes) / adhesions, hydrosalpinx, infertility Chronic salpingitis bilateral / hydrosalpinx, pyosalpinx / ectopic pregnancy Granulomatous salpingitis granulomas / epithelial hyperplasia / systemic / MTB or M. bovis Fallopian Tube Neoplasia Carcinoma of fallopian tube rare / similar to serous ovarian carcinoma Other Fallopian Paratubal cysts (hydatid of Morgagni) common / non-significant / Mullerian origin Ectopic pregnancy Cause of 9% of maternal deaths from exsanguinations / commonly rupture by 12th week Risk factors: prior ectopic, chlamydia (PID), tubal surgery, smoking, increasing age Diagnosis: absence of IUP (ultrasound) and positive B-hCG (< 6000) / transvaginal ultrasound 85% sensitive for IUP at 6-7 wks or B-hCG over 1500 / confusing factors: multiple gestations, failed IUP, obesity, fibroids, uterine axis Labs: normal hCG increase is 66% or more per/48 hrs (15% of normal IUP have lower bhCG) / 17% of ectopics have normal hCG doubling time / doubling rate at 6-7 wks is every 3.5 days Pathology: endometrium may be secretory (Arias-Stella) or normal appearing Treatment: laparoscopy, laparotomy or HYPERLINK "pharm.doc" \l "mtx"methotrexate if small/unruptured / single dose MTX (84% success rate) or multiple dosing regimen / with leucovorin rescue Absolute contraindications: breastfeeding, immunodeficiency, alcoholism, alcoholic liver disease, chronic liver disease, blood dyscrasias (bone marrow hypoplasia, leukopenia, thrombocytopenia, severe anemia), known sensitivity to MTX, active pulmonary disease, peptic ulcer disease, hepatic, renal, hematologic dysfunction Relative contraindications: gestational sac > 3.5 cm / embryonic cardiac motion Note: pt must avoid alcohol, folate, NSAIDS, sexual intercourse during treatment Precautions: get LFT, U/A, transvaginal ultrasound within 48 hrs of treatment, Treatment Success: increase in hCG during 1st 1-3 days of treatment, vaginal bleeding/spotting, 2/3 will have increasing abdominal pain Treatment Failure: severely worsening abdominal pain, hemodynamic instability, hCG does not decline by at least 15% between day 4 to 7 / increase or plateau of B-hCG after 1st week Ovary Cystic Ovarian Disease Follicular cysts asymptomatic or increased estrogen causing isosexual precocity, menstrual disturbances, endometrial hyperplasia / may rupture with hemoperitoneum / unilocular / serous, blood clot, or mixed contents / probably due to FSH, LH stimulation Treatment: observe, oral contraceptives, surgery after 6-8wks Corpus luteum cyst continued progesterone secretion / large luteinized granulosa cells / smaller theca lutein cells involution of CLC usually leads to corpus albicans cyst Polycystic Ovaries (PCOD) (Stein-Leventhal) (merge with other) present in 20s with oligomenorrhea, menometrorrhagia, infertility (HYPERLINK "ddx.doc" \l "amenorrhea"amenorrhea), and hirsutism (androstenedione to testosterone), acanthosis nigricans / bilaterally enlarged ovaries / thick, fibrotic cortical tunica / cystic follicles / hyperplasia and luteinization of theca interna w/out CL formation Treatment: clomiphene (blocks pituitary ER), MPA, oral contraceptives, wedge resection / metformin (under investigation) Surface epithelial inclusion cysts invagination of surface epithelium / post-men. / psammoma bodies may give rise to epithelial neoplasms Ovarian Tumors General: 80% benign / 5th most common CA death in women (from intestinal obstructions); 65% of ovarian tumors and 90% of ovarian cancer is from coelomic epithelial, 10%  HYPERLINK \l "krukenberg" Krukenberg (mets from GI, breast, endometrium) Risk factors: nulliparity, family history, BRCA1 gene (history of breast CA ( 2x risk), clomiphene, infertility (10% less risk per childbirth) / oral contraceptives may confer protection Presentation: abdominal pain/distention (pelvic fullness, vague discomfort), GI complaints (early satiety, constipation, bowel obstruction or carcinomatous ileus), urinary symptoms, weight loss, pancytopenia, abnormal uterine bleeding (less than cervical and endometrial CA), ascites (late), cachexia / majority present with stage 3 Diagnosis: difficult to diagnose early, high mortality when malignant / may have peritoneal carcinomatosis on paracentesis, but avoid cyst aspiration (may worsen spread) Ultrasound (malignant): > 8 cm / solid or cystic and solid / multilocular / bilateral / ascites Ddx: ovarian cysts, renal cysts, adrenal cysts, gall bladder, pancreas Method of Spread: direct exfoliation, lymphatics, hematogenous (lung, brain) Tumor markers:  HYPERLINK "labs.doc" \l "ca125" CA-125 not very specific, elevated (>35) with all female reproductive tumors plus pancreas, breast, lung, colon and pregnancy, endometriosis, PID and fibroids /  HYPERLINK "labs.doc" \l "afp" AFP and  HYPERLINK "labs.doc" \l "hcg" hCG Staging: TAH/BSO, omentum, washings, appendix, paraaortic lymph nodes, peritoneal biopsy Treatment: see below Prognosis: 5 yr survival 30% (because 80% present at late stage); if caught early, survival is 90%  HYPERLINK \l "ovarianepithelial" Epithelial (70%) % of malignant ovarian bilateral prognosis Serous (fallopian) 40 30-60 good Endometrioid 20 40 very bad Mucinous (cervical) 10 10-20 - Clear (kidney) 6 40 poor Brenner (bladder) < 3 - excellent Undifferentiated 10 - poor  HYPERLINK \l "ovariangermcell" Germ Cell Tumors (15-20%) prognosis Dysgerminoma good Endodermal Sinus Tumor (Yolk Sac Tumor) moderate Embryonal Polyembryonal Choriocarcinoma Teratoma (Dermoid) 96% benign good  HYPERLINK \l "ovarianstromal" Sex cord-stromal (5-10%)  HYPERLINK \l "ovarianmetastatic" Mets to ovaries (5%) Meigs syndrome benign ovarian tumor, ascites, hydrothorax Epithelial Tumors 85% of ovarian tumors (usually > 40 yrs / peak in 70s / more in nulliparous or few pregnancies) 50% benign, large, bilateral, cystic 33% malignant 16% borderline (younger women, diagnosis from morphology, not stage) Stage I - IV (III allows for superficial liver mets) Prognosis: 5 yr survival (20%) / Stage I (90%), Stage II (50%), Stage III (30%), Stage IV (10%) Treatment: taxol and cisplatinum x 6 cycles Serous (fallopian) - good prognosis most common / unilocular or multilocular / usually bilateral / cystic to solid benign (60%): simple cystadenoma borderline (15%): ciliated, stratification, solid buds, psammoma bodies, no invasion malignant (25%): invasion, fine papillae, irregular lumens, tight nests, solid sheets, psammoma bodies / can have primary peritoneal papillary serous carcinoma (and normal ovaries); treated with debulking and chemotherapy (carboplatin or cisplatin + paclitaxel); 10% remission at 2 yrs Endometrioid - very poor prognosis S! accompanied by independent endometrial cancer / association with endometriosis usually carcinomatous Mucinous (cervical) largest ovarian tumors / borderline version may be intestinal (85%) or mullerian origin / mucinous carcinoma exceeds 4 layers / borderline type may display pseudomyxoma peritonei (peritoneum fills with mucin, must be repeat / high association with Peutz-Jeghers syndrome / CA-125 not useful, but CEA is useful (highly associated with appendix tumor) benign (80%): simple cystadenoma borderline (10%): malignant (10%): Clear cell adenocarcinoma - poor prognosis unilocular / solid nodules / highly associated with endometriosis clear, hobnail, flattened pattern contain glycogen / aggressive tumor Brenners tumor - excellent prognosis 98% benign / small, well demarcated nests of epithelial cells / fibrous stroma / may surround eosinophilic material / grooved, coffee bean nuclei Germ Cell Tumors -15-20% / 0-25+ yrs -resection and chemotherapy (BEP) is generally treatment of choice Treatment: BEP (bleomycin, etoposide, cisplatinum) Dysgerminoma - good prognosis young age / most common malignant GCT / 10-15% bilateral / primordial germ cells / solid / stroma is fibrous trabecula infiltrated by lymphocytes / granulomas may be present / very radiosensitive (BEP still preferred?) / LDH useful marker Endodermal sinus tumor (Yolk Sac Tumor) - moderate prognosis young age / sudden onset abdominal pain / elevated a-FP / large tumor / reticular pattern / Schiller-Duval bodies (papillae, central vessel) / hyaline droplets (contain a-FP, PAS+, eosinophilic) / moderate prognosis with combination chemotherapy Embryonal aFP and hCG [may differentiate into endodermal sinus tumor or choriocarcinoma] Polyembryonal aFP and hCG Choriocarcinoma hCG Dermoid cyst (Mature Teratoma) - good prognosis most common GCT / 96% benign / 15% bilateral / usually cystic / 2-3 embryonic layers / sebaceous, hair, teeth (ectodermal mostly) / Rokitanskys protuberances / torsion may occur / occasionally develop squamous carcinoma (1-2%) Struma Ovarii (Monodermal Teratoma) thyroid tissue predominates / 1/3 associated with ascites / rarely associated with Meigs syndrome / 5-10% malignant Immature Teratoma - poor prognosis young age / neuroectodermal elements / large / graded I - III with level of immaturity / 60% survival for all stages Sex-Cord Stromal Tumors -affects all ages -associated with Peutz-Jeghers Fibroma most common SCST / middle-age / associated with basal-cell nevus syndrome / 40% w/ ascites / 1% with Meigs syndrome (ovarian tumor, ascites, hydrothorax) / storiform pattern Granulosa cell tumors usually estrogenic / usually post-menopausal (adult vs. juvenile form) / may present with precocious puberty / macro/microfollicular pattern (call-exner bodies) / insular, trabecular, diffuse, luteinized / thecomatous component / size <5cm most important factor Thecoma estrogenic / post-menopausal / benign Sertoli-Leydig cell tumors (Arrhenoblastomas) < 1% of solid ovarian tumors Presentation: testosterone/androgen levels higher than PCOS and virilization is much more pronounced Treatment: chemotherapy? / hormone therapy will not suppress androgens Metastatic Tumors (mets to ovaries) Krukenberg Tumor signet-ring cells / primary stomach, GI tumor / usually bilateral / can cause mild, reactive hypersecretion of androgen Female Breast Estrogen - proliferation of duct cells Progesterone - proliferation of lobules, stroma and stromal edema Others: prolactin, human placental lactogen menstruation - sloughing of ECs and reduced edema 90% benign (40% fibrocystic) / 10% Ca ASPIRATION (of lump) has a 70-80% sensitivity Increased density: younger age, HRT, luteal (versus follicular) phase Benign Changes Fibrocystic Changes (FCD) 90% of reproductive women / relative estrogen predominance Non-proliferative changes blue-dome cysts / fibrosis, cyst formation, apocrine metaplasia, sclerosing adenosis microcalcification, (acini with intralobular fibrosis) Proliferative changes (2x Ca risk) > 2 duct layers / papillomatosis (project into lumen) / EC hyperplasia (irregular spaces in dilated ducts bridged by ECs), regular spaces may be Ca in situ / atypia or FH is 5x risk breast abscess unilateral / lactation / staphylococcus duct ectasia plasma cell mastitis / inspissation / mistaken for carcinoma fat necrosis resembles carcinoma, chalky nodule / foreign body rxn resolves w/ fibrosis granuloma (foreign substance) breast implant, self-induced, iatrogenic gynecomastia (male) Ddx: cirrhosis,  HYPERLINK \l "testicularcancer" testicular tumors (secreting estrogen),  HYPERLINK \l "klinefelters" Klinefelters Benign tumors 90% of breast lumps are benign Fibroadenoma Most common tumor in < 30 yrs / reproductive age / fibrous, gland element (stroma compressed ducts) / upper outer quadrant / increased E sensitivity ~ / occasionally foci for carcinoma / juvenile form is fast-growing Cystosarcoma phyllodes - worse prognosis painless / older women / lobulated, enormous / larger stromal cells surround leaf-like glands / Phylloides painless / treated with wide excision along with sarcomas Intraductal papilloma Most common cause of bloody nipple discharge / papillary architecture / near large ducts Treatment: excise duct system Adenoma of nipple elderly onset / crusted, ulcerated nodule beneath nipple / Treatment: excision Others lipoma, hemangioma, hamartoma Malignant Changes Non-invasive Intraductal carcinoma in situ (DCIS) most common / 28% become invasive / comedocarcinoma (necrosis) Treatment: almost as aggressive Lobular carcinoma in situ (LCIS) marker for invasive CA (30% develop invasive CA in same or contralateral breast) Invasive carcinoma (adenocarcinoma) Scirrhous carcinoma (ductal carcinoma) - poor prognosis majority / radiating, infiltrating / Blacks nuclear grading I - III (reverse of normal) Lobular carcinoma - worse 20% bilateral / multicentric / cells smaller than ductal carcinoma / Indian filing LCIS component / may co-exist with scirrhous (ductal carcinoma) Medullary carcinoma - good prognosis pushing borders / solid aggregates of tumor cells / reactive lymphocytes Colloid carcinoma (mucinous) - good prognosis clusters of malignant cells in lakes of mucin / infrequent node mets Pagets Disease (different from  HYPERLINK \l "pagets" bone disease) - poor prognosis not too common / form of ductal carcinoma / eczematoid nipple / Pagets cells surrounded by clear halo / 40% have axillary node mets / poorer prognosis b/c skin involvement Breast Cancer Pathology: Infiltrating ductal carcinoma 70% Medullary carcinoma 6% Lobular carcinoma 5% Colloid, Tubular 19% Staging: Stage I < 2 cm, no nodes/mets Stage II < 5 cm w/ nodes or > 5 cm Stage III direct spread, nodes Stage IV disseminated mets Patient Age: < 35 fibrocystic / fibroadenoma / mastitis 35-50 fibrocystic / carcinoma / fibroadenoma > 50 carcinoma / fibrocystic / fat necrosis Risk Factors: Nulliparity (women who are pregnant by age 18 have 30-40% reduced risk) Menarche (menarche at 16 confers 40-50% reduced risk vs. menarche by 12) Early menopause (occurring by age 40 reduces risk by 35%) Duration of maternal nursing (longer nursing decreases risk) Obesity increases risk previous h/o breast Ca (2x risk in contralateral breast) FH of breast CA / BRCA1/BRCA2 confer 10x risk (breast, ovary, colon) Suspicion of genetic carrier (can get testing) early exercise and lower fat during menarche reduces later incidence of breast CA Note: 75% of breast cancers occur with no family history or other high-risk factors Prevention/Screening [HYPERLINK "http://www.annals.org/cgi/content/full/122/7/539"annals] < 20 yrs monthly self-exam 20-40 medical exam (physical breast exam) every 3 yrs 35-40 baseline mammogram (30-40 with FH, or 10 yrs ahead of age of 1o relative) 40-50 mammogram every 2 yrs 50 mammogram yearly suspicious lump < 35 yrs ( likely need U/S if seems like simple cyst on U/S or seems benign on exam, can watch for regression with next menstrual cycle, but if it doesnt go away ( FNA, core biopsy or excisional biopsy if cyst regrows or mass effect does not resolve post FNA, then need to get excisional biopsy positive mammogram ( biopsy suspicious lump in pt > 35 yrs or more risk factors ( proceed with U/S, FNA, referral to specialist during pregnancy (persistent lump NOT normal; seek attention) Genetics: BRCA1 higher in A. Jews (60-80% incidence of breast cancer; 33% ovarian) (DCIS) BRCA2 women (breast) and men (breast/prostate) / higher in Ashkenazi Jews Rad 51 tumor suppressor p53 tumor suppressor PTEN Her-2/neu (erbB2) aggressive behavior of tumor Therapy Stage I ( modified radical or lumpectomy + radiation +/- hormonal Stage II ( surgery + adjuvant (hormonal and/or chemo) Stage III, inflammatory, poor histological features ( chemo/hormonal before surgery Advanced, metastatic disease ( ~surgery + chemo (definitely) Chemotherapy FAC (5FU, adriamycin, Cytoxan) AC (adriamycin, Cytoxan) CMF (Cytoxan, MTX, 5FC) Paclitaxel (Taxol) Docetaxel (Taxotere) Gemzar* (new) Xeloda (oral 5FU transformed in liver) Herceptin (new agent) Used only in Her-2/Neu (+) cancers (30%) Used as single agent in chemo-resistant metastatic disease Combination with chemotherapy in primary or 1st recurrent cancer Toxicity: cardiomyopathy (do not use with doxorubicin) High-dose chemo + autologous bone-marrow (remains controversial) Surgery modified radical or lumpectomy both involve axillary node dissection or sentinel node sampling / extensive lymph node resection (levels I, II and III) can lead to massive/chronic lymphedema (20-30% of patients), which can increase relative risk of angiosarcoma (rare to begin with) [HYPERLINK "http://dermis.net/dermisroot/en/17409/diagnose.htm"dermis] / decision between lumpectomy versus modified radical also depends on exact tumor location in breast and if patient has access to radiation treatments Hormonal given for 5 years (longer has not shown benefit)  HYPERLINK "pharm.doc" \l "Tamoxifen" Tamoxifen (Noveldex) acts as E for bone Raloxifene (Evista) similar action to Tamoxifen / large scale studies ongoing Progesterone (Megase) Aromidase inhibitors newer, use increasing ( HYPERLINK "pharm.doc" \l "exemestane" exemestane) Radiation Therapy takes 6 wks Used in certain treatment strategies (e.g. after lumpectomy) Note: small increase in incidence of contralateral breast CA (in very young pts), also increases risk of lung cancer (esp. in smokers), chest wall sarcoma Prognosis [keep in mind these statistics do not account for newer treatments so real odds may be higher] overall 10 yr survival 50% / stage I 80% II 60% III 20% Estrogen/progesterone receptors increase survival (E+ and E+/P+ tumors respond to hormonal agents/oophorectomy with 70% regression) Other Womens Health Issues Most common cause of death in females: CAD, lung cancer, breast cancer, CVA Health maintenance > 65 yrs Pap, lipid panel, mammogram, TSH, UA, r/o glaucoma,  HYPERLINK \l "osteoporosis" osteoporosis screening Colon Ca: same as for men Immunizations: Fluvax q yr (> 55 yrs), pneumovax x 1 (65 yrs) Cardiovascular: Womens Healthy Study 2005 to address use of ASA for low-risk pts in MI prevention (did not decrease MI but did decrease CVA) Pap Smears need annual initial but after 3 negative annuals, can consider decreasing to every 3 years in low-risk patients / if suspicious findings, repeat in 3-4 months, check HPV DNA typing or colposcopy depending on patients specific clinical/history Incontinence Diagnosis: in females with long-standing incontinence, may not need workup, but if male or abrupt onset or pain, do cystometrics and/or other workup (cystoscopy) to rule out stones, tumor, infection) Stress incontinence (F) ( surgery Detrussor overactivity (M/F) ( behavioral first, then if necessary, meds ( HYPERLINK "pharm.doc" \l "oxybutynin" oxybutynin,  HYPERLINK "pharm.doc" \l "tolterodine" tolterodine) but careful not to cause retention, avoid indwelling catheters Urge incontinence (M/F) ( behavioral first Functional incontinence (M/F) ( behavioral first Overflow incontinence (M: obstruction, prostate, M/F: atonic bladder) ( workup/treat Menopause always new trends in hormone replacement therapy [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/22/2338" NEJM] Note: 20% of post-menopausal bleeding is endometrial CA Note: can stay on OCP for birth control needs until age 50-52 then stop for 7 days and measure FSH, if elevated, pt likely menopausal, then pt can decided whether to start HRT or wait (OCP not recommended if pt has side effects or RFs such as smoking, DVT, heart disease) PMOF < 40 yrs (> 54 yrs is late) Risk factors: decreased adipose (decreased estrone), abrupt failure Hot flashes result from daily LH surge (lack of negative feedback) Obstetrics Drugs that are teratogenic ( HYPERLINK "pharm.doc" \l "teratogens" see pharm) Ectopic Pregnancy ( HYPERLINK \l "ectopic" see other) Pregnancy and specific diseases Thyroid disease and pregnancy (hypothyroidism) Liver disease and pregnancy (see below) Renal disease and pregnancy Diabetes and pregnancy (see below) Pregnancy helps SLE, migraines Pregnancy hurts Liver disease unique to pregnancy Hyperemesis gravidarum (1st) Cholestasis (2nd/3rd)  HYPERLINK \l "hellp" HELLP (3rd trimester) Acute fatty liver of pregnancy (3rd) prolonged PT (unlike HELLP, not complicated by DIC) Chronic renal disease and pregnancy increased risk of IUGR, prematurity, preeclampsia Cr 1.4 2.0 ( 2% chance of worsening renal function with pregnancy (30% if Cr > 2) Diabetes and pregnancy macrosomia or IUGR / all organs larger (exc. CNS) / increased sub-cutaneous fat / hyperplastic islets, neonate becomes hypoglycemic / clinically reversible, dilated or obstructive cardiomyopathy / increased liver lipid, glycogen increased fetal adrenal cortex, leydig and theca / increased malformations (congenital heart defects) / fetal death 10-30% gestational diabetes screen everyone / dietary measures usu. sufficient for mild gestational diabetes / if cannot maintain < 105 fasting or < 120 2 h postprandial, should use careful insulin ( HYPERLINK "pharm.doc" \l "teratogens" oral hypoglycemics contraindicated) / after pregnancy, must follow for increased risk of eventually developing diabetes Cortisol and pregnancy [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/21/2237" NEJM] cortisol is elevated in pregnancy / cortisol levels in 2nd and 3rd trimester may overlap with  HYPERLINK \l "cushings" Cushings syndrome use  HYPERLINK "pharm.doc" \l "metyrapone" metyrapone to suppress cortisol if needed (ketoconazole is teratogenic) Arrest of Labor 2 hr no dilatation (with adequate contractions: q 2-3 mins lasting 60 seconds or 200 montevideo units) placenta previa bleeding ( C-section stop bleeding < 36 weeks amnio FLM ( C-section Male Reproductive System  HYPERLINK \l "penis" Penis Infections  HYPERLINK \l "prostate" Prostate  HYPERLINK \l "bph" BPH,  HYPERLINK \l "prostateca" prostate CA  HYPERLINK \l "testes" Testes  HYPERLINK \l "testicularinfection" testicular infection,  HYPERLINK \l "testicularcancer" testicular cancer Penis Note: male circumcision shown to reduce risk incidence of HIV by in studies in Africa Malformations hypospadias / epyspadias / phimosis (natural stricture) physiological adhesions usually resolve on their own at an early age / paraphimosis (follows forcible retraction of phimosis) Balanoposthitis inflammation, infection due to phimosis/paraphimosis Urethritis Infectious: Neisseria, C. trachomatis, mycoplasm, ureaplasma, T. vaginalis, HSV, coliforms (in anal intercourse) Autoimmune: Reiters, etc. Other: chemical Treatment: with negative Neisseria culture or DNA probe, consider NGU and give single-dose azithromycin or 7 day course of doxycycline / also treat partner Infections Acute urethritis (presumed infectious) ceftriaxone 250 mg IM (in order to achieve high enough systemic levels) / regular penicillin wont cut it Syphilis ( HYPERLINK "micro.doc" \l "syphilis" see micro) 1) chancre 2) condyloma lata (highly infectious) 3) gummatous HSV1,2 ( HYPERLINK "micro.doc" \l "hsv" see micro) Lymphogranuloma venereum (LGV)  HYPERLINK "micro.doc" \l "ctrachomatis" Chlamydia trachomatis / very rare in U.S. / more common in Africa, India, SE Asia, Caribbean Papule painless, transient Inguinal syndrome lymphadenitis with bubo (painful, progresses to abscess, ruptures) / fever, malaise, anorexia [Groove sign between matted groups of lymph nodes] Anogenital syndrome anal pruritis, proctocolitis, rectal stricture, rectovaginal fistula, genital ulcer, elephantiasis Treatment: azythromycin, doxycycline 100 mg PO bid for 21 days Granuloma inguinale (Donavanosis) Calymmatobacterium donovani / extremely rare in US / more in Caribbean, Africa, Australia Micro: GNR, encapsulated, intracellular / cannot be cultured on solid media Diagnosis: donovan bodies (large histiocytes, dark inclusions) Transmission: may be transmitted by fecal-oral as well as sexually Presentation: firm, clean, painless, papule(s) that ulcerates with pseudo-bubo formation / genital swelling may occur (pseudoelephantiasis) Treatment: azythromycin, doxycycline, bactrim, chloramphenicol Chancroid H. ducreyi / common outside US Presentation: painful, demarcated, non-indurated ulcer (often multiple, extragenital lesions) / often with painful, inguinal lymphadenopathy / can form large ulcer if left untreated Diagnosis: culture difficult (transport swab in Amies, Stuart, chocolate agar) / gram stain: gram negative school of fish Treatment: ceftriaxone, azithromycin, erythromycin, ciprofloxacin, bactrim / treat partner Warts Common warts (verruca vulgaris) [HYPERLINK "pics/verrucavulgaris.jpg"pic][ HYPERLINK "http://dermis.net/dermisroot/en/14003/diagnose.htm" dermis] Condyloma acuminatum ( HYPERLINK \l "accuminatum" see other) HPV 6, 11 / benign / koilocytes Giant condyloma (Buschke-Lowenstein tumor or verrucous carcinoma) HPV 6, 11 / diagnosis: endophytic (invasive) growth w/ lack of normal vessels Treatment: excise, (do NOT irradiate) Carcinoma In Situ (CIS) Bowens disease [ HYPERLINK "pics/bowens.jpg" pic][ HYPERLINK "http://dermis.net/dermisroot/en/14781/diagnose.htm" dermis] > 35 both sexes / plaque / 10% progress to squamous carcinoma Erythroplasia of Queyrat plaque on glans/foreskin / 10% progress to squamous carcinoma Bowenoid papulosis younger / multiple papules / mistaken for condyloma acuminatum Squamous cell carcinoma of penis usually glans / lymphatic spread / exophytic (better prognosis) Risk factors: lack of circumcision / poor hygiene / phimosis / HPV 16,18 / UV light Treatment: surgical, radiation, ?chemotherapy Squamous cell carcinoma of inguinal lymph nodes Regional radiation therapy is curative in up to 5% / chemo not generally useful Prostate Bacterial prostatitis ascending urethral infection reflux of infected urine into prostatic ducts entering into the posterior urethra invasion of colonic bacteria through direct extension or lymphatic spread hematogenous seeding Organisms: E. coli, GNR, Pseudomonas, Proteus, Klebsiella, S. aureus, coagulase-negative Staphyloccocus Acute bacterial prostatitis fever, chills, dysuria / UTI organisms / do not express prostatic secretions (risk of bacteremia) / urine culture usu. positive / fast response to IV antibiotics (treat 4 weeks) Chronic bacterial prostatitis WBCs in secretions / diagnosed by quantitative bacterial localization cultures (3 cultures, 1st 10 ml, 2nd 10 ml, post-DRE 10ml, which it the EPS sample) / may require 1-2 months abx / TURPS in refractory cases, but relapse is common if infection not completely cleared Chronic abacterial prostatitis most common prostatitis / NO Hx of UTI / high WBC, negative culture / low back pain chlamydia (current thinking actually is that chlamydia does not play much role in prostatitis), ?ureaplasma / fungal, anaerobes, RPR, viral / can get chemical prostatitis from urethral spasm and reflux / alpha-adrenergic blockers can sometimes help with voiding Granulomatous prostatitis foreign body reaction to extravasated secretions / hard nodule / may resemble carcinoma Tuberculous prostatitis systemic Tb / may follow BCG immunotherapy for bladder Ca (PSA will return to normal) Benign prostatic hyperplasia (BPH) NOT PRE-MALIGNANT occurs 10 yrs earlier in blacks Symptoms: urinary retention, control / urinary tract infection, prostatitis Complications: may lead to bladder SMC hypertrophy, diverticulum Pathology: transition zone and periurethral glands / 2 cell layers is a good sign Treatment: Medical:  HYPERLINK "pharm.doc" \l "alpha1blockers" a-1 blockers reduce smooth muscle contraction (more immediate benefit with smaller prostates) /  HYPERLINK "pharm.doc" \l "finasteride" finasteride (Proscar) blocks conversion of testosterone to DHT (prostatic hypertrophy and male pattern hair loss) Surgical (no longer 1st line): TURP (prostatectomy) / ? laser and cryoablation Prostate Cancer most common cancer in males / 2nd leading cause of cancer death in males / incidence increasing in U.S. Presentation: presents late in its course (elevated PSA + urinary symptoms is 60% chance of prostate cancer; 16% of cases have elevated PSA as only symptom) / usu. posterior peripheral zone, prominent nucleoli Course: prostate intra-epithelial neoplasia (PIN) precedes CA by > 10 yrs / wide-spectrum of aggressivity / secretory (androgen-dependent growth/receptors synthesize PSA) Blacks early, high grade White middle onset, variable aggresivity Asian later onset, less aggressive (more dietary) Diagnosis: PSA > 3 ng/ml over age 40 (repeat test x 1) / 4.0 to 10.0 ( marginal level (25% chance of malignancy), but must chart over time, because 2 is moving up the curve already / 26-68% newly diagnosed have proven extra-prostate mets / free PSA can help for marginal total PSA (high free fraction is good because it could mean the high total was misleading due to nature of assay) Bone scan: osteoblastic activity well seen (unlike myeloma and sometimes thyroid, renal mets which are osteolytic and do not take up tracer) MRI if trying to assess resectability Staging: Gleasons grading system sum of 1st and 2nd most predominant architectural pattern / 2-10 (over 5-6, aggressive) Stage A (not palpable) Stage B (palpable) note: A2 may have worse prognosis than B1 Stage C (extra-prostatic) most patients present with stage C or D Stage D (distant mets) Prevention yearly DRE and PSA screening > 50 yrs (blacks > 40 yrs) / if value increased > 20% in 1 yr (considered positive PSA test ( consider biopsy) Treatment: (A or B) surgery, radiation / (C or D) hormonal manipulation radical retropubic prostatectomy (may be curative in early stage; impotence, incontinence may result, but sometimes function returns over 4-6 months) radiation therapy another option / PSA levels slowly decline after (side effects occur late) LHRH (GnRH) agonist (goserelin, buserelin leuprolide) ( most efficacious (1st line) antiandrogen ( HYPERLINK "pharm.doc" \l "flutamide" flutamide) ( not quite as efficacious, does not cause impotence combination LHRH + anti-androgen ( more side effects (impotence), only very slight increase in 5 yr survival / total blockade used for months before surgery orchiectomy ( works but most men dont want this adrenalectomy ( ? DES (estrogen) ( efficacious but increased MI, thrombosis chemotherapy ( no increased survival has been shown (this may have changed since 06) Testes [ HYPERLINK "ddx.doc" \l "smalltestes" Ddx of small testes] Cryptorchidism bilateral / contralateral, descended testis may show changes / XXY / seen by age 2 low germ cell development / hyalinization of seminiferous tubule BM / interstitial fibrosis Treatment: scrotal placement < 2 yrs (sterility may ensue if not corrected before age 5) / resection to prevent CA Leydig cell hyperplasia Symptoms: inguinal hernias / orchiopexy may prevent infertility, but not neoplasm risk Testicular Torsion Mechanism: arteries usually patent / hemorrhagic or anemic infarction / structural cause (incomplete descension (high attachment of tunica vaginalis), absence of scrotal ligaments, testicular atrophy) Presentation: high riding, swollen, painful, horizontal Diagnosis: U/S to assess doppler flow / CRP/ESR levels Ddx: advanced epididymitis (torsion of epididymis) Treatment: orchiopexy (unsalvageable after 6 hrs) / fix other side too (it may happen there) Tunica vaginalis lesions hydrocoele (incomplete closure of tunica vaginalis) hematocoele chylocoele varicoele (18% normal males on L or bilateral pampiniphorm plexus issue) spermatocoele (semen fills duct) Testicular infectious disease pediatrics GNR associated with malformations under 35 C. trachomatis, N. gonorrhea over 35 E. Coli, Pseudomonas granulomatous orchitis rare, unilateral enlargement / acute, fever, tender / autoimmune / plasma cells (occasional neutrophil) surrounded by rim of lymphocytes, fibroblasts mumps 20% result in orchitis (may be bilateral) / usu. > 10 yrs old / 70% unilateral / usu. 1wk after parotitis / mononuclear infiltrate - interstitial, patchy / usually does not cause sterility tuberculosis epididymis first, then testis / TB = testicular artery? syphilis testis first, then epididymis / sterility occurs secondary to obliterative endarteritis Testicular cancer Germ cell tumors (GCT)  HYPERLINK \l "Seminomatous" Seminomatous (SGCT)  HYPERLINK \l "seminoma" seminoma  HYPERLINK \l "spermatocyticseminoma" spermatocytic seminoma  HYPERLINK \l "nsgct" Non-seminomatous (NSGCT)  HYPERLINK \l "embryonalcarcinoma" embryonal carcinoma  HYPERLINK \l "yolksactumormale" yolk sac tumor  HYPERLINK \l "choriocarcinoma" choriocarcinoma  HYPERLINK \l "teratoma" teratoma Non germ cell tumors  HYPERLINK \l "leydigcelltumor" Leydig cell tumor,  HYPERLINK \l "sertolicelltumor" Sertoli cell tumor Mixed cell tumors  HYPERLINK \l "testicularlymphoma" Testicular lymphoma General Notes Presentation: painless mass (most solid testicular masses are malignant), dull ache or active pain (in 10% of cases) from hemorrhage into mass or associated epididymitis Ddx: hydrocoele, spermatocoele, inguinal hernia, epididymitis, orchitis, trauma, epidermoid cyst, benign tumor Diagnosis: transillumination (then ultrasound) to distinguish solid from cystic;  HYPERLINK "labs.doc" \l "hcg" hCG,  HYPERLINK "labs.doc" \l "afp" aFP are measured only after confirming solid mass; if diagnosed, must assess peri-aortic lymph nodes by CT/MRI (drainage to periaortic nodes and not inguinal nodes) (scan abdomen, pelvis and chest) Treatment: radiation, chemotherapy, resection post-chemotherapy leukemia relative risk at 5 yrs (15-25%), which equals absolute risk of 0.5% treatment-related solid tumors are radiation-related occurring in bladder, pancreas, stomach with latency of ~10 yrs Germ cell tumors (95%) - peak incidence 15 - 34 yrs / preceded by intratubal germ cell neoplasia Seminomatous (50%) seminomas vs. non-seminomatous GCTs remain localized mets via lymphatics first (?then hematogenous to lung) relatively radiosensitive usu. have normal tumor markers (hCG and/or aFP elevated in 75% NSGCTs) Seminoma most common / 40s / large cells, clear cytoplasm, distinct cell membranes, septated architecture, septal lymphocytic infiltrate Spermatocytic seminoma ( - worse prognosis rare / 60s / indolent / smaller cells and larger seminoma cells / lack of lymphocytes / more mitoses Non-seminomatous (NSGCT) (50%) typical treatment regimen might include  HYPERLINK "pharm.doc" \l "cisplatin" cisplatin,  HYPERLINK "pharm.doc" \l "etoposide" etoposide,  HYPERLINK "mailto:pharm.doc#bleomycin" bleomycin or VBP (vincristine, bleomycin, cisplatinum) decision whether or not to do RPLND (retroperitoneal lymph node dissection to look for mets); depends on stage and other factors [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/8/842" NEJM] high hCG, aFP or LDH > 10x normal confers worse prognosis (still can have 50% cure rate) / half-life of aFP is 6 days, -HCG is 1 day (both markers should be followed with treatment as levels may decrease differently because of production by different populations of tumor cells) relapse for stage I 20-30% (usu. < 2 yrs, rare after 5 yrs) but still 98% eventually cured Embryonal carcinoma (15%) 20s / aggressive / variable pattern (alveolar, tubular, glandular) / nodules separated by slits / most common testicular tumor in infants and children intra/extracellular globules with aFP and a1-AT (Schiller-Duval bodies) Choriocarcinoma (<1%) cyto/syncitiotrophoblastic cells / very aggressive (lymphatic spread) / produce hCG Rx:  HYPERLINK "pharm.doc" \l "mtx" MTX Teratomas ( HYPERLINK \l "teratoma" see other) (3-5%) Mixed NSGCT (35%) 1st - teratoma, embryonal carcinoma, yolk sac tumor w/ hCG syncitiotrophoblast 2nd - teratocarcinoma is a teratoma and embryonal carcinoma 3rd - seminoma, embryonal carcinoma Non-germ cell tumors (5-10%) (sex-cord stromal tumors) usually benign, may elaborate steroids Presentation: testicular mass, impotence, gynecomastia, precocious puberty Leydig cell tumor (interstitial) / 10% invade / contain lipochrome pigment, lipid droplets, Reinke crystalloids (needle-like) Sertoli cell tumor (androblastoma) recapitulate seminiferous tubules / may secrete hormones (ABP) / 10% invasive Testicular lymphoma most common in > 60yrs / diffuse large cell lymphoma Bladder Cancer General 90% transitional cell / squamous, adenocarcinoma Risk factors: males 3x > females / smoking ! 2-4x / chronic cyclophosphamide, external beam radiation, aniline dyes, schistosomiasis Presentation: hematuria, UTI Diagnosis: urine cytology, cystoscopy Treatment: resection and chemotherapy (even for local disease!) /  HYPERLINK "pharm.doc" \l "BCG" BCG vaccine used as intravesicle treatment Transitional cell carcinoma invades by extension - many carcinogenic causes - usually papillary grade - cytology / stage - invasion (inner third of muscle is still safe) smoking is a risk factor Treatment: ?resection, chemo Transitional cell papilloma seven or fewer layers Squamous cell carcinoma of the bladder associated with schistosomiasis (haematobium) Adenocarcinoma of the bladder Cystitis glandularis may resemble adenocarcinoma Malakoplakia inflammatory pattern showing michaelis-gutmann bodies (calcified nodules) Developmental / Pediatrics [HYPERLINK \l "childhood"Pediatric Infectious Disease] [HYPERLINK \l "vaccines"vaccination] [ HYPERLINK \l "metabolism" Fluid Maintenance]  HYPERLINK \l "teratogenesis" Teratogenesis  HYPERLINK \l "maternal" Maternal environment /  HYPERLINK \l "morphogenesis" normal morphogenesis /  HYPERLINK \l "disrupted" disrupted development  HYPERLINK \l "pedrespiratory" Pulmonary  HYPERLINK \l "lungmalformations" lung malformations, neonatal lung  HYPERLINK \l "pediatricheme" Heme  HYPERLINK \l "bilirubin" hyperbilirubinemia,  HYPERLINK \l "abo" ABO incompatibility  HYPERLINK \l "pedintestinal" GI   HYPERLINK \l "pediatricliver" Liver  HYPERLINK \l "pedheart" Congenital Heart Disease Bone  HYPERLINK \l "stills" Juvenile RA HYPERLINK \l "pediatricskin"Derm  HYPERLINK \l "atopic" atopic dermatitis, HYPERLINK \l "seborrheic"seborrheic dermatitis, miliaria rubra  HYPERLINK \l "pediatricneuro" Neuro NEC, PVLM  HYPERLINK \l "pedtumors" Childhood Tumors histiocytoses, renal tumors, neural tumors, other tumors  HYPERLINK \l "genetic" Genetic Syndromes  HYPERLINK \l "downs" Downs,  HYPERLINK \l "turners" Turners, etc.  HYPERLINK \l "metabolic" Metabolic Disorders  HYPERLINK \l "aminoacids" Amino acids Homocystinuria, PKU, porphyria  HYPERLINK \l "otherenzymedeficiencies" Other enzyme deficiencies  HYPERLINK \l "lysosomalstorage" Lysosomal storage disorders  HYPERLINK \l "Mucopolysaccharidoses" Mucopolysaccharidoses Hurler, Schei, Hunter  HYPERLINK \l "glycogenstorage" Glycogen storage disorders  HYPERLINK \l "hepatichypoglycemia" hepatic hypoglycemia Von Gierkes, Pompes  HYPERLINK \l "muscleenergydisorders" muscle energy disorders McArdles HYPERLINK \l "developmentimmune"Fetal Immune System Teratogenesis ( HYPERLINK "pharm.doc" \l "teratogens" see pharm) 1-2% live births have obvious congenital malformations (suspected 10%) / account for 30-40% hospitalizations organogenesis 14-56 days, after which teratogens cause deformation, retardation rubella 1st trimester DES - vaginal glands, clear cell carcinoma AD - Marfans / neurofibromatosis AR - errors of metabolism XLR - imperforate anus / congenital cataract multifactorial (gen/env) - cleft lip / pyloric stenosis Maternal Environment transplacental - rubella, coxsackie, hepatitis, HSV, CMV, toxoplasmosis, other (malaria, listeria) delivery - HSV, syphilis, Group B Streptococcus perinatal: low virulence (E. Coli, Aerobacter, Alcaligenes, Proteus, Group B strep) chorioamnionitis: ascending infection fetus swallows maternal PMNs villitis: transplacental (may be asymptomatic) funisitis: inflammation of umbilical cord nutrition: malnutrition, obesity / endocrine: DM, hyperthyroid blood dyscrasias: hypochromic anemia (prematurity) / sickle cell / ITP early abortion: chromosome anomaly, cytotoxic (UV, methotrexate), implantation error, trauma placenta previa: low implantation site over cervix placenta accreta: absent decidua basalis, villi enter myometrium placenta abruptio: separation of placenta from uterus bilobate (succenturiate) placenta: marginal (Battledore) insertion: 1 in 5 / usu. asymptomatic velamentous insertion: placenta in membranes / bleeding risk at delivery single umbilical artery: 1/4 to with malformations placenta extrachorialis: membranes insert on fetus rather than margins amnion nodosum: oligohydramnios causes squamous cell aggregates on fetal skin amniotic bands: adhere to fetus / compress, constrict IUGR: occurs with > 15% placental infarction Pre-eclampsia (see DIC) twins: 1/80 1/3 are monozygotic, 2/3 are dizygotic twin transfusion syndrome / fetus papyraceous Normal Morphogenesis embryo: up to 8 wks <30 mm lungs: embryonic 3-6 / pseudoglandular 6 - 16 / canalicular 16 - 24 / terminal sac 24 - / alveolar 40 kidneys: EC cap persists over glomeruli for 18-24 months postnatally liver: extramedullary hematopoeisis up to 14 days after birth lymph: primary follicles at 24 wks / germinal centers 4-6 wks after birth adrenals: large fetal cortex involutes at birth (produces DHEA precursor for placental estriol E-3) full term: 38-43 wks / 48 cm / 3200g prematurity: <37 wks gestation / <26 wks marginally viable / 7.5% of births / 64% neonatal death type 1 IUGR: symmetric / fetal abnormality type 2 IUGR: asymmetrical with CNS sparing / maternal and placental abnormality Disrupted Development highest susceptibility 14 - 56 days dive reflex - pulmonary artery constriction to preserve brain perfusion RF: prematurity, DM, twins, C-section HMD (lack of  HYPERLINK \l "surfactant" surfactant) occurs at 4 hours / surfactant by 28 wks vascular spasm causes underperfusion / ischemia causes transudation / fluid and hyaline block respiration BPD follows barotrauma and high oxygen therapy results in retrolental fibroplasia Pulmonary Disease in Infants/Children Stages of Neonatal Lung Development embryonic 3-6 wks pseudoglandular 6 - 16 - cartilage, cilia, goblet cells, glands canalicular 16 - 28 - acinae, septa, type I and II pneumocytes terminal sac saccular 28 - 34 -  HYPERLINK \l "surfactant" surfactant alveolar 40 - 2 yrs Respiratory Distress Syndrome Prematurity PDA pulmonary edema capillary leak (see cardiac) surfactant deficiency - immature lung structure Surfactant phosphatidylcholine (lecithin) 70%, phosphatidylglycerol 10%, phosphatidylethanolamine 5%, sphingomyelin 2%, other 3%, proteins 5%, SP A-D 5% Presentation: tachypnea, nasal flaring, subcostal and intercostal retractions, expiratory grunt, cyanosis, diminished air entry CXR: symmetric, homogeneous, ground glass appearance (not well aerated) also decreased pneumothorax mortality Diagnosis: evidence of prematurity, signs and lab, other causes (group B streptococcus), radiologic evidence of HMD (reticulo-granular pattern, air bronchograms [because collapsed lung tissue allows dark bronchi to be seen]) Complications: ICH, PDA,  HYPERLINK \l "bpd" BPD, ROP, Secondary infection, Rupture of Lungs Treatment: supportive care: O2 and/or ventilation, intubation Drug therapy: natural surfactant from cows lungs - human amniotic fluid (not practical, requires 10 C-sections to get one therapy), alveolar washing and lung extracts from cows, pigs, etc. synthetic surfactant (no protein) used to tremendous success, 30% decrease in mortality, 1% decreased in overall infant mortality in US) Prevention: distributes better in liquid interface, may treat when not necessary (40%) (one study shows advantage to prevention therapy before 26 weeks gestation) Congenital Malformations of the Lungs Hypoplastic lung compression, oligohydramnios, obstruction, vascular, CNS Brachial plexus injury, phrenic nerve injury One lung is small on CXR because diaphragm is not functional Pulmonary sequestration acessory lung blood supply systemic, not pulmonary artery extralobar sequestration mass of lung separated, systemic blood supply, diaphragmatic hernia (left) intralobar sequestration more common / systemic blood supply / posterior-basal lung cystic or solid inflammation bronchial connection to foregut predisposes to infection Cystic disease bronchogenic lymphangiectasis may accompany HMD / venous return obstruction / Turners syndrome cystic adenomatoid malformation gastric epithelium (type 1) / unilobar / associated with heart and kidney malformations / prematurity / type 3 is fatal congenital lobar emphysema hyperexpansion due to bronchus collapse / unilobar / normal septa (not true emphysema) Neonatal Pulmonary Disease Hyaline membrane disease insulin retards  HYPERLINK \l "surfactant" surfactant production / thyroxine, glucocorticoids promote surfactant / appears after 4 hours of life / macrophages present after 24 hrs. Bronchopulmonary Dysplasia BPD artificial ventilation, oxygen therapy - may lead to cor pulmonale Stage 1 (2-3 days) - acute, exudative / hyaline membranes, atelectasis, lymphatic dilatation Stage 2 (4-10 days) - regeneration / necrosis, repair, hyperaeration Stage 3 (10-20days) - transition / bronchiolitis obliterans, histiocytes Stage 4 (1 month) - honeycombing, peribronchial muscle hypertrophy, squamous metaplasia Pneumonia ( HYPERLINK \l "pneumonia" see other) true pneumonia (fibrinopurulent, hyaline exudate) v. aspiration of maternal WBCs Meconium aspiration intrauterine distress causes excess meconium release into amniotic sac marked abnormalities and other complications as in HYPERLINK \l "bpd"BPD Hx: term or post-term, asphyxia CXR: hyperinflation (lowered diaphragm), clumpy distribution of lung abnormalities Treatment: mechanical ventilation, lavage techniques being investigated Sudden Infant Death Syndrome (SIDS) URI? / 2/1000 leading COD in infants 1 mo to 1 year chronic hypoxia? / sleep apnea? / Reduce risk by sleeping in prone position Pediatric Hematologic Apt test distinguishes fetal from maternal blood useful in situations like vasa previa Hyperbilirubinemia Physiologic jaundice physiologic jaundice occurs day 3-4 / 8-10mg/dL 2.5 kg infants 6% have level above ? 12.9 mg/dl peak 4th day cephalopedal progression / increased production, higher hematocrit (40-60 normal), decreased red cell survival (80 days), decreased ligandin, decreased glucoronyl transferase, decreases EH circulation Asian >> Caucasian >> black breastfeed > formula males >> females premature >> term diabetic mother Pathological jaundice Definitions: clinical jaundice in 1st 24 hours total bilirubin level rate of rise > 5 mg/dl/day total serum bilirubin > 13 mg in term infant direct serum bilirubin > 2 mg/dl at any time clinical jaundice for > 1-2 weeks in a term infant Mechanism: glucuronide transferase activity- adequate after several days / pregnanediol in mothers milk inhibits conjugation Causes: excessive RBC breakdown (e.g. sepsis, erythroblastosis) defects in uptake (galactosemia, tyrosinemia, hypo/hyperpituitary, breast milk jaundice, prematurity Presentation: Early: lethargy, poor feeding, loss of Moro reflex (usu. present to 6 months) Later: rigidity, opisthotonos, cry, choreoathetosis, more Course: 50% mortality, 80% of survivors with neurological sequelae (kernicterus - bile staining of CNS gray matter) Treatment: phototherapy, hydration (not too much), exchange transfusion,  HYPERLINK "pharm.doc" \l "phenobarbital" phenobarbital?, albumin? Photoisomerization (blue light range) changes ZZ to ZE, which is excreted into bile Also converted to lumirubin, which is excreted into the urine Efficiency based on skin exposure, 15-20 cm from baby, eyes patched, turned frequently, bili blankets use fiberoptics and may increase the exposed surface area Exchange transfusion double volume exchange done through the umbilical vein and artery, infection, hypocalcemia, hyperkalemia Conjugated Hyperbilirubinemia Diagnosis: LFT, liver ultrasound, bacterial and viral cultures, HIDA scan (biliary atresia, HIDA wont be excreted into intestine) More on Bilirubin Metabolism unconjugated indirect, lipid soluble conjugated direct, water soluble Physiologic Jaundice late onset breast milk jaundice elevated 1st week 10-30 mg/dl by 10-15 days, continues for 3-12 weeks, levels normalize 48 hrs stopping breast feeding / can occur early possibly related to dehydration ABO incompatibility ( HYPERLINK \l "transfusionmedicine" see transfusion medicine) most common hemolytic disease of newborn (HDN) Most infants have only mild jaundice, observe for late onset of anemia Some develop hyperbilirubinemia and require phototherapy exchange transfusion is needed only occasionally AO is the most common form Rh incompatibility Mild phototherapy Moderate exchange transfusion Anti-D globulin (RhoGAM), given at 28 weeks and at birth if infant is Rh+ Given to Rh- women who have miscarriages, abortions Kleihauer-Betke test measures amount of fetal Hb in mother [ HYPERLINK "http://en.wikipedia.org/wiki/Kleihauer-Betke_test" wiki] 1 ml can eliminate 10 ml of antigenic fetal cells Congenital Disorders of Bilirubin Metabolism Crigler-Najjar infant death absent UDP-glucuronide transferase / unconjugated hyperbilirubinemia / jaundice, kernicterus Gilberts disease milder form / unconjugated hyperbilirubinemia / Ddx: hemolysis Treatment: plasmapheresis, phototherapy Dubin-Johnson conjugated bilirubinemia, defective secretion of bile / black liver, obstruction Rotors syndrome milder form Pediatric GI Necrotizing enterocolopathy (NEC) 80% are premature / susceptibility requires GI colonization dive reflex lowers perfusion, lowers mucous / enzymes degrade, bacteria invade / perforation / DIC follows necrosis / fibrin covers perforation / pneumatosis intestinalis / multiple segments / reepithelialization 3 days / granulation 8-9 days / scar formation 6 months Tracheoesophageal fistula (1/1000) 90% esophageal atresia w/ tracheal-lower esophageal fistula / H-type compatible w/ life 50% have associated malformations Hypertrophic pyloric stenosis (1/1000) 2-3 wks onset / 80% males / 1/3 first born / 10% associated malformations Cleft palate children with cleft palate or submucosal cleft palate should not have adenectomy because the adenoids help close of nasopharynx during speech Duodenal associated malformations / Downs syndrome Jejunum/Ileum associated malformations rare / hydramnios / ischemia / acquired in utero / idiopathic < 2yrs old Congenital Malrotations associated with Ladds bands (cecum to ULQ, obstruct duodenum) / most cases present with vomiting in first few weeks (can be months, rarely up to 1 year) from Ladds band or midgut volvulus / a few remain asymptomatic / all infants with bilious vomiting are malrotation until proven otherwise Congenital annular pancreas most commonly presents with vomiting from duodenal obstruction Meckels diverticulum (1/50) rule of 2s 50% are gastric epithelium (can be other type) / males > female / 40-90 cm (2 feet) proximal to ileocecal valve on antimesenteric side / remnant of vitelline duct / 2% incidence (90% asymptomatic) fixed duct ( volvulus inverted ( lead point intussusception Imaging: pertechnetate Tc-99 scan for gastric mucosal /barium may be useful Complications: bleeding (50%, ulceration from acid), obstruction (25%), intussusception, volvulus, incarceration), perforation (20%) Presentation: bleeding (1st LGI bleed in < 2 yrs), obstruction / may present w/ granuloma at umbilicus / associated malformations? Ddx: celiac disease, others Treatment: resection Hirschprungs (megacolon) 1 in 5000, 4:1 males aganglionosis with hypertrophy of muscularis occurring in rectum (26%), sigmoid (53%), descending colon (10%) / dilatation of proximal segment / how far did the neurons not get? meconium plug syndrome (not that common) liberated by barium enema? - 20-25% of neonatal obstructions trisomy 21 / 2.5% w/ megaloureters Presentation: FTT, constipation, distention, vomiting, perforation, enterocolitis / 70% 0-3 months / 10% 4-12 months 17% 1-5 yrs enterocolitis has a 30% mortality; 20-30% of mortality? is GN sepsis (rarely over 2 yrs old, 2/3 under 3 months), 50% pseudomembranous (maybe HYPERLINK "micro.doc" \l "cdifficile"C. difficile, other normal flora in many cases) Diagnosis: barium enema (send to pediatric radiologists) anorectal manometry suction biopsy (sub-mucosal plexus, 3-4 cm proximal to pectinate line, dont do it too distally) full thickness biopsy (myenteric plexus, again use experienced pediatric pathologist, ganglion cells, nerve trunks, etc.) Acquired megacolon Chagas disease - trypanosomes destroy plexi obstruction -neoplasm or inflammatory stricture toxic megacolon - ulcerative colitis or Crohns disease psychosomatic disorder ?idiopathic megacolon common onset 2-3 yrs fecal soiling (never in HD) - even from 0-12 yrs age abdominal distension rare infrequent, hard stools cholase DOES NOT really work for constipation the case against mineral oil pts dont like leaking, staining clothes stimulant cathartics are not recommended for long term use Lactulose stool softener / biofeedback has similar success (more cumbersome therapy) Encoprosis (very common) Atresia and stenosis duodenum (most common) / atresia more than stenosis / double-bubble (air in proximal duodenum and stomach, associated with Downs) Congenital diaphragmatic hernia usually occurs on left, posterolateral defect (foramen of Bochdalek) / heart pushed to the right side / unilateral pulmonary hypoplasia other malformations / eventration (elevated diaphragm with attenuated muscle) / scaphoid abdomen / 100% mortality if left untreated Omphalocele Membrane covering / larger defect, may contain liver / associated abnormalities in 50% (pentalogy of Cantrell: diaphragmatic hernia, cardiac, omphalocele, pericardial defect, sternal cleft) / 1 in 5000 Treatment: fluids, antibiotics, surgery Gastroschisis No membrane covering, thickened bowel / R > L (of cord) / 2-4 cm / less common than omphalocele, intestinal atresia in 10-15% (but no other associations) / complications: hypothermia, hypovolemia, sepsis, metabolic acidosis, NEC, prolonged ileus Treatment: similar to omphalocele (90% survival) Pediatric Liver Disease ( HYPERLINK \l "liver" see liver) Neonatal hepatitis - good prognosis most common cause of infantile cholestasis / giant cell transformation Extrahepatic biliary atresia fibrosis obliterates bile ducts / bile duct proliferation / biliary cirrhosis w/ remaining parenchyma susceptible to ischemia / Treatment: Kasai procedure,  HYPERLINK \l "livertransplant" liver transplant Alpha-1-antitrypsin deficiency PiMM is normal genotype / PiS and Piz abnormal / emphysema in adults / chronic liver disease in children / portal hypertension, cirrhosis (50%) / PAS positive globules in periportal hepatocytes Treatment: liver transplantation Tyrosinemia fumarylacetoacetate hydrolase def. / death < 1 (acute) <10 (chronic) / fatty change Treatment: transplant Hemochromatosis (neonatal) iron overload / liver fibrosis / central vein necrosis / early death / Treatment: transplant Other Causes of Cholestasis Alagilles syndrome (paucity of ducts) / Bylers disease / Carolis disease / errors of metabolism Congenital Heart Disease  HYPERLINK \l "asd" ASD,  HYPERLINK \l "vsd" VSD,  HYPERLINK \l "tof" TOF,  HYPERLINK \l "transposition" transposition,  HYPERLINK \l "avvalvemalformations" AV valve malformations, HYPERLINK \l "_patentductus"PDA,  HYPERLINK \l "coarctation" coarctation, Genetic Syndromes  HYPERLINK \l "downs" Downs,  HYPERLINK \l "turners" Turners,  HYPERLINK \l "edwards" Edwards,  HYPERLINK \l "marfans" Marfans,  HYPERLINK \l "praderwilli" Prader-Willi, congenital deafness,  HYPERLINK \l "jln" JLN,  HYPERLINK \l "williams" Williams 1 in 50 births / of all major malformations 1)  HYPERLINK \l "vsd" VSD 2) HLH 3) TOF there are some lesion that are difficult to detect by fetal echo, such as small to moderate size VSDs, coarctation, minor valve abnormalities, and of course, persistence of an ASD or a PDA (can be diagnosed after the baby is born) ASD Ostium secundum (most common) / Lutembachers secundum defect and acquired MS Ostium primum defect endocardial cushion / MR Sinus venosus (2-3%) Usually asymptomatic until 40s / DOE, RHF, pulmonary HTN (50% over 40 yrs) Complications: MR, MS, paradoxical embolism, Findings: wide fixed (or not), split S2, incomplete RBB on ECG (rSr or rsR) Treatment: surgical correction (risk 1-3%) or catheter based insertion of corrective device / treatment is recommended even in patients from time of diagnosis to over 60 yrs VSD Infracristal (80%) - 4 other defects Supracristal - truncus arteriosis Single ventricle - transposition of great arteries Course: may close spontaneously before < 10 yrs / L to R shunt with Qp:Qs > 1.5 will cause problems Findings: loud pansystolic murmur and/or systolic thrill on LLS border, increased pulmonary arterial pressure, PaO2 from RA to RV increases from 60 to 80 mm Hg / S2 splitting? Treatment: afterload reduction (nitrates, intra-aortic balloon counterpulsation) repair VSD at earliest sign of heart failure (urgent) Small shunt ( usually do not repair small defects / small minority can develop TR/AR Moderate shunt ( catheterization for evaluation and surgical or balloon repair / post-repair residual patency rate (20%), re-operation rate (5%), RBB (30-60%), heart block (10%), SCD (2%) Eisenmengers syndrome may occur from ASD > VSD or aortopulmonary shunt / progressive increase in pulmonary vascular resistance leads to reversal of shunting / leads to progressive AR from prolapse of aortic valve leaflet / no longer candidates for surgery, so no need for invasive studies / clubbing in toes > left arm > right arm Ddx (for cyanosis): Ebsteins anomaly, TOF, truncus arteriosis Truncus Malformations Tetralogy of Fallot (TOF) Dextroposition of aorta (overriding aorta) right ventricular hypertrophy (RVH) pulmonary valve stenosis infracristal VSD cyanosis within 1 day, may be late in TOF (mild case may present up to 2 yrs old) RV tap +/- thrill loud & single S2, +/- murmur EKG shows RAD + RVH (? LVH in pulmonary artery) CXR boot-shaped heart Echocardiogram - ? TOF hypoxic spells (blue or tet spells) precipitating causes: bowel movement, crying with hunger, finger stick, etc leads to irritability, loss of consciousness, acidosis, tachypnea, air hunger, increasing cyanosis Treatment: rest, oxygen,  HYPERLINK \l "tof1" knee-chest position (squatting), morphine, bicarbonate, beta-blockers, general anesthesia, emergency shunt (thought to increase systemic resistance and decrease R-L shunting) Treatment: Treat hypoxic spells (above), PGE1 (opens ductus arteriosis), balloon atrial septostomy surgery switch (RV is not capable, long term develops aortic insufficiency) venous mustard or senning arterial before 2-3 weeks of life Must increase blood flow to lungs! before 6 months systemic (aorta or subclavian if older) to pulmonary artery shunt (Blalock-Taussig or modification, Waterston-Cooley or modification, Potts) after 6 months - corrective surgery (switch has been done 15-18 yrs, so far with good success?) Truncus Arteriosus supracristal VSD / single artery to aorta, lungs / pulmonary HT / death < 1yr Transposition of Great Arteries incompatible with life in absence of communication TGA + Intact ventricular septum male predominance, h/o diabetes, newborn cyanosis TGA + defective septum cyanotic at one month? AV, Semilunar Valve malformations Endocardial cushion defect (foramen primum, VSD, etc.) / Trisomy 21 (Downs) Endocardial fibroelastosis usually causes CHF in 1st year of life Tricuspid valve atresia all have ASD Presentation: cyanosis or heart failure, overactive cardiac impulse, holosystolic murmur CXR shows prominent RAD, ?EKG RAE, LAD + LVH Treatment: PGE1, decongestive therapy, balloon atrial septostomy, SHUNT, BT SVC to pulmonary artery shunt At 3-4 months, bi-directional Glenn bring SVC blood into pulmonary arteries At 4-6 months Fontan procedure - bring IVC blood into pulmonary arteries Ebsteins anomaly Downward displacement of tricuspid (HYPERLINK "psycdrug.doc" \l "lithium"lithium) ECG: peaked P waves, wide, bizarre QRS Findings: pre-excitation (20%), SVT, Afib/flutter (30-40%) Pulmonary valve stenosis ( CHF Pulmonary valve atresia death w/out shunt Mitral valve atresia hypoplastic LV - fatal Aortic valve atresia same Patent Ductus (PDA) Findings: Continuous murmur from L-R shunt (1st or 2nd left ICS), systolic murmur from high pulmonary vascular resistance, widened pulse pressure ECG: LA enlargement and LVH / prolonged PR in 20% CXR: calcification at PDA, dilated ascending aorta and pulmonary artery, LA/LV enlargement Course: 1/3 die from infective endocarditis (0.45%/yr after 20 yrs) / 2/3 die by age 60 yrs / causes congestive heart failure in premature infants Treatment: closure recommended even for small defects / surgery or catheter-implanted Rashkind prosthesis (residual shunt rate < 10% at 3 yrs) / 5% develop Eisenmengers (operation not recommended) Coronary arteries - origin from pulmonary artery - angina, MI sooner or later - fistula from coronary artery to right ventricle - L-R, R-L shunt anomalies of aortic arch ductus arteriosus aortic arch obstruction hypoplasia or interruption is associated with other intracardiac defects Coarctation of the aorta (localized) 7% of cardiac malformations / men 2x > women / most common distal to origin of left subclavian / lower incidence of associated intracardiac defects (mostly: gonadal dysgenesis/Turners and bicuspid aortic valve and also: aberrant subclavian artery, PDA, VSD, parachute mitral valve, berry aneurysm) Presentation: HTN in upper body, epistaxis, leg claudication Findings: LVH, enlarged collateral vessels in upper body, reduced development of lower limbs; may be no murmur or midsystolic murmur over anterior chest and back Diagnosis: clinical or TEE or CT/MRI of chest Course: leads to CHF early (3-6 months) or late (adulthood) / made worse when ductus closes anomalous venous connection -many types TAPVR (with and without obstruction) With obstruction will produce pulmonary congestion with reticular pattern on CXR Will be benefit from balloon opening an ASD to allow mixing? Pediatric Neuro Intraventricular (germinal matrix) hemorrhage terminal veins subject to anoxia (or pressure ?) and rupture into ventricles Grade I - IV (IV involves cerebral parenchyma) / associated with RDS Periventricular leukomalacia hypoxic-ischemic injury / coagulation, liquefactive necrosis of white matter / effects full-term too Childhood Tumors Unsorted:  HYPERLINK \l "leukemia" leukemia  HYPERLINK \l "pedcnstumors" CNS lymphoma ( HYPERLINK \l "hodgkins" Hodgkins) HYPERLINK \l "histiocytoses"Histiocytoses  HYPERLINK \l "pedtumorrenal" Renal  HYPERLINK \l "pedtumorother" Other hemangioma - appears invasive, but is not  HYPERLINK \l "neuroblastoma" neuroblastoma - may regress even w/ mets juvenile melanoma - anaplasia w/out malignant behavior Note: histology and progression do not always correlate Histiocytoses Langerhans cell histiocytosis children of any age / solitary form, eosinophilic granuloma occurs in children > 2 yrs Letterer-Siwe (fatal < 2 yrs) Acute disseminated histiocytosis X (type of Langerhans cell histiocytoses) / infancy, behaves malignant although not cytologically malignant / primary visceral RES (lymph nodes, liver, spleen / lungs (diffuse honeycombing) and skin (greasy, scaly, hemorrhagic or petechial, maculopapular, NOT urticarial) [ HYPERLINK "http://dermis.net/dermisroot/en/12300/diagnose.htm" dermis], lytic lesions in skull or long bones / can mimic almost any type of neoplasm Course: death within months left untreated Treatment: responds to vincristine or methotrexate Farquhars familial phagocytic reticulocytosis Localized eosinophilic granuloma long bone or rib, necrosis Disseminated eosinophilic granuloma (Hand-Schller-Christian) bone and viscera, diabetes insipidus Fibromatoses quasi-neoplasia / locally invasive / may recur / do not metastasize Infantile myofibromatosis Multiple (90%) lesions of skin, subcutaneous tissue, soft tissue, bone, viscera Nonossifying fibroma Usually eccentric, can cause deviation of cortex Ossifying fibroma (osteofibrous dysplasia) Almost always < 20 yrs (usually < 10 yrs) Lytic lesions, sclerosis, bowing deformity of tibia / usually tibia/fibula / often intracortical with intramedullary extension Hemangiomas capillary - localized, regression cavernous - not localized, no regression / large vascular sinusoids mixed - not localized, no regression / thrombocytopenia gonadal teratoma (2 tissue layers in pediatrics) ovary - malignant, testis - benign (opposite of adult) sacrococcygeal - females, highly malignant after 4 months old yolk sac tumor - malignant after 1 year / Schiller-Duval bodies / elevated aFP Renal Tumors of Childhood Wilms tumor - good prognosis 90% renal tumors in < 5 yrs old / abdominal pain, hematuria, anemia, fever / 10% bilateral pattern: undifferentiated, epithelial, stromal or anaplastic associated with aniridia (20% will have Wilms tumor, absence or hypoplasia of iris) Radiology: distorts renal image (whereas neuroblastoma will displace entire kidney downward) Congenital mesoblastic nephroma most common congenital renal tumor / appears early nephroblastomatosis - trisomy 18 / diffuse, subcapsular clusters / good survival clear cell sarcoma rhabdoid tumor Childhood Neural tumors Children (infratentorial) cerebellar astrocytoma (benign) > medulloblastoma > ependymoma Prognosis: < 1 yr old onset - better prognosis / adrenal origin - poor prognosis / triploid is good, di/tetraploid is bad / chromosome 1 or n-myc is bad Staging: Evans staging / Stage IVS (small resectable primary w/ bone marrow, skin, liver mets / usually regress spontaneously) Clinical: may produce compensatory head tilt from cranial nerve involvement with strabismus Neuroblastoma (2nd most common childhood neoplasm) Childhood (< 5 yrs) tumor of adrenal medulla, abdomen, mediastinum / secrete NE Location: adrenal > abdomen, pelvis > cervical, thorax Labs: VMA, HVA, n-myc are elevated Pathology: Homer-Wright pseudorosettes surround a central fibrillar material / mitoses present small blue cell tumor / widespread mets Course: spontaneous regression (even stage IVs with micromets) / may differentiate to ganglioneuroma (benign) primary tumor abdominal mass, RDS, paralysis, bowel/bladder dysfunction, Horners, heterochromia of iris (affected side), incidental finding on CXR metastatic hepatomegaly, bone pain (up to 50% of cases involve bone diffusely), ecchymoses, subcutaneous nodules (purpuric rather than diffuse, greasy as in histiocytosis), anemia, fever, FTT paraneoplastic VIP (diarrhea, abdominal distension), opsonoclonus (myoclonus, cerebellar ataxia), catecholamine overproduction Ganglioneuroblastoma nodular, intermixed, borderline (more NB component) Ganglioneuroma - prognosis? posterior mediastinum / differentiated, benign / plasma, lymphocyte infiltrate / may occur in isolation or as part of  HYPERLINK \l "men" MEN III Craniopharyngiomas rare - benign but invasive tumor of children (7-12 yrs) / increased ICP, calcifications of sella turcica (75%), visual deficits, endocrine dysfunction (most common pituitary tumor in children, causes growth failure) / post-surgical radiation Other Childhood Tumors Hepatoblastoma - poor prognosis < 2-3 yrs old / hepatocellular or mixed / aggressive, lung mets / 30-50% 5 yr survival in young children with surgery (slower metastasis in children) and chemotherapy / Labs: elevated a-FP and AP / associated with hemihypertrophy, Beckwith-Wiedermann syndrome, diaphragmatic and umbilical hernias Rhabdomyosarcoma most common soft tissue sarcoma of childhood / may arise anywhere / 18% mets at presentation orbital, GU primaries do better / relapse carries poor prognosis embryonal rhabdomyosarcoma - better prognosis / younger children / head, neck alveolar rhabdomyosarcoma - worse prognosis / older children Cystic hygroma (benign) lymphangioma of infancy and early childhood / present in head/neck / easy to diagnose on physical exam do not regress, must be surgically removed Retinoblastoma 40% genetic basis / siblings get eye exams until 7 yrs Genetic Syndromes Autosomal DominantAutosomal RecessiveGI HYPERLINK \l "gilberts" Gilberts  HYPERLINK \l "fap" Familial polyposis,  HYPERLINK \l "gardners" Gardners,  HYPERLINK \l "peutzjeghers" Peutz-Jeghers,  HYPERLINK \l "juvenilepolyposis" Juvenile polyposis HYPERLINK \l "a1lungs" Alpha-1-antitrypsin deficiency  HYPERLINK \l "Hemochromatosis" Hemochromatosis  HYPERLINK \l "wilsons" Wilsons diseaseRenalAdult polycystic kidney disease ( HYPERLINK \l "apkd" APKD)EndocrineFamilial combined hypercholesterolemia Familial hypertriglyceridemia  HYPERLINK \l "men" MEN Benign familial hypocalciuriaDysbetalipoproteinemia Vitamin D dependent ricketsHeme HYPERLINK \l "vwf" von Willebrand disease C/S/ATIII deficiency  HYPERLINK \l "Dysfibrinogenemia" Dysfibrinogenemias Sickle cell anemia Beta-thalassemia Factor deficiency (5, 7, 10, 11, 12, 13) Glanzman thrombasthenia Bernard-SoulierNeuro HYPERLINK \l "cmt" Charcot-Marie Tooth I (some II)  HYPERLINK \l "huntingtons" Huntingtons chorea  HYPERLINK \l "myotonicdystrophy" Myotonic dystrophyCharcot-Marie Tooth IIOther HYPERLINK \l "marfans" Marfans  HYPERLINK \l "hocm" HOCM (IHSS)  HYPERLINK \l "nf1" Neurofibromatosis  HYPERLINK \l "hereditaryangioedema" Hereditary angioedema mastocytosis HYPERLINK \l "cysticfibrosis" Cystic fibrosis Homocystinuria Albinism Deafness  Downs Syndrome (Trisomy 21) endocardial cushion defects, prominent PDAs / leukemia ( HYPERLINK \l "aml" AML), lymphoma, myelodysplasia / Fanconis / early onset Alzheimers (40s) / hypo/hyperthyroid Physical Findings: flat-face, epicanthal folds, Mongolian slant (eye), Brushfield spot, low-set ears, narrow eustachian canal, large tongue, high arch palate, duodenal atresia (double-bubble sign), bilateral Simian crease (50%) (palm, no), brachiodactyly, clindactyly (little finger in), sandal toe Turners (46 X,O) - infertile coarctation (and other AV malformations) X,O - shield chest, wide neck, wide nipples, infertility, short stature lymphedema of hands/feet as neonates Klinefelters (47,XXY) - infertile very common / tall stature, delayed puberty (but often with significant initial virilization), gynecomastia from excessive testicular estrogen production, small testes from defective spermatogenesis (in spite of normal testosterone levels) / low testosterone, elevated gonadotropins Trisomy 18 (Edwards) - 95% die at birth multiple malformations / low set ears? micrognathia? clenching middle finger, rocker-bottom feet / Cardiac: central fibrous body - A/M/T valve all anchored to it / AV node travels through it Trisomy 13 (Patau) Marfans syndrome AD / skeletal (long bone deformities) / cardiac (5th yr of life, dissecting aortic aneurysm, floppy mitral valve), eye (subluxation of lens), arachnodactyly (long fingers) / Testicular feminization XLR / end-organ insensitivity to androgens / undescended testes Reifensten syndrome androgen receptor dysfunction (infertile males) wide range of virilization (male to female phenotype) Prader-Willi Hypotonia, hypogonadism, mental retardation, undescended testes in males, micropenis / feeding problems early, then obesity later Aperts syndrome syndactyly, craniosynostosis (premature fusion) Blooms [ HYPERLINK "http://dermis.net/dermisroot/en/10038/diagnose.htm" dermis] facial erythema, telangiectasia, dwarfism / increased incidence of ALL Congenital Deafness Waardenbergs (AD) uni/bilateral deafness / white forelock, heterochromic iris Pendreds (AR) hearing loss and goiter (< 10 yrs) / Treatment: thyroid replacement Ushers (AR) retinitis pigmentosa (progressive loss of night vision, tunnel vision), deafness Leopard (ADVP) multiple lentigines, ocular hypertelorism, pulmonary stenosis, abnormal genetalia, growth retardation, profound deafness Jervell-Lange-Nielsen hereditary deafness and prolonged QT interval / syncope, sudden death Alports syndrome ( HYPERLINK \l "alports" see renal) More syndromes Beckwith-Wiedermann Syndrome extra part of chromosome 11 / LGA, large tongue hypoglycemia, polycythemia, which resolves at risk for Wilms tumor, hepatoblastoma? Williams Syndrome Mild MR aortic stenosis, eye anomalies / diagnosis: FISH probe Fragile X Syndrome XLD (reduced penetrance) / mostly males / most common inherited cause of mental retardation / big ears, elongated face (prognathia), macrorchidia, behavior problems (hyperactivity, aggressivity, autism), seizures Note: S! of affected females have mental retardation Potter s pulmonary hypoplasia  not enough amniotic fluid Holoprosencephaly failure of forebrain to divide and other midline defects  sonic hedgehog gene and other causes Cerebral Palsy spastic type / 25-30% risk of epilepsy Congenital Nephrogenic Diabetes Insipidus (see renal) XLR, very rare Familial Dysautonomia AR / Ashkenazi Jews FTT, irritability, insensitivity to pain, hypoactive DTRs, chronic respiratory distress (repeated aspirations?) / crying without tears, absence of fungiform papillae VACTERL Vertebral defects, Anal defects, Cardiac defects, Tracheo-Esophageal, Renal, Limb 3 or more minor anomalies usually means at least one major renal + middle and external ear? Metabolic Disease [HYPERLINK "pics/lir-metabolism.jpg"Diagram of Energy Metabolism] [HYPERLINK "pics/lir-glycolysis.jpg"diagram of insulin/glucagon in glycolysis] Metabolic disorders of amino acids Hyperhomocysteinemia [ HYPERLINK \l "clottingcascade" clotting cascade] rare / AR / methylenetetrahydrofolate reductase gene (C677T) (CC variant may be the worst) homocysteine ( ( methionine or homocysteine ( cystathionine Labs: fasting homocysteine level (> 15 is bad), elevated thrombin Hypercoagulability: increased arterial/venous thromboembolism (2-3 x relative risk) inhibition of thrombomodulin (a cofactor for protein C activation and ATIII function) Endothelial damage: increased factor VII release, increased conversion and deposition of LDL ( may cause some of aortic aneurysms Other: associated with dystonia (primary idiopathic torsion dystonia) Treatment: B12 100 mg qd / B6 3 mg qd / Folate 400 mg qd (goal ( > 15 nmol/L) Trends: 6/06 HOPE 2 and NORVIT failed to show decreased risk of cardiovascular events with homocysteine supplementation. Homocystinuria 10-25% prevalence / relatively asymptomatic disease / defect in cystathionine synthase (used to metabolize methionine to succinyl CoA) deficiency / Treatment: increase cys, decrease met decreased affinity for pyridoxal, accumulation of cystathione / benign proprionyl-CoA carboxylase deficiency / odd-numbered fatty acids accumulate in liver / developmental problems / biotin cofactor Untreated: thromboembolisis, ectopia lentis (subluxation of lens), mental retardation (mild to severe), renal stones (can lead to ESRD) Acquired: B6, B12, folate deficiency Maple syrup urine blocked degradation of branched amino acids leucine, isoleucine, valine due to absence of alpha-ketoacid dehydrogenase / severe CNS defects, mental retardation, death / Treatment: special synthetic diet Methylmalonic acidurea AR inheritance / 2 types absence of methylmalonyl-CoA mutase (converts methylmalonyl-CoA to succinyl-CoA diagram) impaired glucogenic utilization of val, ile, met, thr [HYPERLINK "pics/lir-metabolism.jpg"diagram] defect in converting  HYPERLINK \l "b12" B12 to deoxyadenosylcobalamin cofactor (also cannot convert homocysteine to methionine) Symptoms: lethargy, failure to thrive, RDS, mental retardation Treatment: can give B12 for type 2 PKU (Phenylketonuria) AR deficient phenylalanine hydroxylase leads to high serum phenylketones, diffusion into CNS untreated leads to skin depigmentation (decreased melanin), eczema, musty odor, mental retardation, seizures / (4) PAH mutations or defect in BH4 cofactor (tetrahydrobiopterin) synthesis or recycling / Treatment: decreased phenylalanine, increased tyrosine / diagnosis: newborn screening (> 20 mg/dl) Alkaptonuria (benign) defect in homogentisic acid oxidase (degradation of tyrosine) / alkapton bodies produce dark urine on standing, dark connective tissue / benign condition Albinism congenital deficiency of tyrosinase / lack of melanin / can result from failure of neural crest cell migration / increased risk of skin cancer Porphyria [HYPERLINK "pics/lir-porphyria.jpg"diagram] Defects in heme synthesis / erythropoietic or hepatic / AD inheritance (except congenital erythropoietic porphyria is AR) Presentation: acute abdominal pain (severe) and neuropathy, neuropsychiatric / symptoms often triggered by barbiturate induction of P450 Diagnosis: Watson-Schwartz detects excess urinary PBG (qualitative) ?during acute attack visceral/neurological symptoms ( check urine ALA and PBG (random or 24 hr) cutaneous symptoms ( check total plasma porphyrins, if (+) check more specific tests Treatment: IV dextrose and IV hematin to decrease ALA synthase, avoid sunlight, take lots of free-radical scavenging vitamins Acute Intermittent Porphyria (Swedish) uroporphyrinogen I synthetase (AD) / confusion, hallucination, seizures, weakness, paralysis, HTN? / urine darkens on exposure to light, air Congenital Erythropoietic Porphyria uroporphyrinogen III cosynthetase (AR) Porphyria Cutanea Tarda uroporphyrinogen decarboxylase (AD) / skin lesions (fragility of the skin on the dorsal surface of his hands) but no GI symptoms [HYPERLINK "http://dermis.net/dermisroot/en/24078/diagnose.htm"dermis] / can be associated with HCV / ? phlebotomy if iron stores elevated Hereditary coproporphyria coproporphyrinogen oxidase (AD) Metabolic disorders of carbohydrates high fructose / entry not insulin-dependent (also does not stimulate insulin secretion) / bypass of diet PFK regulation, direct metabolism to DHAP (pyruvate) and glyceraldehyde (TG, pyruvate) / overwhelming of aldolase B / accumulation of ADP (catabolism leads to hyperuricemia) / high glucose/fructose leads to sorbitol accumulation (cataracts) Fructosuria deficiency of fructokinase / mild or asymptomatic Fructose intolerance deficiency of aldolase B / fructose-1-P accumulated / depletes Pi / inhibits glycogenolysis, gluconeogenesis / severe hypoglycemia Treatment: no fructose or sucrose Galactosuria (mild) deficiency of galactokinase / buildup of galactitol / mild or asymptomatic / cataracts (common), benign increase in ICP (rare) Galactosemia (severe) absence of galactose-1-P- uridyltransferase / buildup of galactitol, galactose-1-P Presentation: vomiting, hepatomegaly, jaundice, cataracts, mental retardation, death Treatment: no galactose or lactose, contraindication for breast feeding Other Enzyme Deficiencies Urea cycle defect AR or XLR deficient OTC (ornithine transcarbamylase) leads to buildup of ammonium and sepsis picture / may present late in some males and female carriers Treatment: low protein diet,  HYPERLINK \l "dialysis" dialysis Pyruvate dehydrogenase deficiency backup of pyruvate and alanine (major amino acid entering cycle) results in lactic acidosis Presentation: neurological Treatment: increase intake of ketogenic (enter at level of acetyl-CoA) amino acids (e.g. lysine, leucine, etc.) Lesch Nyhan XLR deficient HGPRTase (hypoxanthine to inosine monophosphate, guanine to guanine monophosphate) leads to uric acid buildup / defective purine salvage pathway Presentation: spasticity, choreoathetosis, self-mutilation, hyperuricemia (resulting in obstructive neuropathy and nephrolithiasis), growth retardation, mental retardation, aggressivity / mild cases may present with gout / Diagnosis: urate to creatinine ratio > 2 is suspicious Treatment: allopurinol reduces urate levels (does not affect CNS problems) Kelley-Seegmiller syndrome partial HPRT deficiency / hyperuricemia but no neurological decline Bilirubin Disorders  HYPERLINK \l "crigler" Crigler-Najjar, Gilberts, Dubin-Johnson, Rotors Lysosomal Storage Diseases Note: mostly all result in very early death except  HYPERLINK \l "gauchers" Gauchers Sphingolipidoses (all autosomal recessive except Fabrys) Tay-Sachs (infant death) (example of allelic heterogeneity) 3 proteins for ganglioside metabolism: hexosaminidase A (alpha, beta), B (beta, beta), and activator protein / results in GM2 ganglioside accumulation Tay-Sachs deficient hexosaminidase A (alpha subunit) Sandhoffs deficient hexosaminidase A and B (beta subunit) variant AB activator error Presentation: motor weakness 3-5 months, increased startle, hypotonia, decreased attentiveness, rapid deterioration / 10-12 months, cherry red spot, high in Ashkenazi Jewish population (1 in 30 carrier rate vs. 1 in 300) / Treatment: no treatment Gauchers (normal life span) deficiency of B-glucocerobrosidase / accumulation in brain, liver, spleen, bone marrow / Gaucher cells (enlarged cytoplasm, crinkled paper) fill Virchow-Robin spaces / most CNS neurons appear shriveled (but dont contain abnormal storage lipids) / elevated ACE levels / type 1 (more common) is compatible with normal life span Neimann-Pick (infant death) deficiency of sphingomyelinase / build up of sphingomyelin and cholesterol in RES and parenchymal cells and tissues / CNS: shrunken gyri, sulcal widening / hepatosplenomegaly / cherry red spot in Type A (30%) Fabrys (XLR) [ HYPERLINK "http://www.annals.org/cgi/content/full/146/6/425" annals] deficiency of alpha-galactosidase A / ceramide trihexoside (globotriaosylceramide) accummulates in vascular epithelium, kidneys, heart, cornea, other tissues ( angiokeratomata, painful / acroparesthesias, hypohidrosis, renal failure, cardiac and neurological disease (mostly peripheral nerves) / Treatment: recombinant a-galactosidase A (cool) Cardiac Variant [HYPERLINK "http://content.nejm.org/cgi/content/full/345/1/55"NEJM] can present later on in life / only manifestation is cardiomyopathy / cause of ~10% of LVH and hypertrophic non-obstructive cardiomyopathy in adults / heart function can actually be ameliorated with enzyme replacement (even as adult!!!) / galactose infusion of 1 g/kg over 4 hrs every other day until forever Metachromatic leukodystrophy aryl sulfatase deficiency causes accumulation of cerebroside sulfates / brain (juvenile), liver, kidney, and peripheral nerves (juvenile) / tissue exhibits metachromasia (salfatides change dye color) / metachromasia found in urine Krabbes (infant death) deficiency in galactosylceramide B-galactosidase / accumulation of psychosine optic atrophy, spasticity, early death / loss of myelin in white matter and peripheral nerves / multinucleated globoid cells S positive around blood vessels Other congenital neuronal disorders Adrenoleukodystrophy (XLR) defect in fatty acyl-CoA ligase / spastic paraplegia, adrenal insufficiency / onset at 10-20 yrs / linear membranous inclusions, linear clefts on EM Alexanders disease demyelinization, megalencephaly, numerous Rosenthal fibers (eosinophilic blobs in white/grey matter) Neuronal ceroid lipofuscinosis vacuolization of neurons / seizures, blindness, retinitis pigmentosa Mucopolysaccharidoses (GAGs) Hurler 6-18 months: corneal clouding, hepatosplenomegaly, stiff joints, nasal discharge < 10 yrs hydrocephalus, course face, umbilical, large head, large tongue, short neck, ribs splaying, kyphosis, HSM, mental retardation Schei 5 yrs onset, normal intelligence and lifespan / corneal cloudiness, stiff joints, valvular heart disease, visual impairment Hurler/Schei Hunter XLR (gene is cloned) / similar to Hurler w/ slower progression, no corneal clouding, unique pebbly skin lesion / idursulfase first approved treatment being tried 2009 Sanfilippo A aggression / most severe form / neurodegeneration / mild somatic features / underdiagnosed Sanfilippo B less severe form / heterogeneous clinical picture Glycogen Storage Diseases (locus heterogeneity) Hepatic Hypoglycemia Type Ia Von Gierkes (severe) glucose-6-phosphatase deficiency / common / die < 2 yrs (ketoacidosis et al) Symptoms: hypoglycemia, HSM, short stature, bleeding diathesis, delayed adolescence,  HYPERLINK \l "hepaticadenoma" hepatic adenomas, enlarged kidneys Labs: increased lactate, cholesterol, TG, urate Treatment: frequent feeding CHO, restrict sucrose, lactose / HCO3 and allopurinol PRN Type II Pompes (infant death) alpha-1-4-glucosidase deficiency / accumulation of glycogen in lysosome (skeletal and cardiac) infant death from cardiac failure (massive cardiomegaly on CXR) IIb juvenile form (die < 10 yrs) Type III Coris debrancher enzyme deficiency / common / hepatomegaly may remit by puberty with relapse of mild myopathy in adulthood / symptoms: hypoglycemia, HSM, short stature, delayed adolescence Labs: increased cholesterol, TG, and SGOT Treatment: cornstarch feeding at night, 50% CHO, 20% protein Type IV Brancher enzyme deficiency / die < 10 yrs from hepatic cirrhosis Ketotic hypoglycemia impaired gluconeogenesis / males 1.5 to 4-5 yrs / spontaneous remission usually by 8-9 yrs Labs: low serum alanine, normal insulin levels / patients usually thin / attacks may be induced by high-fat, low-cal diets Muscle-Energy Disorders McArdles V muscle phosphorylase deficiency / pain, cramps and myoglobinuria on exertion Treatment: avoid exertion, glucose or fructose before exertion Type VII muscle phosphofructokinase deficiency / rare / mild hemolytic anemia / similar symptoms/treatment as McArdles Metabolism and Fluid Maintenance maintenance fluid: 100 ml/kg (1st 10 kg) / 50 ml/kg (2nd 10 kg) / 20 ml/kg (remaining kgs) normal fluid maintenance: 1500-2000 ml/M2 100 ml fluid required per 100 cal expended, which is 110 cal/kg/day insensible loss is 45 ml / 100 cal 50-70 ml fluid / 100 cal for renal excretion of metabolic waste products Na 3 mEq / 100 cal K 2.5 mg/kg/day (?) Dehydration: mild (5% infant, 3% adult) moderate (10%, 6%), severe (15%, 9%) 285-295 mOsm/L 180 mg/dL glucose = 10 mOsm/L [normal contribution is 10 mOsm/L] breast fed infant 6 stools/day at 2 wks Endocrine  HYPERLINK \l "pituitary" Pituitary Gland  HYPERLINK \l "pituitaryadenoma" Pituitary Adenomas,  HYPERLINK \l "hypopituitary" Hypopituitary,  HYPERLINK \l "diabetesinsipidus" Diabetes Insipidus,  HYPERLINK \l "siadh" SIADH  HYPERLINK \l "thyroid" Thyroid !  HYPERLINK \l "hyperthyroidism" Hyperthyroidism, !  HYPERLINK \l "hypothyroidism" Hypothyroidism,  HYPERLINK \l "thyroiditis" Thyroiditis, Thyroid  HYPERLINK \l "thyroidneoplasms" Neoplasms,  HYPERLINK \l "thyroidmalformations" Thyroid Malformations  HYPERLINK \l "parathyroid" Parathyroid !  HYPERLINK \l "hyperpth" Hyperparathyroid, !  HYPERLINK \l "hypopth" Hypoparathyroid,  HYPERLINK \l "pseudohypopth" Pseudohypoparathyroid,  HYPERLINK \l "parathyroidhyperplasia" Parathyroid Hyperplasia,  HYPERLINK \l "parathyroidneoplasms" Parathyroid Neoplasms,  HYPERLINK \l "men" MEN  HYPERLINK \l "adrenal" Adrenal ! HYPERLINK \l "cushings" Cushing s, !  HYPERLINK \l "adrenalhyperplasia" Adrenal Hyperplasia,  HYPERLINK \l "adrenaladenoma" Adrenal Adenoma,  HYPERLINK \l "adrenallymphoma" Adrenal lymphoma ! HYPERLINK \l "addisons" Adrenal Insufficiency, ! HYPERLINK \l "conns" Conn s,  HYPERLINK \l "cah" CAH,  HYPERLINK \l "mccune" McCune-Albright  HYPERLINK \l "adrenalmedulla" Adrenal Medulla  HYPERLINK \l "pheochromocytoma" pheochromocytoma,  HYPERLINK \l "paraganglioma" paraganglioma,  HYPERLINK \l "neuroblastoma" neuroblastoma  HYPERLINK \l "diabetes" Diabetes Mellitus Pituitary Pituitary Labs Thyrotropin T3/T4 FTI Thyroid hormone binding index  HYPERLINK "labs.doc" \l "cortisol" Cortisol  HYPERLINK "labs.doc" \l "prolactin" Prolactin Alpha-subunit (TSH, FSH, LH)  HYPERLINK "labs.doc" \l "fsh" FSH Diabetes 1-2% in US / 7th leading COD / non-enzymatic glycosylation (advanced glycosylation end-product or AGE results in atherogenesis, increased capillary permeability) / intra-cellular hyperglycemia (swelling and opacity of lens, neuronal damage) Type 1 (10-20%) lack of insulin only some impairment of insulin action/secretion (by hyperglycemia) / whites, European origin / associated with other autoimmune diseases 80% have antibodies, 0.3% incidence, 5-7% incidence with family history Renal: 25% develop CRF within 10-15 yrs Type 2 (90%) impairment of insulin action/secretion (by hyperglycemia) type 2 acanthosis from increased insulin levels Diagnosis: current standard is now > 126 on fasting glucose / GTT (oral glucose tolerance test) is out of fashion (exception is  HYPERLINK \l "pcos" PCOS patients, which can have normal fasting yet positive/abnormal GTT) Renal: often develop CRF within 10 yrs / retinopathy and nephropathy develop together Metabolic syndrome (associated with atherosclerotic disease) Diagnosed by 3 of 5 criteria (abdominal obesity, high blood pressure, low HDL, high TG, insulin resistance) central obesity, may or may not have elevated lipids (small, dense LDL particles are more atherogenic, however), hyperandrogenism, increased coagulation from increased PAI1 (inhibitor of tPA) often occurs before abnormalities of sugar levels occur hyperinsulinemia decreases secretion of uric acid (not part of definition of metabolic syndrome but does cause hyperuricemia) Microangiopathy thick, leaky BM (PAS stain), hyalinized arteriolosclerosis, atherosclerosis Nephropathy both afferent and efferent arterioles / arteriolar hyalinization / UTI / glycosylation of basement membrane leads to membranous GN (5-15% by 10-15 yrs) / 50% have Kimmelstein-Wilson bodies (focal and nodular sclerosis) Retinopathy proliferative / cotton wool / associated with increased floaters Neuropathy axonal and demyelinating Skin acanthosis nigricans ( HYPERLINK \l "acanthosisnigricans" see other) yellow discoloration [ HYPERLINK "pics/diabetes-yellow.jpg" pic] necrobiosis lipoidica diabeticorum [HYPERLINK "pics/necrobiosis.gif"pic] [HYPERLINK "http://dermis.net/dermisroot/en/37833/diagnose.htm"dermis] anterior leg / ulceration and hypopigmented scarring Treatment: whirlpool therapy, occlusive dressings, topical steroids, aspirin Lipid abnormalities (see below) Immunocompromise fungus (yeast, other) / mucormycosis Hypercoagulable State (increased post-MI mortality) Increased 2b3a receptor expression (2b3a are essential in treatment of DM w/ acute coronary syndrome) Increased plasminogen activator inhibitor (PAH) Increased blood viscosity (sheer stress on plaque) Other abnormalities in clotting factors Treatment: [see HYPERLINK "pharm.doc" \l "diabetes"diabetes medications] [ HYPERLINK "http://content.nejm.org/cgi/content/short/347/17/1342?query=TOC" NEJM] Control Glucose various agents (from different class) work well in combination A1C measures glucose levels over last 2-3 months oral agents (alone or in combination) can achieve A1C of 7.5 in up to of patients hemolytic anemia will artificially lower A1C Insulin requirement ! with stress, ! with exercise (insulin potentiated by exercise; esp. in type I DM) Insulin requirement over 1.5 units/kg suggests overtreatment, rebound hyperglycemia or Somogyi effect (insulin resistance is a less common reason) Dawn phenomenon hyperglycemic? in the morning is it rebound or do they need more insulin qAM / check sugar at 2 am at night (nadir of FBS is 23 am) to investigate (if low, you need to reduce qHS insulin, if high, you can increase qHS insulin) Glucose control in ICU setting is class I recommendation: DIGI-AMI showed 30% decrease in 1 yr mortality for post-AMI patients randomized to tight glucose control Protect Kidneys ACE inhibitors lower intraglomerular pressure and reduce hemodynamically mediated FSGN (Cr may rise slightly upon initiation 2o to decreased GFR) ARBs may provide additional protection (by direct anti-TGF-B action) remodeling glomeruli to reduce protein filtration (proteins damage glomerulus) protein restricted diets lipid lowering agents are also renal-protective Protect Heart Physicians Health Study ( ASA 325 mg qd reduced MI for DM by 60% over 5 yrs (versus 44% for general population) Hypertension Proteinuria: loss of antithrombin, protein C and S leads to hypercoagulable state renal failure (GFR actually increased early on due to microalbuminuria) papillary necrosis, pyelonephritis Pathology: afferent and efferent hyalinization (unlike HT) / diffuse or nodular sclerosis / exudative lesions of DM (Kimmelstein-Wilson) / capsular drop or lipohyaline cap / Armanni-Ebstein Lesion (glycogen vacuolization of tubules) Ddx: rule out amyloidosis (Congo red) Hyperlipidemia ( HYPERLINK \l "hyperlipidemia" see other) 9/06 current goal LDL < 100 mg/dL Retinopathy control hypertension; see ophthalmologist at least once a year Neuropathy control glucose, hypertension; see podiatrist; treat neuropathy (if not due to other causes) Diabetic ketoacidosis (DKA) Causes: infection, MI, stress/trauma, not enough insulin or drug effect (phenytoin, thiazides, cortisol), new-onset diabetes Presentation: Hyperglycemia ( polyuria, polydipsia, weight loss, visual blurring, mental status change Acidosis ( nausea, vomiting, abdominal pain, fatigue, malaise, dyspnea cardiovascular collapse most common COD in DKA Diagnosis: must differentiate from hyperosmolar nonketotic coma Workup: CXR, amylase/lipase,  HYPERLINK \l "cardiacenzymes" cardiac enzymes, ABG, other tests Exam: dehydration, Kussmauls respirations, fruity breath Labs: hyperglycemia (usu. > 250 mg/dL), ketonuria (can check b-hydroxybuturate etc too),  HYPERLINK \l "aniongap" anion gap acidosis, moderately elevated amylase why?, hypokalemia results from increased K excretion with diuresis of (anionic) ketones Complications: mucormycosis of paranasal sinuses due to acidosis-induced block of iron binding to transferrin (provides fungus w/ iron) / vascular thrombosis from hypercoagulable state + intravascular contraction / cerebral edema / respiratory distress (like ARDS w/ low PCWP), fluid overload, acute gastric dilatation Treatment: Replace fluids: usu. 3-5 L (1-2 L NS over 1st 2 h, replacing volume takes precedence over free water deficit, but can switch to NS if hypernatremia (goal is to correct total body water deficit 250-500 ml/h), can use lactated ringers to avoid hyperchloremic metabolic acidosis, which often occurs during/after treatment of DKA) Potassium: very tricky, must be careful, insulin Rx can make initial hyperkalemia become hypokalemia, but must be careful not to overcompensate, best way is to check q 1-2 h K levels until stable (add K to IVF once < 5 mEq/L) Insulin: 0.1 to 0.2 units/kg IV push then same each hour until normalized (or 50 U then 10-20U/hr), measure every hour (should aim for 80-100 mg/dL/h decrease) but use anion gap as a guide / avoid cerebral edema / give SC insulin 30 mins before stopping IV to avoid rebound acidosis Glucose: start infusion when glucose 250-300 (then decrease insulin to 0.05 U/kg/hr) / important because ketones dont normalize until point at which patient may already become hypoglycemic (but you need to keep the insulin going until anion gap normalizes (< 12) (urine is free of ketones) Bicarbonate: controversial // try not to give bicarbonate unless pH is really low (i.e. patient is hyperventilating and about to tire out) as it can cause worsening of hypokalemia, paradoxical CNS acidosis, delay in ketone clearance Phosphate: give if < 1 mg/dL or moderate hypophosphatemia and respiratory problems Mg, Ca: prn Hyperosmolar nonketotic coma Elderly patients with Type II diabetes (often undiagnosed) Findings: more marked hyperglycemia > 1000 mg/dl / more severe dehydration (longer undiagnosed) / serum osmolality of > 320-370 may cause mental obtundation, seizures, focal neurological signs / lactic acidosis is a poor prognostic sign Treatment: similar to DKA, but replace fluids carefully to avoid precipitation of heart failure in underlying heart disease Alcoholic ketoacidosis Mechanism: ratio of NADH:NAD shifted in favor of unreduced NAD / causes anion gap metabolic acidosis from ketoacidosis and lactic acidosis Presentation: similar presentation as DKA Treatment: NS and glucose / insulin usually not necessary Pituitary Adenomas Microadenoma < 10 mm (S! can be missed even by MRI) / found in 20% of all autopsies / hemorrhage involving most of gland is called pituitary apoplexy / microadenoma can cause stalk hyperprolactinemia by interrupting the inhibitory dopaminergic tone between the hypothalamus and the pituitary gland. Macroadenoma may become invasive / may compress adjacent structures Note: must ask for specific views of pituitary by CT or MRI Chromophobe adenoma most common in adults rare in childhood Somatotropic (GH, PRL) [HYPERLINK "http://content.nejm.org/cgi/content/full/355/24/2558"NEJM] 20% of pituitary tumors (macro>micro) / most are plurihormonal GH and PL Presentation: acromegaly, gigantism (enlargement of hands, feet, jaw, and forehead), skin tags, thickened skin (coarse facial features), arthritis or carpal tunnel syndrome may develop, the pituitary adenoma may cause headaches and visual loss, often h/o kidney stones Complications: increased cardiovascular disease (50% with left ventricular hypertrophy, HTN is common) Diagnosis: insulin challenge does not decrease GH serum insulin-like growth factor (somatomedin-C) ( screening test of choice (reflects average GH level over several days, whereas GH itself is pulsatile, diurnal, variable), then confirm with GTT or ITT oral glucose tolerance test ( GH should normally reduce to < 1-2 ng/ml insulin tolerance test ( GH should increase in response to insulin (analogous to cosyntropin stim test to rule out adrenal insufficiency) Treatment: transphenoidal resection (complete tumor resection with cure of acromegaly often impossible) / low GH (75% cure with surgery) / high GH (35% cure with surgery) / radiotherapy may reduce regrowth (also  HYPERLINK "pharm.doc" \l "octreotide" octreotride 100 g SC tid reduces GH secretion) / +/- bromocriptine Prolactinoma (PRL) - benign 30%, most common pituitary tumor / primary hyperprolactinemia / serum PRL > 300 ug/ml ( > 100 is suggestive; must get MRI) Macro male / micro female Presentation for macro: ocular movement defect (5-10%), females: galactorrhea, males: sexual dysfunction/gynecomasita (15%) Ddx (elevated prolactin): prolactinoma, loss of dopaminergic inhibition (neuroleptics), post-seizure, stalk hyperprolactinemia, uremia Treatment (macro): resection (80% success, 20% relapse), radiation (highly efficacious but causes panhypopituitary syndrome) Treatment (micro): bromocriptine, resection (80% success, 40% relapse, 40% still fertile) Corticotrophic adenoma (ACTH) 15% of pituitary tumors / micro, basophilic / Crookes hyaline may accumulate in surrounding cells Cushings Disease (must also include diabetes, hypertension) 80% from pituitary adenoma (ACTH) / 20% from adrenal adenoma (cortisol) Diagnosis: dexamethasone suppresses micro, but NOT macroadenomas Gonadotrophs (LH, FSH) 5-15% of pituitary tumors / result in hypogonadism Presentation: signs of compression / male: decreased libido / female: no change Diagnosis: increased LH, FSH levels Treatment: surgery Hypopituitarism Presentation: depends on which hormones are lacking Causes: Neoplasm: adenoma, mets, lymphoma, Rathkes cysts, germ cell tumors, gliomas (rare),  HYPERLINK \l "craniopharyngioma" craniopharyngioma (children) Inflammatory: meningitis (others?), sarcoidosis, other inflammatory Damage (see below): subarachnoid hemorrhage, cranial trauma, surgery/radiation therapy Null-cell adenomas 20% of pituitary adenomas / local mass effects (e.g. compression of stalk interfering with dopamine release ( stalk prolactinemia, which is only mild increase, unlike true prolactinoma) / will often be positive for alpha-subunit (TSH, FSH, LH) Sheehans syndrome post-partum pituitary necrosis (may present even years after pregnancy) / infarction of adenohypophysis from combination of hemorrhagic shock of delivery and blood supply compressed by pregnancy-related hypertrophy of pituitary / also caused by DIC, DM, arteritis, trauma Empty sella syndrome herniation through defect in diaphragma sella leads to atrophy / often can still produce normal amounts of pituitary hormones (even though sella appears empty on MRI; functional rim of pituitary tissue) / risk factors: female, obese, hypertension Presentation: asymptomatic or chronic headaches Lymphocytic Hypophysitis Occurs in late pregnancy, post-partum / less commonly occurs in men, post-menopausal women Associated with autoimmune thyroiditis, adrenalitis, atrophic gastritis, Sjgrens, SLE, Cogans, Takayasus Labs: often positive ANA, RF, ESR usually elevated (not > 100) / can have normal prolactin (may only affect stalk) Location: generally diffuse involvement in anterior >> posterior (sometimes both, sometimes only stalk) / can also involve optic chiasm Diagnosis: clinical or biopsy Granulomatous Hypophysitis Either as part of above or sarcoidosis Posterior Pituitary Syndromes Physiology: ADH released in response to 1st osmolality and 2nd volume shift of 10% / also nausea, drugs Central Diabetes Insipidus ( HYPERLINK \l "nephrogenicdi" see nephrogenic DI) lack of ADH / lesion of neurohypophysis (supraoptic, paraventricular) Presentation: polyuria, polydipsia, thirst (often seek cold liquids to stimulate ADH release) Causes: tumor, histiocytosis, sarcoidosis, trauma Complications: hypernatremia Treatment: HYPERLINK "pharm.doc" \l "desmopressin"desmopressin Syndrome of Inappropriate ADH Release (SIADH) unregulated ADH release / excessive water reabsorption leads to hyponatremia half of elderly patients with hyponatremia, usually resolves following removal of the drug Presentation: normal skin turgor Causes ( HYPERLINK \l "siadhddx" see other for more): pulmonary, CNS, infection, malignancy, excessive fluid intake, conditions that limit free water excretion Drug-Induced SIADH: vasopressin and its analogues, thiazide and thiazide-like diuretics, chlorpropamide, carbamazepine, antipsychotics, antidepressants, acetaminophen and NSAIDS Treatment: fluid restriction (2/3 maintenance), hypertonic saline given only with CNS symptoms (temporary correction of Na balance, do not correct too quickly), furosemide (causes medullary washout, kidneys cannot concentrate urine) / demeclocycline (AVP antagonist) can be used in divided daily doses for long-term therapy Thyroid ( HYPERLINK \l "thyroidmalformations" malformations,  HYPERLINK \l "hyperthyroidism" hyperthyroidism,  HYPERLINK \l "hypothyroidism" hypothyroidism,  HYPERLINK \l "thyroiditis" thyroiditis,  HYPERLINK \l "thyroidneoplasms" neoplasms) Notes PTH function usually transiently lost following thyroidectomy !Ca, Phos, Albumin, Mg (EtOH can decrease Mg)  HYPERLINK "pharm.doc" \l "levothyroxine" levothyroxin 1.6 ug/kg (recheck in 6-8 wks) Ca replacement (2-3 g/day) calcitriol (0.25 mg bid), Do not jump to replace thyroid hormone in complicated cases Illness and various drugs can lower T3 (T4 and TBG can also be decreased) Thyroid Function Studies TSH / normal [1-4] Lower TSH: recovery from severe illness, metoclopramide, dopamine and corticosteroids Increase TSH: chlorpromazine, haldol, and amiodarone Serum T4 measures circulating bound (~99%) and unbound T4 / values vary with TBG (see below) equilibrium dialysis (gold standard of free T4 assays) or by immunometric techniques (influenced by serum levels of lipids, proteins, and certain drugs) Serum T3 Bound to TBG (just like T4) / elevated in hyperthyroidism (usu. earlier and more than T4), useful in confusing cases (not as a screening test) Useful to diagnose: Thyrotoxicosis: increased T3, normal FTI Toxic nodular goiter: increased T3, normal or increased T4 Iodine deficiency: normal T3, possibly decreased T4 Serum thyroglobulin Elevated in thyroid cancer and thyrotoxicosis emanating from the thyroid gland Normal in thyrotoxicosis secondary to iatrogenic ingestion of thyroid hormone Increased TBG (increased T4) Decreased TBG (decreased T4)Pregnancy Androgens, glucocorticoidsEstrogens Nephrotic syndrome, cirrhosisAcute infectious hepatitis AcromegalyOral contraceptives HypoproteinemiaFamilial Phenytoin, NSAlDs, high-dose penicillin, asparaginaseFluorouracil, clofibrate, heroin, methadoneChronic debilitating illnessFamilial T3 resin uptake (T3RU or R T3U) Indirectly measures amount of thyroid binding protein Free thyroxine index (FTI) T4 x T3RU / 100 (corrects for variations in protein binding) Reverse T3 measures in inactive metabolite of T4 / used to diagnose "euthyroid sick syndrome" (alteration in TSH secretion and peripheral thyroid hormone binding and metabolism 2o to severe nonthyroidal illness or stress) Radioactive Iodine Uptake (I-123 scan) Normal 24-hour (10-30%) Increased homogenous ( Graves, iodine deficiency Increased heterogeneous ( multinodular goiter Increased single focus ( hot nodule Decreased uptake ( thyroiditis Ingestion of thyroid hormone (thyrotoxicosis factitia) increased serum T4 and serum T3R , but the RAI is decreased instead of increased as it would be in other causes of hyperthyroidism; Note: serum thyroglobulin levels also decrease in thyrotoxicosis factitia and increase in thyrotoxicosis emanating from the thyroid gland Pre ablative therapy, calculate the I131 dose needed to administer Note: I131 therapy actually increases the risk of exophthalmos (which was already small) Serology Anti-microsomal (also anti-TPO) 80-90% sensitive for thyroiditis (not causal) Anti-thyroglobulin Antibodies Anti-TSH receptor antibodies can be tested for (usually not necessary) Malformations Maldescent pyramidal lobe (common) / ectopic thyroid tissue (papillary carcinoma met if found w/in lymph node) Thyroglossal duct cysts predispose to infection / surgical removal Hyperthyroidism  HYPERLINK \l "graves" Graves,  HYPERLINK \l "thyroidstorm" thyroid storm,  HYPERLINK \l "thyroidinfectious" infectious thyroiditis,  HYPERLINK \l "hypothyroidism" hypothyroidism Causes of Hyperthyroidism  HYPERLINK \l "graves" Graves disease Toxic multinodular goiter Toxic adenoma Iatrogenic/factitious (L-thyroxine, amiodarone, etc.) Transient hyperthyroidism Subacute and  HYPERLINK \l "hashimotos" Hashimotos Rare causes: hypersecretion of TSH (e.g., pituitary neoplasms), struma ovarii, ingestion of large amounts of iodine in a patient with preexisting thyroid hyperplasia or adenoma (Jod-Basedow phenomenon), hydatid mole, carcinoma of thyroid, amiodarone Effects of hyperthyroidism Heart: tachycardia (resting rate >90 bpm), palpitations, atrial fibrillation (effects on AV node are mediated by increased Na/K pump activity and tend to be refractory to digoxin control) Psychological: insomnia, anxiety, irritability, emotional lability, panic attacks heat intolerance Autonomic: sweating, tremor, hyperreflexia, diarrhea Metabolism: weight loss, weight gain from increased appetite (less common) proximal muscle weakness, menstrual dysfunction (oligomenorrhea, amenorrhea) Eyes: blurred vision, photophobia, increased lacrimation, double vision, deep orbital pressure (Note: Graves ophthalmopathy tends to worsen at 12-18 months, then stabilize, but can worsen in spite of thyroid status) Skin: fine, smooth, velvety, moist (warm), onycholysis (brittle nails) Reproductive: oligomenorrhea, reduced sperm count, impotence, gynecomastia Diffuse goiter; bruit over thyroid Note: too much thyroid can increase bone turnover and risk of fracture / use Fosamax type agents in women being treated with thyroid hormone for thyroid cancer Note: elderly hyperthyroid patients may have only subtle signs (weight loss, tachycardia, fine skin, brittle nails) called apathetic hyperthyroidism (lethargy rather than hyperkinetic) / may not have enlarged thyroid / look for unexplained CHF, worsening of angina, or new-onset atrial fibrillation resistant to treatment Labs: increased free T4 (or FTI), decreased TSH (should be undetectable in Graves), increased T3 anti-thyroid Ab bind TSH receptors (activate AC) increased I-123 uptake (because theres still some TSH around) ?elevated ferritin Graves Disease TSH-like-antibodies (think autoimmune disease) / can cross placenta ( neonatal thyrotoxicosis Genetics: HLA-B8 and HLA-DR3 in Caucasians with Graves disease. Associations:  HYPERLINK \l "hoa" HOA, Type I diabetes, Addisons, vitiligo, pernicious anemia, alopecia areata, myasthenia gravis, HYPERLINK \l "celiac"celiac disease, other HLA-DR3 Features unique to Graves: (mostly by activated fibroblasts) Infiltrative ophthalmopathy: exophthalmos [ HYPERLINK "pics/eye-exophthalmos.jpg" pic], lid retraction, lid lag (sclera can be seen above iris as patient looks downward) Infiltrative dermopathy: pretibial myxedema (raised, hyperpigmented areas involving the pretibial region and the feet, which is actually rare; orange peel texture papules) Thyroid acropachy: clubbing of fingers associated with periosteal new bone formation in other skeletal areas Diagnosis: radioactive uptake scan will reveal diffuse increased uptake of iodine Treatment:  HYPERLINK "pharm.doc" \l "ptu" PTU (50-100 mg PO q8h) or  HYPERLINK "pharm.doc" \l "methimazole" methimazole (10-20 mg PO q8h or 30-60 mg/day single dose) Propranolol: as needed for sympathetic symptoms (tachycardia, tremor, etc.) 20-40 mg PO q6h (taper upward to control symptoms)  HYPERLINK "pharm.doc" \l "i131" Radioactive (I131) 1st line for men and women over 20 yrs and younger pts who do not achieve remission by 1 yr of meds (many pts have difficult time with meds and fluctuating symptoms) / will need to be on replacement thyroxine after / contraindicated during pregnancy (can cause fetal hypothyroidism) Surgery (subtotal thyroidectomy) pregnant patient refractory to (or does not tolerate) low-dose PTU / obstructive goiter complications: hypothyroidism (30% by 10 yrs), hypoparathyroidism, damage to recurrent laryngeal nerve (this is unfortunately a common occurrence) Graves ophthalmopathy (in severe cases) high-dose steroids, external radiation, or orbital decompression / methylcellulose eye drops (e.g., Tears Naturale) are useful for dry eyes Course: 20-40% can remain euthyroid for long periods after treatment with PTU et al (15% get autoimmune hypothyroidism about 10-15 yrs later) Toxic multinodular goiter Usu. women > 55 yrs Presentation: usu. insidious and symptoms (tachycardia, tremor, heat intolerance) may be masked by manifestations of coexisting diseases (e.g., a patient with ASHD may have CHF secondary to atrial fibrillation with a fast ventricular response) Diagnosis: thyroid scan demonstrates heterogeneous increased uptake Treatment:  HYPERLINK "pharm.doc" \l "i131" radioactive iodine (I131) after initiation of B-blockers or surgery Toxic adenoma (Plummer Disease) (see  HYPERLINK \l "thyroidneoplasms" thyroid neoplasms) Note: hot nodule is almost never malignant Diagnosis: thyroid scan demonstrates increased uptake (flag of Japan pattern), usu. > 3 cm Treatment: surgical removal of adenoma is preferred in young hyperthyroid patients and patients with very large adenoma / all other pts get I131 radioablation Thyroid Storm Causes: major stress (e.g., infection, MI, surgery, DKA) in undiagnosed hyperthyroidism, inadequate replacement therapy in a hyperthyroid patient Presentation: fever ( > 100 F), marked anxiety and agitation, psychosis, hyperhidrosis, heat intolerance, marked weakness/muscle wasting, tachyarrhythmias, palpitations, diarrhea, nausea, vomiting / elderly patients may have a combination of tachycardia, CHF, and mental status changes Exam: goiter, tremor, tachycardia (>140), fever (104-106), moist skin, vomiting, diarrhea, lid lag, lid retraction, proptosis, altered mental status (psychosis, delirium, coma, seizures), other evidence of precipitating factors (infection or trauma) Labs: increased free T4 or FTI, decreased TSH / always rule out sepsis Treatment: start empirically if suspected (do not wait for labs) Block synthesis PTU 30O-600 mg PO or NG tube, then 150-300 mg q6h If GI obstruction or vomiting, can give methimazole (Tapazole), 80 to 100 mg PR followed by 30 mg PR q8h Block release (of T4 that has already been made) Iodide: sodium iodide, 250 mg IV q6h; potassium iodide (SSKI), 5 gtt PO q8h; or Lugols solution, 10 gtt q8h. Give PTU 1 hr before iodide to prevent thyroid from oxidizing iodide to iodine (which would make more hormone) Corticosteroids: dexamethasone, 2 mg IV q6h, or hydrocortisone, 100 mg IV q6h (~48 hrs) / inhibits release, impairs peripheral conversion (T4 to T3), covers for cortisol deficiency, suppresses effects of T4/T3 Supportive Propranolol: 80 to 120 mg PO q4-6h; in acute situations propranolol may also be given IV 1 mg/min for 2 to 10 min under continuous ECG and blood pressure monitoring / can use cardioselective agents in patients with bronchospasm / Anticipate increasing rate control (digoxin may not work as normal in this case) for patients prone to AF Acetaminophen, 300 to 600 mg q4h, or cooling blanket if necessary (do not use ASA as it displaces thyroid hormone from TBG) FEN (add glucose and multivitamins) Blood/Urine cultures, may need IV antibiotics if infection suspected Hypothyroidism 2% of women / 0.2% of men / > 60 years (6% of women / 2.5% of men) Primary hypothyroidism (95% of cases) (problem with thyroid gland) Hashimotos thyroiditis (chronic lymphocytic thyroiditis); 1st in US ( > 8 yrs) Previous radioactive I- therapy or surgical thyroidectomy; 2nd in US Idiopathic myxedema (possibly a nongoitrous form of Hashimotos thyroiditis) Subacute thyroiditis Iodine deficiency/excess most common worldwide Drugs (lithium, PAS, sulfonamides, phenylbutazone, amiodarone, thiourea) Radiation therapy of the neck (usually for malignant disease) Congenital (approximately 1:4000)  HYPERLINK \l "Hypothyroidismofpregnancy" Hypothyroidism of pregnancy Secondary hypothyroidism (pituitary problem) pituitary dysfunction, postpartum necrosis, neoplasm, infiltrative disease causing low TSH Diagnosis: can do TRH stimulation test to distinguish secondary/tertiary (note: most postpartum thyroiditis cases recover in 3-6 months so watching/waiting can be viable approach) Tertiary hypothyroidism hypothalamus/TRH deficiency (granuloma, neoplasm, or irradiation) tissue resistance to thyroid hormone (rare) Presentation: fatigue, lethargy, weakness, constipation, weight gain (usually < 15 Ib) muscle weakness, muscle cramps, arthralgias, carpal tunnel cold intolerance CNS (depression, irritability, mental slowing ( dementia in elderly) slow speech with hoarse voice (myxedema of vocal cords), transfer dysphagia hyperlipidemia Hashimotos ataxia (can happen any time/later on) oligomenorrhea, galactorrhea (in association with prolactinoma) Exam: Skin: dry, coarse, thick, cool, sallow (yellow color caused by carotenemia); nonpitting edema in eyelids/hands (subcutaneous deposition of hydrophilic mucopolysaccharide ( leads to myxedema syndrome in severe, prolonged form Hair: brittle and coarse, loss of outer third of eyebrows Face: dulled expression, thick tongue, and thick slow-moving lips Cretinism: pot-bellied, puffy face, protuberant tongue Neck: thyroid gland +/- palpable (depends on cause of hypothyroidism) Toxic multinodular goiter may resemble carcinoma / may be associated with hyperprolactinemia Diffuse non-toxic (simple) goiter Endemic: iodine deficiency / goitrogens in foods Sporadic: young females / defects in T4 production / compensatory thyroid hypertrophy CV: distant heart sounds (pericardial effusion may be present), bradycardia ! intravascular volume, ! cardiac output, ! HR, ! catecholamines, ! PVR, ! HTN 20-40% get ! systemic HTN in spite of decreased cardiac output (HTN is diastolic with diminished pulse pressure) GI: non-mechanical obstruction (ileus) Musculoskeletal: stiffness, weakness CNS: delayed relaxation phase (return phase) of DTR, cerebellar ataxia, hearing impairment, poor memory, peripheral neuropathies/paresthesias, carpal tunnel Autonomic: hypothermia ( part of myxedema coma (medical emergency, requires IV thyroxine 300-500 mcg bolus then daily IV doses (also give steroids, IV fluids, rewarm patient slowly to not precipitate cardiac arrhythmias) Complications (the cardiac ones are not all intuitive at face valuejust know the consequences) (+) periorbital edema and nonpitting edema of hands, feet (interstitial ! GAG s and H2O) Laboratory results Decreased free T4 or FTI !TSH (may be normal with 2o or 3o hypothyroidism or is on dopamine/corticosteroids or with severe illness) ! LDL and ! TG, ! LDH, ALT, AST, and MM band of CPK Decreased Hgb/Hct, hyponatremia ! antimicrosomal and antithyroglobulin antibody titers (seen in Hashimoto s) Treatment L-thyroxine (Synthroid) / 1.6 ug/kg / Sx should improve within 24 hrs Dose depends on age/severity / may increase q 4-6 wks (depends on response) TSH takes 6-8 wks to reflect dose adjustments Decreased dose for elderly and CAD (higher doses can precipitate angina) Low and slow with CAD, ex. 25 mcg x 2 wks then 37.5 mcg x 2 wks then 50 mcg x 6 weeks then recheck TSH Maintain TSH (0.5 to 3) / can measure FTI with central disorders (upper of normal range) Subclinical Hypothyroidism Labs: elevated serum TSH and normal T4 or free T4 concentration (and no symptoms) Treatment: individualized / replacement recommended with TSH > 10 or > 5 with goiter or thyroid antibodies / otherwise, can just wait and see Course: does not always lead to primary hypothyroidism / women with increased TSH and thyroid Abs have 5% annual incidence of overt hypothyroidism / those pts over 65 yrs with both findings usu. develop hypothyroidism within 4 yrs / euthyroidism with reset thyrostat may not progress to hypothyroidism (probably from subtle insult to thyroid gland) Hypothyroidism of pregnancy 1-2% incidence of hypothyroidism in young women / hypothyroidism causes impaired cognitive development and increased pregnancy causes increase in levothyroxine requirement by 5th week gestation / recommendation is increase replacement dose by 30% at start of pregnancy and adjust based on TFTs thereafter Thyroiditis I123 uptake usually decreased Hashimotos thyroiditis autoimmune disease / most common cause of hypothyroid in US / may have non-tender goiter (rubbery with scalloped borders) / can check for anti-microsomal Abs (also called anti-thyroperoxidase or TPO) / Pathology: Hurthle cells Subacute granulomatous thyroiditis (DeQuervrains) Presentation: pain, tenderness, symptoms of hyperthyroid (usu. takes about 6-8 weeks to achieve spontaneous remission) / often associated with viral illness (URI, etc.) Diagnosis: clinical and/or I123 scan Findings: increased free T4 or FTI but decreased I-123 uptake because of the follicular cells inability to concentrate iodine Treatment: treat symptoms (NSAIDs, B-blockers, may need steroids) / PTU/M not effective Subacute lymphocytic thyroiditis common post-partum / unknown etiology / painless Riedels thyroiditis (Struma) unknown etiology / can compress neck structures and/or cause hypothyroidism / fibrosis of gland / PET-scan may be useful in diagnosis Medications:  HYPERLINK "pharm.doc" \l "amiodarone" amiodarone-induce (side effect), iodine or T4 (factitious or overdose) Other causes: TSH-secreting pituitary adenoma, hydatidiform moles, choriocarcinomas (hCG secretion), ovarian teratomas, metastatic follicular thyroid carcinomas Thyroid Neoplasms (thyroid nodules) Common, occur in 5% of adults Presentation: nodules usually painless unless they ulcerate or compress other things Diagnosis: if incidentally discovered by imaging, small (< 1 cm), normal TSH, asymptomatic, no h/o radiation or thyroid cancer, can watch and re-evaluate in 6 months, otherwise I-123 radioactive uptake scan (cold has 5-10% chance of malignancy ( probably need to do FNA (15% will be suspicious and require surgical evaluation) / ultrasound shows cystic or solid (but still probably will need FNA or Bx) / pentagastrin test for medullary carcinoma Ddx: follicular adenoma, multinodular goiter, colloid nodule, Hashimotos, cyst, lymphoma, mets, parathyroid 90% of all thyroid nodules benign (incidental, < 1 cm even more likely benign) nodules increase with age (younger patient means increased chance of malignancy) nodules usually cold (do not take iodine) Treatment: Iodide may be used to decrease vascularity (pre-op for thyroid resection) / excision +/- lymph node dissection / if thyroid completely removed, then lifelong exogenous T4 to suppress TSH production (keep TSH at barely detectable levels) / follow-up I-123 uptake scan to ensure no active thyroid tissue present Complications of surgery: 50% becoming hypothyroid (complications: recurrent and superior laryngeal nerve paralysis, recurrence and hypoparathyroid), may have to remove hyoid to remove all accessory tissue Follicular adenoma encapsulated / usually euthyroid / Treatment: as above Thyroid Carcinomas Papillary carcinoma - good prognosis 1st in U.S. / indolent (slow growth), +/- bilateral Pathology: ground-glass nuclei, longitudinal nuclei, psammoma bodies lymphatic spread / previous irradiation gives a 2-fold higher risk Exam: may have lymphadenopathy (mets), even with normal thyroid palpation Follicular carcinoma - bad prognosis 2nd in U.S. / vascular spread (brain, bone, etc) / middle aged women / may mimic follicular adenoma Medullary carcinoma - bad prognosis 3rd in U.S. / lymphatic spread / bilateral / parafollicular C-cells / secrete calcitonin / FH of disease is better / isolated or as part of  HYPERLINK \l "men" MEN II and III Undifferentiated (anaplastic) - extremely bad prognosis radiation + chemotherapy is only palliative Parathyroid Physiology Total serum calcium 9 mg/dl bound to proteins (albumin) and PO4 / regulated indirectly Ionized serum calcium 4.5 mg/dl regulated directly PTH increases bone resorption (osteoclast activation) increases serum calcium lowers fractional reabsorption of PO4 from kidney (normally set at 80-90%) increases formation of 1,25-OH increases Ca and PO4 absorption in GI increases urinary cAMP Vitamin D causes GI absorption of PO4, Ca and increased renal PO4 and Ca reabsorption, and lowers PTH Vitamin D deficiency occurs in 25% of elderly / affects seen in children more acutely due to lower calcium stores in bones/ may cause lowered Ca and PO4 leading to secondary hyper PTH Reasons: lower intake, lack of sun exposure, direct renal damage (conversion enzymes), anticonvulsants (increased inactivation) Labs: 25-OH 1000 fold higher than 1,25-OH useful to measure vitamin D deficiency 1,25-OH useful for diagnosis hypercalcemia caused by secretory tumor Treatment: 1000-2000 vitamin D / 1 to 1.5 g Ca supplement Calcitonin increases renal excretion of calcium / increases bone formation [more like an escape mechanism / not a primary regulator of serum calcium] PTHrP protein functions identically to PTH causing hypercalcemia / can be measured directly by lab Hyperparathyroidism ( HYPERLINK \l "hypercalcemia" other causes of hypercalcemia) Not uncommon (3 in 1000 middle-age women) / female 2x > male (usually after puberty) Causes: primary adenoma (90%), secondary adenoma, carcinoma, MEN I (10%) Increased PTH: pancreatitis, nephrolithiasis, nephrocalcinosis, gout, pseudogout, HTN, PUD Presentation: can present in hypercalcemic crisis Bones: renal stones, UTI, renal failure, nephrocalcinosis (less common) Stones: aches, arthralgias, pseudogout Abdominal groans: dehydration, constipation, pancreatitis, PUD (CA stimulates gastrin secretion), nausea, vomiting Psychic overtones: anorexia, personality changes, polyuria/polydipsia Fatigue: muscle fatigue or atrophy, lassitude Labs: Hypercalcemia Hypercalciuria only seen in 2/3 of cases Alk phos only ! with significant bone disease serum chloride ! due to PTH-induced bicarbonaturia (more consistent finding than hypophosphatemia) Parathyroid hyperplasia chief cell - solid area of chief cells, reduced fat clear cell - uniform distribution of clear cells, reduced fat Parathyroid adenoma common, 80% parathyroid neoplasms / chief cells (no fat within capsule) / surrounded by normal or atrophic gland, fat cells / usually secretes PTH (hypercalemia) Exam: rarely find palpable neck mass / brown tumors (osteoclasts clump in bone causing focal swelling) Diagnosis: U/S, CT, thallium, venous sampling / radiography is positive in 60-80% of cases / selective venous catheterization and PTH detection is second line Ddx: ectopic PTH, HYPERLINK \l "sarcoid"sarcoid, milk alkali, HCTZ, vitamin D/A overdose, hyperthyroid multiple myeloma, Pagets, Addisonian crisis, familial HH? Treatment: resection for hyperplasia (leave of 1 gland) / adenoma (remove only 1 gland) / can cause hungry bones phenomenon (hypocalcemia) perioral numbness, Chvosteks, seizures / 5% recur (can re-operate) Parathyroid carcinoma rare / invasive / squamous / mets to lung, head/neck, kidney, ovary As part of multiple endocrine neoplasia ( HYPERLINK \l "men" see other) Secondary hyperparathyroidism (renal osteodystrophy) CRF ( ! serum PO4 ( CaPO4 deposition ( ! serum Ca ( ! PTH release ! vitamin D-1-25-OH (due to renal failure) ( ! serum Ca ( ! PTH release Complications: osteodystrophy, myopathy, can get severe muscle atrophy Treatment: vitamin D supplementation, ! PO4 intake, PO4 binders (calcium carbonate) Familial hypocalciuric hypercalcemia AD / poorly understood mechanism / low urinary calcium excretion (rarely causes stones/renal failure) / does not have bone resorption seen with other hyperPTH states Treatment: surgery is not helpful / must rule out before surgery for hyperPTH Idiopathic Hypercalciuria Does not have elevated serum calcium level Vitamin D intoxication Treatment: stop intake / steroids reduce GI absorption of calcium Hypoparathyroidism Status post surgical removal of thyroid (with inadvertent PTH gland removal), autoimmune (e.g. as part of polyglandular syndrome) /  HYPERLINK \l "wilsons" Wilsons / iron-storage disease / others Acute hypocalcemia ( tetany Diagnosis: measure PTH, can actually measure anti-parathyroid Abs as well Pseudohypoparathyroidism PTH receptor not working / Albrights / low calcium Adrenal Gland Cushings Syndrome iatrogenic ectopic ACTH (bronchogenic ca) or ( HYPERLINK \l "corticotrophicadenoma" pituitary adenoma) adrenal tumor ( HYPERLINK \l "adrenaladenoma" adenoma,  HYPERLINK \l "adrenalcarcinoma" carcinoma) Findings: amenorrhea, secondary sex changes, hypertrichosis, obesity, short stature, osteoporosis, muscle wasting, skin (increased POMC) HTN: direct pressor effect and cortisol cross-stimulation of aldosterone receptors, increased intraocular pressure Metabolism: glucose intolerance and hyperinsulinemia CNS: emotional lability, depression, psychosis/paranoia Immunosuppression: ~40% get infections (1st bacteria, can also be things like Aspergillus) Diagnosis: overnight dexamethasone suppression test (supposedly is able to suppress a pituitary tumor secreting ACTH, but not an adrenal tumor) / fair amount of false positives on dexamethasone suppression test / best test to see if patient has elevated cortisol is 24 hr urine cortisol level can measure corticotropin levels (best in AM) ( < 10 suggests corticotropin-independent tumor Cushings Disease young women / 65% of endogenous / single pituitary adenoma or (more often) multiple microadenomas / adrenal glands show bilateral nodules of clear cells with hyperplasia of intervening parenchyma Ectopic ACTH 15% of endogenous Cushings syndrome / 50 yrs, men / small cell carcinoma and carcinoid of lung Nelsons syndrome bilateral adrenalectomy / skin pigment from increased ACTH (POMC) / pituitary adenoma grows from loss of cortisol negative feedback Adrenal Adenoma 50 yrs, women / compact and clear cells (fasciculata), eosinophilic cells (reticularis) / contralateral gland atrophic / less in children / 2% of autopsies have non-functional versions / workup for incidentally discovered adrenal mass [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/6/601" NEJM] Adrenal Carcinoma - poor prognosis 40 yrs / 50% of childhood Cushings syndrome / 80% function / contralateral gland atrophic / invasive Primary Adrenal Lymphoma - poor prognosis Always check adrenal function before mechanical manipulation FNA to distinguish infection vs. primary vs. mets (may or may not obviate open biopsy) Treatment: doxorubicin, vincristine, prednisone Prognosis: usually < 1 yr Primary hyperaldosteronism (PHA) adrenal adenoma (Conns syndrome) (70%) or hyperplastic adrenal gland (30%) / women, 40s / uninvolved cortex is normal (not atrophic) / < 5% will be from carcinoma and ectopic aldosterone production Presentation: fatigue, nocturia, hypokalemia,  HYPERLINK \l "secondaryhtn" secondary hypertension, metabolic alkalosis Note: escape from renal sodium retention limits fluid gain to 1.5 to 2 L (no escape in CHF) Ddx: licorice, tobacco (inhibition of intra-renal anti-cortisol activity of 11--H) Diagnosis: plasma aldosterone/renin ratio: taken at 8AM (> 30-50 diagnostic) / spot aldosterone is too variable 24 hr urine aldosterone is most sensitive, specific to confirm hyperaldosteronism (after 2 wks of no ACE ( oral salt loading (saline loading) would normally suppress aldosterone; if not, then positive for primary hyperaldosteronism) Note: if above tests positive, get CT/MRI abdomen thin-cut through adrenal glands (look for > 1 cm adrenal lesions) Treatment: resection / consider selective adrenal vein sampling (to determine unilateral or bilateral) if hyperplasia only, can do trial of spironolactone/dexamethasone Congenital Adrenal Hyperplasia (CAH) 21-hydroxylase deficiency (90% of cases) may present at puberty (very mild form) / rare in blacks / complete block is fatal Mechanism: defective p450c21 cannot convert 17-hydroxyprogesterone to 11-deoxycortisol causing ! androgens, !aldosterone (also increased ACTH and adrenal hyperplasia) Findings: hyponatremia, hyperkalemia, hypotension, elevated 17-hydroxyprogesterone girls ( stunted growth, virilization (pseudohermaphrodites), infertility boys ( precocious puberty, not-infertile Treatment: steroids and IV fluids immediately 11-B-hydroxylase 5 % of cases / ! androgen, ! aldosterone Diffuse micronodular hyperplasia children / familial / AD / unilateral / glands of normal size / hyperplasia of intranodular area, remaining tissue is normal / diffuse cortical hyperplasia is uncommon McCune-Albright syndrome ( HYPERLINK \l "mccune" see bone) Primary Adrenal Insufficiency (Addisons disease) 1st in US (autoimmune, cortex only) / world: Tb / Other causes: sarcoidosis, histoplasma, cocci, CMV/MAI (HIV patients), hemorrhage, adrenal mets (lungs, breast, stomach), lymphoma, leukemia, X-linked adrenoleukodystrophy, myelipoma, cysts Presentation: Acute: weakness, hypotension (less responsive to pressors), nausea, fever, tachycardia Chronic: skin pigmentation ( HYPERLINK \l "acanthosis" acanthosis) from excess POMC, anorexia, weight loss, personality changes Mechanism: requires 90% destruction / can also affect aldosterone production Labs: hyponatremia, hyperkalemia, hypoglycemia (unlike sepsis), eosinophilia, mild hypercalcemia, acidosis Diagnosis: AM cortisol < 5 mcg/dL / basal (am peak) or post-stimulation increase by 7 or maximum > 18 (some say 20-25) generally rules out Addisons (cortisol can be stimulated by ACTH or insulin) / elevated  HYPERLINK "labs.doc" \l "renin" plasma renin concentration (PRC) / insulin-glucose tolerance test (entire HPA access is tested; stress of hypoglycemia should stimulate ACTH ( cortisol) Treatment: Acute: may need D5NS infusion / hydrocortisone 100 mg q 6-8 hrs Long-term: hydrocortisone 20/10 mg/day or solumedrol (methylprednisolone) / may also need mineralocorticoid replacement (fludrocortisone) 0.1-0.2 mg/d type I rare, AR, children, females, triad of adrenal insufficiency, hypoparathyroid, chronic mucocutaneous candidiasis (and other autoimmune findings) type II (Schmidt syndrome) women in 30s / adrenal and thyroid disease / diabetes and ovarian failure common Acute/secondary adrenal insufficiency stress, abrupt corticosteroid withdrawal, Waterhouse-Friederichsen syndrome (infarction from sepsis, birth-trauma, DIC) / rapid, progressive hypotension leading to shock ? hyponatremia without hypokalemia? does not have increased pigmentation as POMC is not increased does not have hyperkalemia as renin-aldosterone axis preserved Tertiary adrenal insufficiency impaired secretion of CRH from the hypothalamus Disorder HYPERLINK "labs.doc" \l "Aldosterone" Aldosterone HYPERLINK "labs.doc" \l "Cortisol" Cortisol HYPERLINK "labs.doc" \l "renin" ReninPrimary hyperaldosteronism (Conns syndrome)HighNormalLowSecondary hyperaldosteronismHighNormalHighCushings syndromeLow-normalHighLowAdrenal insufficiency (Addisons disease)LowLowHighPituitary diseaseNormalLowNormal Adrenal medulla major site of epinephrine production / some NE, DA, others chromaffin cells (Zenkers solution oxidizes catecholamines to brown-black) Metabolism: Epi, NE to VMA / DA to HVA Pheochromocytoma 40s / (rule of 10s) ( 10% extra-adrenal, bilateral, mets, familial ( HYPERLINK \l "men" MEN II, III) Pathology: rarely may secrete ACTH more than E, NE / hard to distinguish benign from malignant by appearance / pleomorphism, but infrequent mitoses Presentation: hypertension may be constant with paroxysmal or intermittent attacks (may be precipitated by a number of events including palpation of the tumor!) or hypotension (from pressure induced natriuresis), headaches, diaphoresis, hyperglycemia (catecholamine suppression of insulin and stimulation of glycogenolysis) Associations: associated with HYPERLINK \l "nf1"neurofibromatosis, von Hippel-Lindau (VHL gene),  HYPERLINK \l "sturge" Sturge-Weber and  HYPERLINK \l "mccune" McCune-Albright syndrome / in MEN, there is diffuse or nodular hyperplasia (RET protooncogene) Diagnosis: urine markers, clonidine suppression test / CT scan / 123I-MIBG Lab markers (24 hr urine): VMA (may be elevated even without acute hypertension), metanephrines (most sensitive), catecholamines / yield increased if collected during episode / should discontinue any alpha or B-blockers / spot serum levels not a good test due to fluctuations/false positives (if you must use this, patient should rest 30 mins before and must use indwelling catheter to collect venous sample) Treatment: alpha then beta blockade (avoids crises of hypoperfusion with excess peripheral vascular resistance while heart rate is being b-blocked) phenoxybenzamine (irreversible a-blocker begun 1 wk prior to surgical resection) may need to give IV nitroprusside for acute HTN may need to give volume (if volume depleted) Prognosis: surgery has 40% morbidity / f/u labs in 2 wks to see if mets were missed // sometimes mets can be treated with chemo/radiation Paraganglioma - poor prognosis extra-adrenal pheochromocytoma, but does not produce catecholamines / 30s to 60s, sporadic or familial, usually recur / usually have mets (especially retroperitoneal versions) / mitoses absent / encapsulated but adherent, difficult to excise  HYPERLINK \l "neuroblastoma" Neuroblastoma - good prognosis METASTASES TO THE ADRENAL GLANDS lung CA >> metastatic melanoma, RCC, and colorectal cancer nonfunctioning adrenal mass > 6 cm (35% to 98% carcinoma) ( resect between 3 and 6 cm ( MRI smaller than 4 to 6 cm ( could be incidentaloma (unknown adrenal mass) [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/6/601" NEJM] work up to r/o other primary includes timed urine catecholamines, dexamethasone (1 mg) suppression test, and androgen/estrogen levels unifocal adrenal mets from unknown primary is rare (0.2%), so no need for FNA with no history (lung, breast, stomach, kidney, colon, melanoma, lymphoma), signs, symptoms, radiographic or laboratory findings suggesting an occult malignancy / can follow with serial clinical examinations and abdominal imaging Infectious Disease  HYPERLINK \l "sepsis" Sepsis  HYPERLINK \l "primary" Primary Site  HYPERLINK \l "uti" UTI,  HYPERLINK \l "pyelonephritis" pyelonephritis,  HYPERLINK \l "pneumonia" pneumonia,  HYPERLINK \l "meningitis" meningitis,  HYPERLINK \l "cellulitis" cellulitis,  HYPERLINK \l "infectiousarthritis" septic arthritis,  HYPERLINK \l "osteomyelitis" osteomyelitis,  HYPERLINK \l "peritonealinfection" peritonitis,  HYPERLINK \l "pid" PID,  HYPERLINK \l "endocarditis" endocarditis  HYPERLINK \l "sexual" Sexually Transmitted  HYPERLINK "micro.doc" \l "hiv"HIV,  HYPERLINK "micro.doc" \l "hepatitis" hepatitis, HYPERLINK "micro.doc" \l "chlamydia"Chlamydia,  HYPERLINK "micro.doc" \l "hsv" HSV, more  HYPERLINK \l "hematologic" Hematologic  HYPERLINK \l "opportunistic" Opportunistic HYPERLINK \l "exotic"Exotic  HYPERLINK "micro.doc" \l "parasitology" Parasite  HYPERLINK "micro.doc" \l "fungus" Fungal HYPERLINK "ddx.doc" \l "diarrhea"Infectious Diarrhea HYPERLINK \l "childhood"Pediatric I.D. (a.k.a. Pediatrics) [pre-op antibiotics] For details on specific organisms, please see  HYPERLINK "micro.doc" microbiology or a  HYPERLINK "bugs/" folder full of bugs  HYPERLINK "http://www.hopkins-id.edu/education/id_caserounds/index_case.html" Case Presentations from Johns Hopkins Infectious Diseases Studies used for infections Nuclear Medicine Tagged white cell scan ( HYPERLINK \l "osteomyelitiswbcscan" see osteomyelitis) 99mTc (methylene diphosphonate) 67Ga (WBCs) and 111In Note: either Ga or In concentrates more in GI, thus making it worse for GI lesions (increased background noise) Sepsis ( HYPERLINK \l "pedsepsis" pediatric sepsis) [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/16/1643" NEJM] septic splenitis, bacteremia, body temperature dysregulation, leukocytosis/leukocytopenia, hypotension, DIC, end-organ damage (DAD, acute renal failure, ATN, heart failure, liver failure) Mechanism: mediators: endotoxin, IL-1 (fever), TNF General causes: pancreatitis, perforated bowel, cholangitis, abscess, pneumonia, empyema, urosepsis, line sepsis, abscess Specific infections: miliary Tb, pulmonary Tb, fungemia, overwhelming parasitic infections, cerebral malaria, toxic shock syndrome (TSS),  HYPERLINK "micro.doc" \l "cdifficile" C difficile colitis Treatment: Volume repletion: fluids + PRBC if Hct low Hemodynamic support: pressor (levafed for low SVR, may add dopamine for contractility) Antibiotics: broad spectrum such as vanc/zosyn, meropenem, etc. Steroids: trend toward empirically treating for relative adrenal insufficiency; do cosyntropin stim test 0, 30, 60 upon admission then empirically add hydrocortisone 50 mg q 6 and fludrocortisone 50 ug qd for total 7 days (decreases mortality in some trials) Nutrition: Harris-Benedict for caloric intake in a male 66 + (13.7 x wt) + (5 x ht) (6.8 ? age) Other: activated protein C (reduces mortality by 10%) Lactic Acidosis [HYPERLINK "pics/lir-anaerobicglycolysis1.jpg"diagram][HYPERLINK "pics/lir-anaerobicglycolysis2.jpg"diagram] Lactic acid > 4 mmol/L / increased anion gap in only 50% / Type A or B / late marker of ischemic gut Mechanism: arterial vasodilation, catecholamine insensitivity, decreased cardiac contractility, decreased O2 uptake in lungs, increased work of breathing, increased catabolism/decreased synthesis of protein Complications: osteomalacia (increased PTH) Rule out other causes of acidosis: hyperchloremia, TPN, saline acidosis, colonic ureteral diversion (80% will develop LA), RTA, diarrhea, drugs Treatment (controversial): HCO3, DCA, THAM, Carbicarb / CVVHD may improve survival only minimally Line Sepsis (catheter-related) make sure they get 2 inches of cath tip for CFU count to determine if primary or secondary catheter infection some evidence suggests utility of drawing simultaneous cultures from peripheral and through catheter; if catheter culture grows faster, it suggests infection is line related Primary infection Urinary Tract Infection ( HYPERLINK \l "childhooduti" see pediatrics) Risk factors: incontinence, prior UTI, neurological impairment, polypharmacy ( HYPERLINK "pharm.doc" \l "anticholinergic" anticholinergics), immunosuppression, poor nutrition, comorbid disease states / major cause of sepsis in elderly Organisms: E. coli, pseudomonas, proteus, klebsiella, enterobacter, Enterococcus, rarely (Staph, Corynebacterium), Candida Diagnosis: > 105 CFU/mL from clean catch, > 102 CFU/mL from catheter specimen Labs: nitrites (converted from nitrates by some bacteria, esp. GNR), Leukocyte esterase (released by neutrophils) Treatment: Asymptomatic bacteriuria (50% women, 30% men > 65 yrs): should treat pregnant and immunosuppressed patients (including diabetics) Candida in urine / if asymptomatic, changing catheter clears in 40% / treatment with fluconazole or ampho B recommended for immunocompromised, neutropenic, obstruction, invasion of upper pole / bladder washings is only a temporary measure Acute uncomplicated cystitis: empiric treatment for women with symptoms of acute cystitis and positive dipstick / fluoroquinolone x 3 days  HYPERLINK \l "pyelonephritis" Pyelonephritis: IV ceftriaxone then fluoroquinolone (or other) to complete 10 days (change to PO when appropriate) Urosepsis: supportive as for any  HYPERLINK \l "sepsis" sepsis / ampicillin + gentamicin or imipenem or Zosyn Pneumonia ( HYPERLINK \l "pneumonia" see pulmonary) ( HYPERLINK \l "childhoodpneumonia" see pediatrics) Peritonitis ( HYPERLINK \l "peritonealinfection" see peritoneal infection) Cellulitis erythema, warmth, and tenderness Organisms: Strep A (most common), Staph, Erysipelothrix (fish), E. coli (nephrotic in children), aeromonas, Vibrio, C. perfringens (gas gangrene) Labs: Gram stain and culture (aerobic and anaerobic) on aspirate of (advancing edge and any vesicles) / swab of any drainage material / punch biopsy (sometimes) / blood cultures / ASLO titer (in suspected streptococcal disease) Note: must consider necrotizing fasciitis ( HYPERLINK \l "fasciitis" see below) and osteomyelitis ( HYPERLINK \l "osteomyelitis" see below) Note: recurrent cellulitis should prompt consideration of venous insufficiency (Milroys syndrome), chronic foot trauma or tinea pedis Q: who should get U/S doppler on lower extremities? Erysipelas (Strep A) distinguished by indurated, elevated margin [ HYPERLINK "http://dermis.net/dermisroot/en/10777/diagnose.htm" dermis]; lymphatic involvement and vesicle formation are common / face and legs; facial may follow URI strep infection Treatment: treat for both Staph and Strep anyway Staphylococcal cellulitis Differentiated from erysipelas by nonelevated, poorly demarcated margins Local tenderness and regional adenopathy are common; up to 85% of cases occur on the legs and feet (look for sign of entry such as chronic athletes foot) Treatment: nafcillin IV (1 to 2 g q 4-6hrs) for a while (~few days) followed by PO dicloxacillin 250 to 500 mg qid (for another few days or as needed, but with lymphatic/venous insufficiency, you can expect your patient to come back and need more IV nafcillin because you sent them home too early on PO) Alternative: PO augmentin or Cephalosporins (cephalothin, cephalexin, cephradine) Vancomycin for MRSA or penicillin allergy H. influenza cellulitis Area involved has a blue-red-purple-red color mainly in children (face) and sometimes adults (neck or upper chest) Blood cultures frequently positive Treatment: PO amoxicillin (30% resistance), cefaclor, cefixime, cefuroxime; IV cefuroxime or ampicillin; bactrim or chloramphenicol for penicillin allergy; IV cefuroxime for severely ill patients Vibrio vulnificus Higher incidence in patients with liver disease (75%) and in immunocompromised hosts (corticosteroids, diabetes mellitus, leukemia, renal failure) History of exposure to salt water or eating raw seafood Large hemorrhagic bullae, cellulitis, lymphadenitis, myositis, DIC and septic shock occur frequently / mortality rate over 50% in septic shock Treatment: aminoglycoside plus tetracycline or chloramphenicol Necrotizing fasciitis deep-seeded subcutaneous infection ( progressive destruction of fascia and fat diffuse swelling of an arm or leg, followed by bullae filled with clear fluid (maroon or violaceous in color) Systemic symptoms may include shock and organ failure CT or MRI is useful in locating the site and depth of infection Treatment: surgical debridement and antibiotics Panniculitis Inflammation of subcutaneous tissue, occasionally complicates alpha-1-antitrypsin deficiency Mediastinitis Post-surgical: ~ 2-8% incidence / CT chest is about 65% sensitive / surgery is best answer although sometimes, pt will recover with antibiotics with suspected infection (was there an infection?) Deep-Neck Infections Ludwigs Angina from oral infection Lemierres syndrome ( HYPERLINK \l "lemmieres" see other) Pharyngitis ( HYPERLINK \l "pharyngitis" see pediatrics) [HYPERLINK "http://content.nejm.org/cgi/content/full/344/3/205"NEJM] Many causes (microbial and non-microbial) / pediatrics vs. adult / try ctrl-F Viral: rhinovirus (20), coronavirus (5), adenovirus (5), HSV (4), parainfluenza (2), influenza (2), coxsackievirus, EBV, CMV, HIV Bacterial:  HYPERLINK "micro.doc" \l "strepa" Strep A (15-30),  HYPERLINK "micro.doc" \l "strepc" Strep C (5), Neisseria, Corynebacterium, Arcanobacterium, Chlamydia, Mycoplasma Diagnosis: gold standard is throat culture (90% sensitivity) Treatment: depends on organism suspected Osteomyelitis [ HYPERLINK \l "osteomyelitisrx" Treatment] [ HYPERLINK \l "osteomyelitismechanisms" mechanisms] HYPERLINK \l "_osteomyelitishematogenous"Hematogenous (20%)  HYPERLINK \l "osteomyelitiscontiguous" Contiguous (majority)  HYPERLINK \l "osteomyelitisvertebral" Vertebral,  HYPERLINK \l "osteomyelitisvascular" Vascular Insufficiency,  HYPERLINK \l "osteomyelitischronic" Chronic Neonates E. coli, S. aureus and Group B streptococcus Early childGroup A Strep, H. FluElderlyGNR and S. aureusIVDAS. aureus, pseudomonas, serratiaAIDS et al fungusSickle cellS. aureus, SalmonellaOthersyphilis, varicella, vacciniaCV surgery Above plus GN enteric, atypical mycobacteria, MycoplasmaFoot puncture or burnsPseudomonasCat bitesPasteurella Diagnosis: Culture: culture of overlying wound may or may not correlate with underlying bone lesion (except in the case of S. aureus, which for reasons unclear to me, usually does) Plain films: positive periosteal reaction > 10 days / lytic lesions by 2-6 wks / use at presentation and follow-up Scintigraphy: 95% with positive 99mTc (methylene diphosphonate) within 24 hrs (false positives from bone remodeling, false negatives only with obstruction to blood flow) / 67Ga (WBCs) and 111In (WBCs or hIVIG) may be more specific for inflammation / total-body scintigraphy to detect metastatic infection, can be repeated later if negative Ultrasound detects surrounding inflammation / Doppler measures blood supply CT and MRI: edema and the destruction of medulla, periosteal reaction, cortical destruction, articular damage, and soft-tissue involvement (even with normal plain films) CT can be too sensitive to artifacts from bone/metal (useful for guiding FNA) MRI (no local ferromagnetic material, titanium is okay) / often earlier detection than scintigraphy T1-weighted ( infectious processes have low signal intensity (appear dark on standard films) T2-weighted ( inflammation and infection seen as abnormally bright paramagnetic IV contrast agent (gadopentetate di-N-methylglucamine) may help differentiated vascularized/inflamed tissue from peripheral rim enhancement of abscess Hematogenous Osteomyelitis (20%) Osteomyelitis develops after bacteremia mostly in prepubertal children and in elderly patients Older patients and IVDA ( spine (see below) Children ( metaphyseal area of long bones (particularly the tibia and femur), single focus 5% progress to chronic if untreated (see below) / 95% single organism (> 50% S. aureus) Presentation: chills, fever and malaise, local pain, and swelling Ddx: Charcot foot, fracture, cellulitis Labs: Elevated ESR, elevated CRP (can be used to follow) Positive blood cultures in 1/3 of acute/childhood/hematogenous and adult/vertebral Negative blood cultures ( need FNA or biopsy Contiguous Focus of Infection - most common Organisms: S. aureus ( >50%), S. non-aureus and polymicrobial Presentation: +/- low-grade fever, painful, unstable joint on physical exam or films after bone insult ( most prevalent (open fracture, bone reconstruction, prostheses) < 12 wks ( acute infection of prosthesis < 24 months ( chronic infection, often less virulent bugs Even later ( hematogenous infection Diagnosis: Grams stain and quantitative cultures (colonization vs. infection) Vertebral Osteomyelitis More rare in adults / often spans 2 vertebrae and 1 disk space lumbar > thoracic > cervical / IVDA (cervical), urinary catheters (lumbar), Tb (thoracic) Risk factors: IVDA, DM, hemodialysis Presentation: > 50% of cases with subacute (low grade fever, normal WBC), 15% with nerve root irritation (neck or back pain) / elevated WBC suggests ongoing bacteremia Diagnosis: blood cultures often negative / needle biopsy with multiple specimens / 2nd CT-guided biopsy if 1st is negative (if 2nd negative, choose empirical therapy or an open surgical biopsy) CT or MRI: must not miss  HYPERLINK \l "epiduralabscess" epidural abscess Additional organisms: E. coli (25%), Tb, Brucella Treatment: spinal surgery only for failed medical therapy, huge abscess, instability, worsening neurological deficits Chronic Osteomyelitis fever usually only with soft tissue involvement / months or even years of low-grade inflammation, pus, microorganisms, sequestra, compromised soft-tissue envelope, fistula (sometimes) Late complications: fractures, squamous cell carcinoma (of sinus tracts), amyloidosis Treatment: group decision by patient, medical, orthopod/CV surgeon Vascular Insufficiency diabetes or vascular insufficiency / almost exclusively in the feet / previously traumatized skin Cellulitis may be minimal / Physical exam ( no pain (advanced neuropathy) or big pain (acute destruction of bone) transcutaneous oximetry and Doppler to assess vascular supply (once inflammation controlled) arteriography if indicated Antibiotic Prophylaxis in Bone Surgery closed fractures, antistaphylococcal penicillins and 1st, 2nd, 3rd generation cephalosporins open fractures (already contaminated) Treatment: antibiotics within 6 hrs ( 1st (cefazolin) or 2nd (cefamandole and cefuroxime) for 24 hrs complex fractures with extensive soft-tissue damage ( broader coverage for longer periods insertion of prosthetic devices (current rate of infection ~0.5%) Treatment Basic Principles bacteriocidal antibiotics plus 4 to 6 wks and bed rest combination of medical and surgical management high dose PO after 5-10 d IV often used in compliant children usually see improvement after 1-2 d therapy ESR or CRP should decrease to < T! previous level (if doesn t, do not stop treatment; re-evaluate) early, IV, at least 4 to 6 wks Hematogenous in children ( IV phase then several weeks PO (usu. not B-lactams due to limited PO bioavailability and GI tolerance) Long-term PO quinolones for Enterobacter (still investigational for Pseudomonas, Serratia, and S. aureus (add rifampin) / metronidazole also penetrates bone well MRSA and MDR GNR requires long term IV vancomycin or broad-spectrums local administration antibiotic-coated beads (under investigation) Surgical Management surgical decompression for refractory infection / complete debridement for chronic infection / then cover with skin, bone (cancellous +/- Papineau technique), muscle graft (all have high failure rates due to persistent infection / revascularization procedures are helpful / complex orthopedic techniques for large defects (Ilizarov technique and others) prosthetic joints ( remove device (exceptions: stable hip prosthesis and wuss microorganisms such as streptococci and early device-infections with S. aureus (some success with PO quinolones and rifampin) / two-stage exchange arthroplasty vs. one-stage (higher risk of recurrent infection) vascular insufficiency (diabetes) consider amputation vs. revascularization surgery and/or debridement and 4 to 6 wk course of antimicrobial therapy may work with good oxygen tension (hyperbaric oxygen not proven to be effective) Epidural abscess [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/19/2012" NEJM] Diagnose and treat quickly! Organisms: S. aureus (66% with ~40% MRSA) Presentation: back pain (75%), fever (50%), neurological deficit (33%) Diagnosis: clinical + imaging [HYPERLINK "pics/epiduralabscess.jpg"MRI][ HYPERLINK "pics/epiduralabscess-mri.jpg" MRI] + labs (60% positive bacteremia; 75% abnormal LP but non-specific so only do LP if myelogram already being performed) Risk factors: diabetes, alcoholism, HIV, spinal abnormality or intervention (degenerative joint disease, trauma, surgery, drug injection, or placement of stimulators or catheters), or potential source of infection (skin and soft-tissue infections, osteomyelitis, urinary tract infection, sepsis, indwelling vascular access, intravenous drug use, nerve acupuncture, tattooing, epidural analgesia, or nerve block) Treatment: empiric vancomycin + cefepime or specific therapy if organism determined (at least 6 weeks duration) / neurosurgical consult (may need urgent decompressive laminectomy) Prognosis: paralysis (5-20%), death (5%) Meningitis  HYPERLINK \l "viralmeningitis" Viral /  HYPERLINK \l "bacterialmeningitis" Bacterial Aseptic meningitis (see below) echovirus, coxsackievirus, nonparalytic poliovirus Pyogenic meningitis E. coli, B strep, H. influenza, N. meningitidis, pneumococcus / S. aureus Iatrogenic aseptic meningitis NSAIDS, immunosuppressants (azathioprine, OKT3), antibiotics (bactrim), IVIG Chronic meningoencephalitis ( HYPERLINK \l "chronicmeningitis" see other) neurosyphilis (Argyll Robertson pupil, tabes dorsalis, Charcot joints, gummas), Tb, borrelia (lyme), pseudomonas (IV drug users) protein increased, glucose may be normal Other CNS infections:  HYPERLINK "micro.doc" \l "cryptococcus" Cryptococcus,  HYPERLINK "micro.doc" \l "toxoplasmosis" Toxoplasmosis,  HYPERLINK \l "cnsamoebiasis" Amoebas Viral meningitis Labs: CSF pleocytosis (almost always present) / usu. 100 to 1000 (up to several thousand) early neutrophils may dominate, then lymphocytes within 48 hrs protein (< 100 mg/dL) and glucose usually minimally altered PCR has 90% specificity culture takes from 3-8 days (60% yield, Coxsackie A is worst) Transmission: shedding is for about 1 wk (throat) and several weeks (rectum) / asymptomatic shedding ~5% during epidemic (thus, shedding could be from past infection)  HYPERLINK "micro.doc" \l "enterovirus" Enterovirus most common agent (70%), occurring late summer/early fall Presentation: URI prodrome, fever (80%), nuchal rigidity (50%), frontal headache (90%), nausea, vomiting, irritability, lethargy, photophobia, pleurodynia, rash, conjunctivitis, myopericarditis Maculopapular rash ( Echovirus 9 Herpangina ( Coxsackievirus A Pericarditis/pleurisy ( Coxsackievirus B Splenomegaly ( EBV Vesicopustular rash ( VZV Diagnosis: clinical and via  HYPERLINK \l "lp" lumbar puncture / type I atypical lymphocytes suggestive / PCR of CSF can detect many types / may also be able to culture enterovirus from stool samples Course: usu. self-limited to < 1 week with improvement after LP Treatment: abx to cover bacterial until specific organism identified  HYPERLINK "micro.doc" \l "hsv1" HSV (encephalitis) Most common sporadic acute focal encephalitis in U.S. / < 20 or > 50 yrs look for herpangitic or herpetic rash, in CSF, predilection for inferior, medial temporal lobes, frontal lobes and orbital gyri Presentation: altered personality, hypersexuality, sensory hallucinations Diagnosis: MRI with contrast (hyperintensity on T2), may be normal first few days, should repeat if high suspicion) PCR for HSV-1 DNA in of CSF (+) > 24 hrs CSF: lymphocytic pleocytosis < 500, ! RBC s (or xanthochromia), mildly ! protein, normal glucose EEG: focal slowing and periodic complexes localized to one temporal lobe Prognosis: more CNS changes means worse prognosis HSV-2  Mollaret s meningitis / of neonates with maternal HSV-2 will become infected  HYPERLINK "micro.doc" \l "cmv" CMV in utero (periventricular necrosis, calcification, microcephaly) / immunosuppressed (ependyma/subependymal glia, Cowdry A, 20% of HIV pts) / detected by PCR EBV detected by PCR  HYPERLINK "micro.doc" \l "mumps" Mumps CSF: WBC usu. < 500 / may persist for weeks / usu. > 80% lymphocytes Complement fixation and hemagglutination inhibition on serum specimens are the most reliable serologic tests / CSF culture has 40% yield HIV (primary infection) CSF: WBC usu. < 200 / usu. normalizes by 2 wks AIDS dementia memory loss, apathy, confusion / vacuolization looks like B12 deficiency / childhood HIV (fewer opportunistic CNS infections) PML (JC virus) demyelination / does not enhance on MRI / diagnostic EM pattern (biopsy) / may occur in HIV (60% of cases) or other immunocompromised population / CSF may show mild pleocytosis (25%) and slightly elevated protein Treatment: HIV meds may slow progression +/- cytarabine (debatable)  HYPERLINK "micro.doc" \l "syphilis" Syphilis (usu. presents like viral meningitis) Lymphocytic choriomeningitis (HYPERLINK "micro.doc" \l "lcv"LCV) Begins like enteroviral meningitis, then takes a turn for the worse / late manifestations include orchitis, arthritis, myopericarditis, and alopecia CSF: WBC usu. < 750 / low sugar (25%) / culture from blood and CSF early, urine later / diagnosis usu. made by serology St. Louis encephalitis (see micro) Poliomyelitis anterior horns / post-polio syndrome (progressive weakness 30 yrs later) Rabies paresthesia around wound, HA, fever, GI / late CNS disease (Negri bodies) Bacterial meningitis Causative organisms: [ HYPERLINK \l "agemeningitis" see breakdown by patient status] ( HYPERLINK \l "meningitisorganisms" more organisms) Neonatal: HYPERLINK "micro.doc" \l "strepb"Group B Strep, HYPERLINK "micro.doc" \l "ecoli"E. coli, Listeria, citrobacter Children/adult:  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus,  HYPERLINK "micro.doc" \l "nmeningitis" N. meningitidis, HYPERLINK "micro.doc" \l "hinfluenza"H. influenza / E. coli, Klebsiella,  HYPERLINK "micro.doc" \l "listeria" Listeria, Enterococcus, Salmonella, HSV, Rickettsia Basilar meningitis (ataxia, incontinence): TB, fungal, Listeria, syphilis, sarcoid Post-surgical: S. aureus and S. epidermidis Presentation: fever (90%), headache (80%), mental status change (70%), seizures (40%), vomiting (30%), nuchal rigidity (meningismus) (80%) Kernigs (50%) painful/limited extension of leg after passive flexion Brudzinskis (50%) reflexive leg contraction on passive (forceful) neck flexion focal CNS findings (15%) - usu. cranial nerve palsies [from ischemia or focal suppuration] rash ( Neisseria, viral Tip-offs papilledema ( suggests cryptococcus (get CT 1st with signs of increased ICP) early, prominent CNS findings suggest Listeria CSF leak (otorrhea, rhinorrhea following trauma, pneumococcus, Hib) Risk Factors: more frequent with < 5 or > 50 yrs and winter months trauma, mastoiditis, sinusitis, anatomic defects, VP shunt, asplenia, antibody deficiency, terminal complement deficiency Ddx: Infection:  HYPERLINK \l "viralmeningitis" viral meningitis, brain abscess, cerebral/spinal epidural abscess CNS problem:  HYPERLINK \l "sah" subarachnoid hemorrhage, recent sustained anoxia or hypoxia, intracranial hematoma, malignant hypertension, and developmental or demyelination disorders Malignancy (leukemia, lymphoma, metastatic carcinoma) Thrombotic: septic intracranial thrombophlebitis, endocarditis with embolism Drugs:  HYPERLINK "pharm.doc" \l "bactrim" bactrim (SMX),  HYPERLINK "pharm.doc" \l "nsaids" NSAIDs,  HYPERLINK "pharm.doc" \l "inh" INH Vaccinations: mumps, measles Workup: CT (before LP with increased ICP) LP (HYPERLINK \l "lp"see below) blood cultures CXR (look for TB) RPR for syphilis (can present as aseptic meningitis) empiric treatment for ABM (if suspected) Electrolytes: may be hypoglycemic and SIADH symptoms MRI: meningeal enhancement will be present, but is a very non-specific finding Complications: SZ, CVA, thrombosis, increased ICP mortality (25% for adults) morbidity (61% for neonates) cerebral infarction (5% to 15% of ABM, 30% in neonates) neonates get arteritis/thrombophlebitis (larger, +/- hemorrhagic infarcts, +/- secondary abscess formation) / venous thrombosis and hemorrhagic necrosis (associated with Pseudomonas, Proteus, Enterobacter, and Serratia) Septic venous sinus thrombosis/thrombophlebitis (up to 5%, usu. < 1 or 2 weeks) Note: sinus, middle ear, skull infection can beget cerebral vasculitis without detectable meningitis / also, basilar infection can causes vasculitis of ascending arteries Mechanisms of damage Immune-mediated damage to blood vessel cells, humoral (antibody mediated), cellular (cell mediated, granuloma formation), immune complex deposition (complement activation), bystander damage to blood vessel cells, direct damage to vessel (e.g. VZV), infection-associated immune dysregulation Toxin-mediated damage to blood vessel cells, postinfectious syndrome Treatment: Ceftriaxone 2 g q 12 hrs covers S. pneumo, Neisseria Vancomycin MUST be given to cover resistant S. pneumo Ampicillin for Listeria Steroids (dexamethasone) recommended to reduce CNS inflammation (most useful at initiation of therapy and definitely < 6 hrs, presumably from lysis of organisms) / note: dexamethasone may decrease penetration of vancomycin into CSF Acyclovir if HSV suspected serial LPs may benefit patients with increased ICP (Cryptococcus) consider anticoagulation for thrombosis (must rule out bleeding first) ABM can cause profound hyperventilation and respiratory alkalosis (watch PO43-), consider this when giving  HYPERLINK "pharm.doc" \l "diamox" Diamox to reduce ICP ? COX inhibitors, Ab to adhesion molecules For meningococcus, treat exposure of close contacts (dormitory residents, family members, health care workers, etc):  HYPERLINK "pharm.doc" \l "rifampin" rifampin bid x 2 days or  HYPERLINK "pharm.doc" \l "cipro" cipro x 1 dose Note: must get 10-30 times MIC, dose may be higher than other bacterial infections, must use HYPERLINK "pharm.doc" \l "bacteriocidal"bacteriocidal agents because CSF lacks compliment, etc., protein levels and low pH of CSF may decrease activity of certain antibiotics Vaccines available for: pneumococcus, Neisseria, H. influenza, others Duration: 14 days with good clinical response / antibiotics may be stopped after 48 hrs with probable viral meningitis Course: Neonatal: S! mortality, with a small minority developing hearing loss, developmental delay, profound MR, hydrocephalus requiring shunting, seizures, spasticity Childhood/Adult: under 5% mortality (15-30% with persistent hearing loss, developmental delay, behavioral problems, motor incoordination, seizures (13%) Note: CSF parameters may take weeks to normalize / glucose tends to normalize much faster than the protein (WBCs may take longer) Lumbar Puncture [HYPERLINK "procedurevids/"video] Note: contraindicated with increased ICP, site skin infection, cardiopulmonary instability / technically, you should be able to use various criteria to determine if need CT prior to LP, but nowadays, everyone just gets a non-contrast CT before LP / record opening pressure on LP - may need to drain CSF to relieve pressure (prevent blindness) Note: do not delay antibiotics to do diagnostic studies, results valid up to 2 hours (can do  HYPERLINK \l "latexagglutinationpanel" latex agglutination panel) 1st culture/sensitivity/gram stain 2nd glucose/protein 3rd cell count 4th always tell lab to hold a tube in reserve (for future studies) WBC ProteinGlucoseOpening Pressure Bacterial < 100 to 10,000 (usu. 1000 to 5000)100-500< 40> 20 mm H2OViral 25-100 50-100> 40< 18 mm H20M Tb 4000-500010-50020-40Normal0-1 < 900-60 Note: glucose should be 60% blood level over 2 years, but 70-80% in neonates Left shift may be early on and then lymphocyte predominance later (like viral) / lymphocytic often seen in neonatal GNR and Listeria / 10% of Meningococcus will have normal CSF / elevated CSF lactate (> 35 mg/dl) suggests bacterial / sterilization usu. takes 24 to 36 hrs. Gram-stain in ABM pre-treatment (sensitivity 70%, specificity 99%) S. pneumo 90% / H. influenza 85% / Neisseria 75% / GNB 50% / Listeria - < 50% Latex agglutination panel (specificity is 95%) S. pneumo (83 types; 70-100% sensitive) Neisseria (A, C, Y, W135; 33-70% sensitivity) H. influenza B GBS (type 3) E. coli (K1) some panels can detect Staph too GNR best detected by special limulus lysate assay (for endotoxin) Standard Studies Opening pressures (usu. > 60 mm H20 w/ bacterial) Cell counts (opening and closing) and WBC differential RBCs (would clear by 4th tube if traumatic (unlike HSV or subdural hemorrhage) Extra (can be ordered) India Ink and Cryptococcal Ag (cannot trust presentation or CSF) Latex agglutination (bacterial Ag panel) - useful w/ prior abx (otherwise, bacteria would usu. grow) AFB VDRL et al for syphilis Bacterial culture: Listeria, Nocardia Anaerobic culture Viral Culture PCR for just about anything: Tb, EBV, CMV, VZV, HSV, JC, West Nile, Enterovirus? Bacterial Ag Latex (various bugs) usu. dont need unless pretreated with Abx Antibodies for toxoplasma, St. Louis, Eastern Equine Amoeba usually requires biopsy to detect / cells can mimic histiocytes on path Age breakdown for septic meningitis InfantsChildrenAdultsElderly HYPERLINK "micro.doc" \l "strepb" Strep B (40%) HYPERLINK "micro.doc" \l "neisseria" N. meningitidis (30%)Enterovirus HYPERLINK "micro.doc" \l "pneumococcus" S. pneumo HYPERLINK "micro.doc" \l "ecoli" E. coli (25%) HYPERLINK "micro.doc" \l "pneumococcus" S. pneumo (20%) HYPERLINK "micro.doc" \l "pneumococcus" S. pneumo (40%)GNROther GNR (10%) HYPERLINK "micro.doc" \l "enterovirus" enterovirus HYPERLINK "micro.doc" \l "neisseria" N. meningitidis (20%) HYPERLINK "micro.doc" \l "listeria" Listeria (5-10%) HYPERLINK "micro.doc" \l "hinfluenza" Hib (<10%)Staph (5%) HYPERLINK "micro.doc" \l "listeria" Listeria (10%)EnterococcusGNR (5%) HYPERLINK "micro.doc" \l "listeria" Listeria (5%)Other Strep (5%) HYPERLINK "micro.doc" \l "herpes" HSV Immunocompromised HIV/AIDSRespirator Head trauma, surgeryRuptured brain abscess  HYPERLINK "micro.doc" \l "listeria" Listeria (10%)Proteus Staph aureusGNR TbPseudomonasStaph epidermidisAnaerobesCryptococcusSerratiaGNRFlavobacterium Meningitis Organisms Group B Strep 3rd bacterial meningitis / neonatal meningitisE. coli (K1 antigen) Neonatal meningitisS. pneumoniae 1st bacterial meningitisH. influenza 5th bacterial meningitis (much less with vaccine)N. meningitides 2nd bacterial meningitis / biopsy of skin lesions can be helpfulListeria monocytogenes 4th bacterial meningitis (up to 10% of newborns) and nursing home/immunocompromised patientsM. Tb WBC s < 500 (! monocytes), very low glucose, very high protein / PCR because AFB usually negative (although PCR has low sensitivity) / MRI will show basilar location (cranial nerves, hydrocephalus ( often high opening pressure)SalmonellaKlebsiellaEnterococcususu. post-surgical Enterobacter2 drugs or cefepime as single agent / Unasyn or ZosynCitrobacter diversus causes abscessesS. aureuscauses abscessesMycoplasma uncommonF. tularemiaRMSFCoxiellaSyphilismimics aseptic meningitisLyme diseasemore HA and neuropathy, less meningeal signsLeptospirosis HYPERLINK "micro.doc" \l "cryptococcus" Cryptococcus 1st in AIDS population / high CSF pressure / lymphocyte predominance, low sugar, high proteinCandidaHistoplasmosisNaegleria causes purulent meningitis (no good treatment)Toxoplasmosis uncommonEnterovirus (80%)MumpsLCMlow sugar in CSF (unusual for a virus)EBVCMVVZV HYPERLINK \l "hsv1" HSV-1 (and HSV-2) most common acute viral encephalitis / focal, subtle CNS findings / normal glucose, protein and WBC elevated, bloody CSF (does not clear by 4th tube) / community acquired form is not related to immune status / MRI will show temporal lobe involvement / EEG may show periodic sharp, slow wave complexes in temporal lobes (within 2-15 days)HIV Chronic meningitis syndrome Diagnosis: CSF studies and extraneural cultures / neuroimaging: > 75% sensitivity / hyponatremia (25% to 90%) / PPD/CXR can be negative / all should get HIV test Treatment: combination antibiotics +/- corticosteroids for standard CNS reasons as well as for decompensation on initiation of antibiotics Causes of asymptomatic meningitis: meningovasculitis, parenchymatous neurosyphilis, general paresis, tabes dorsalis, gummatous neurosyphilis Hematologic Infection Serologic testing available (list keeps growing; always check for latest): toxoplasma, cryptococcus, blastomyces, coccidioides, bartonella, brucella, Coxiella burnetii, Borrelia burgdorferi, EBV PCR (major partial list; this is a stub): HYPERLINK \l "whipples"T. whippelii Granulomatis lymphadenitis Tb (scrofula in neck, Potts in spine) / histoplasmosis (GMS, Mississippi River Valley) / coccidiomycosis (Southwest US) / sporothrix, blastomycosis (local or systemic) / cryptococcus (worse in HIV) / aspergillus (causes allergic COPD or opportunistic infection) / mucormycosis (opportunistic) Cat scratch disease ( HYPERLINK "micro.doc" \l "bartonella" see Bartonella) self or gentamicin-limited / AIDS pts may get bacillary angiomatosis, peliosis Toxoplasmosis (see parasitology,  HYPERLINK \l "toxoplasmosis" toxoplasmosis) protozoa / self-limited / uncooked meat, cat feces Epstein-Barr Virus ( HYPERLINK "micro.doc" \l "ebv" EBV) Visceral leischmaniasis (HYPERLINK "micro.doc" \l "Leishmania"see other) L. donovani / amastigotes in macrophages / discoloration of hands, feet, face, abdomen / AIDS Malaria ( HYPERLINK "micro.doc" \l "malaria" see other) P. falciprum may cause black-water fever / falciprum will not relapse Filariasis HTLV-1 T-cell leukemia / IV drug users, prostitutes Parvovirus B19 ( HYPERLINK "micro.doc" \l "parvovirus" see other) 5th disease / mild exanthem / non-immune hydrops fetalis / transient aplastic crisis Sexually Transmitted Diseases HIV ( HYPERLINK "micro.doc" \l "hiv" see other)  HYPERLINK "micro.doc" \l "hsv" HSV Cowdry A / multinucleated giant cells / Tzanck smear / acyclovir, etc. HYPERLINK "micro.doc" \l "chlamydia"C. trachomatis  HYPERLINK \l "lgv" LGV, conjunctivitis, UTI, trachoma (blindness) / azythromycin, doxycycline  HYPERLINK "micro.doc" \l "ngonorrhea" N. gonorrhea GN diplococci / UTI, PID / opthalmia neonatorum / arthritis ceftriaxone, quinolone, dissemination, spectinomycin  HYPERLINK "micro.doc" \l "trichomonas" T. vaginalis protozoa / UTI / strawberry mucosa / treat partner metronidazole (note alternative for the alcoholic couple paromomycin) Gardnerella vaginalis fish odor / clue cells / metronidazole H. ducreyi  HYPERLINK \l "chancroid" chancroid / painful / ceftriaxone, azythromycin / treat partner  HYPERLINK "micro.doc" \l "hpv" HPV (condyloma) warts / cidofovir Calymmatobacterium granuloma inguinale (papule) / tropics / tetracycline / donovan bodies Giemsa stain  HYPERLINK "micro.doc" \l "syphilis" Syphilis non specific VDRL, RPR / specific FTA, MHA-TP, TPI / tree-bark aorta / tabes dorsalis / palms, soles / pen G or tet / doxycycline  HYPERLINK "micro.doc" \l "hepatitis" Hepatitis Exotic diseases Treponema sp. yaws, pinta, bejel (transmitted by fomites)  HYPERLINK "micro.doc" \l "lyme" Borrelia burgdorferi lyme disease / erythema migrans, disseminated, persistent (CNS, (deer tick) peripheral neuropathy, requires 1 mo IV ceftriaxone) Coxiella burnetii facultative intracellular parasite / animals / inhalation / ingestion Q fever (no rash) - chronic hepatitis, endocarditis Ehrlichia chaffeensis deer tick / monocytic or granulocytic ehrlichiosis (different organisms) / leukocytopenia / usually no rash / tetracycline Vibrios sp. v. cholera (enterotoxin), v. parahaemolyticus (invades colon, toxin), v. vulnificus, v. alginolyticus (wound sepsis) Rickettsia obligate intracellular parasite R. rickettsii rocky mountain spotted fever (South-Central-mid-Atlantic) / large ticks / centripetal spread (palms, soles to trunk) / 20% mortality untreated / tetracycline R. akari mites, mouse / rickettsialpox (mild febrile illness) / eschar gives way to rash R. prowazekii human louse / centripetal rash / epidemic typhus (Brill-Zinsser is recrudescent disease-usually effects elderly) R. typhi fleas / endemic / murine typhus (milder typhus) R. tsutsugamushi mites / scrub typhus Fever of Unknown Origin Classic Nosocomial T > 38.2 on several occasions in hospitalized patient; no infection known at admission (after 3 days evaluation and 48 hrs culture negative) / 50% are infectious (IV catheter-related, UTI, C. difficile, septic phlebitis) / 25% non-infectious (alcohol withdrawal, drug fever, pancreatitis, adrenal insufficiency Neutropenic HIV Fetal Immune System Thymus functional at 12 weeks gestation Lymph node follicles at term / germinal centers after birth intestinal plasma cells 2-4 wks after birth IgG functions at week 6 - of life? IgA small amounts produced after birth, 25% adult levels by 1 year IgM produced at 28 weeks gestation eosinophils functional at birth chronic fetal infection after 6 months gestation causes elevated plasma cells, IgM < 20 wks - mononuclear 26-40 wks - PMNs 2 wks after birth - 4 yrs - lymphocytes predominate, neutrophils decrease GI - lactobacillus in breastfed infants / maternal E. Coli pattern / Echovirus appears early Lungs - staph, strep, diptheroids Pediatric Infectious Diseases  HYPERLINK \l "heent" HEENT ( HYPERLINK \l "pedsconjunctivitis" conjunctivitis,  HYPERLINK \l "otitis" otitis media,  HYPERLINK \l "pharyngitis" pharyngitis,  HYPERLINK \l "epiglottitis" epiglottitis,  HYPERLINK \l "pertussis" pertussis,  HYPERLINK \l "croup" croup,  HYPERLINK \l "ebv" mononucleosis)  HYPERLINK \l "bronchiolitis" Viral Pneumonias (HYPERLINK \l "bronchiolitis"RSV,  HYPERLINK "micro.doc" \l "adenovirus" adenovirus, parainfluenza, influenza,  HYPERLINK "micro.doc" \l "enterovirus" enteroviruses)  HYPERLINK \l "childhoodpneumonia" Bacterial Pneumonias (Pneumococcus, Mycoplasma, Hib,  HYPERLINK "micro.doc" \l "saureus" S.aureus,  HYPERLINK "micro.doc" \l "strepa" Strep A,  HYPERLINK "micro.doc" \l "strepb" Strep B,  HYPERLINK "micro.doc" \l "listeria" Listeria,  HYPERLINK "micro.doc" \l "chlamydia" Chlamydia)  HYPERLINK \l "viralmeningitis" Viral Meningitis (HSV, enterovirus)  HYPERLINK \l "bacterialmeningitis" Bacterial Meningitis HYPERLINK \l "childhooduti"Urinary Tract Infections HYPERLINK \l "diarrhea"Infectious Diarrhea  HYPERLINK \l "pedsepsis" Pediatric Sepsis Viral Diarrhea ( HYPERLINK "micro.doc" \l "rotavirus" Rotavirus,  HYPERLINK "micro.doc" \l "norwalk" Norwalk, etc) Bacterial Diarrhea ( HYPERLINK "micro.doc" \l "salmonella" Salmonella,  HYPERLINK "micro.doc" \l "shigella" Shigella,  HYPERLINK "micro.doc" \l "ecoli" E. Coli,  HYPERLINK "micro.doc" \l "vibrio" Vibrio,  HYPERLINK "micro.doc" \l "yersinia" Yersinia) and  HYPERLINK "micro.doc" \l "giardia" Giardia Childhood Exanthems (MMR Other Infectious ( HYPERLINK \l "endocarditis" Endocarditis, HPV, vulvovaginal,  HYPERLINK "micro.doc" \l "rmsf" RMSF, Lyme, scabies) Neonatal/Congenital ( HYPERLINK \l "pedimmune" Fetal Immune System) link to special congenital section in micro-bug  HYPERLINK \l "congenitalinfections" Congenital Infectious Disease (Toxoplasmosis,  HYPERLINK "micro.doc" \l "syphiliscongenital" Syphilis, Listeria, Coxsackie B, CMV,  HYPERLINK \l "hsv" HSV, Rubella, VZV, HIV, Chlamydia) Dermatologic Infections ( HYPERLINK \l "skin" see Skin) Sepsis in Children Uncommon in immunocompetent children over 3 months Organisms: Group B Strep (neonatal), gram negative enteric bacilli, Listeria, Enterococcus High fatality rate, GBS and Listeria can produce late onset meningitis H. influenza b, S. pneumoniae (asplenia, can produce nephrotic syndrome), N. meningitidis, S. aureus and Salmonella (sickle cell) are also possible, HIV patients get Pseudomonas Aeruginosa (ecthyma gangrenosum) / Coxsackievirus in neonates Treatment: kill microbes with antibiotics (drain foci if possible), hemodynamic stability, modulate inflammatory response (pentoxifylline, IL-1ra?) manage fluid and electrolyte balance: age adjusted MAP, skin appearance, peripheral perfusion, temperature, urinary output 100 / 50 / 20 maintenance fluid (10cc/kg bolus) + KCl HR increases 10 for each oF Prognosis: 25-35% for severe sepsis and 40-55% in septic shock die within 30 days Bacteremia in Children Fever over 38.5, usually  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus, usually self-limiting from 24-48 hrs Early Infancy loss of maternal IgG allows infection by Strep, Meningococcus, H. influenza, many viruses Pediatric HEENT Conjunctivitis ( HYPERLINK \l "Conjunctivitis" see optho) Lacrimal gland stenosis (most common) annoying for parents, must wipe tears Chlamydia Gonorrhea silver nitrate drops HYPERLINK "micro.doc" \l "hsv"HSV treat with F3T Older children common URI viruses, TSS / Treatment: erythromycin cream? Otitis Media Presentation: ear pain, fever (neither) 30% are viral, self-limited* 70% are  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus (33%),  HYPERLINK "micro.doc" \l "hinfluenza" H. influenza (20%),  HYPERLINK "micro.doc" \l "moraxella" Moraxella catarrhalis (6-10%) Complications: hearing loss, tympanosclerosis, cholesteatoma formation, chronic suppurative OM, meningitis Chronic Otitis Media usually caused by  HYPERLINK "micro.doc" \l "saureus" S. aureus,  HYPERLINK "micro.doc" \l "pseudomonas" Pseudomonas or other mixed, prophylaxis with sulfisoxazole or tympanostomy tube placement Treatment: PO amoxicillin or bactrim, may require  HYPERLINK "pharm.doc" \l "augmentin" Augmentin or 2nd or 3rd  HYPERLINK "pharm.doc" \l "cephalosporin" Cephalosporin or  HYPERLINK "pharm.doc" \l "macrolide" macrolide / can give topical anesthetic such as Auralgan (lidocaine) for pain *Sudden onset of bilateral sensorineural hearing loss - believed to be viral labyrinthitis with destruction of cochlea Otitis Externa (Malignant Otitis Externa) Usually in elderly diabetics / almost always Pseudomonas Sinusitis similar organisms as otitis media / higher incidence in CF, asthma, severe allergic rhinitis Clinical: fever, purulent rhinorrhea (10 days +), head banging in children Diagnosis: CTs are reliable when necessary (better than plain films) Ddx: postnasal drip (see below), asthma,  HYPERLINK \l "gerd" GERD Complications: osteitis, bony erosion, optic neuritis, orbital cellulitis, intracranial extension Treatment: similar to otitis media (14-21 day course or until symptoms resolve plus 3 days) / can require surgical drainage / can give decongestants (repeated uses of local phenylephrine produces rhinitis medicamentosum) Nasal polyps usually ethmoid sinus / associated with severe allergic rhinitis, cystic fibrosis and asthma (50% of asthmatics with aspirin sensitivity) Treatment: medications or surgery (high recurrence rate) Postnasal drip Treatment: try antihistamines, decongestants then nasal steroids Herpangina Presentation: high fever and sore throat, progress to tender, vesicular lesions (which form bullae then ulcers) [ HYPERLINK "pics/herpangina-lips.jpg" pic] / additional lesions garner title of hand, foot and mouth disease (dorsum of hands [HYPERLINK "pics/herpangina-hand.jpg"pic]; 1/3 also have rash on feet [HYPERLINK "pics/herpangina-foot.jpg"pic]) Organisms:  HYPERLINK "micro.doc" \l "enterovirus" enteroviruses (coxsackie A16 and enterovirus 71) Treatment: usually self-limited to 5-7 days Differential: primary herpetic gingivostomatitis Streptococcal Pharyngitis Organism: Group A Streptococcus Presentation: non-throat symptoms may include nausea and abdominal pain, viral signs of rhinorrhea and coughing are absent, scarlet fever (scarlitiniform or sandpaper-like rash appears on neck and trunk, then extremities, caused by toxin) [ HYPERLINK "http://dermis.net/dermisroot/en/10181/diagnose.htm" dermis] Note: Strep A in < 1 yr presents with fever, rhinorrhea and NOT pharyngitis Diagnosis: if 3 of 4 (fever, exudate, adenopathy, absence of cough) present, do rapid antigen test (may have some false negatives, cannot distinguish acute vs. chronic carriage), but consider culture if clinical suspicion very high / rapid strep 85% sensitive Differential: HYPERLINK "micro.doc" \l "mycoplasma"mycoplasma pharyngitis, viral pharyngitis,  HYPERLINK \l "ebv" infectious mononucleosis Complications: suppurative (peritonsillar abscess, retropharyngeal abscess), non-suppurative ( HYPERLINK \l "rheumaticfever" rheumatic fever (3-4 weeks),  HYPERLINK \l "psgn" PSGN (10 days) Spread by oral secretions, usually 3 yrs to adolescent Treatment: 10 day course of penicillin (amoxicillin, erythromycin); treatment typically shortens course of pharyngitis by only 1-2 days and shortens period of infectivity; treatment does not prevent development of PSGN; no known resistance of GAS to PCN Infectious Mononucleosis ( HYPERLINK \l "ebv" see EBV) Epiglottitis Common in children 6 months - 5 yrs and elderly (peak at 3-5 years, common up to 7 yrs) Causes: usually  HYPERLINK "micro.doc" \l "hinfluenza" H. influenza, and uncommonly HYPERLINK "micro.doc" \l "pneumococcus" HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus and  HYPERLINK "micro.doc" \l "strepa" Group A Streptococcus Course: fever, soar throat, hoarseness, and stridor develop over 1-2 days Clinical: toxic appearing, tachypneic, leaning forward, neck extended, drooling CXR: lateral neck films more helpful ( steeple sign (narrowed airway), thumbprint sign NOTE: dont agitate throat or you might induce laryngospasm Differential Diagnosis: similar to  HYPERLINK \l "croup" Croup Treatment: transport to ER for intubation under anesthesia, IV HYPERLINK "pharm.doc" \l "cefuroxime"Cefuroxime / cefotaxime while awaiting blood and throat cultures Respiratory Infections in Children RSV Bronchiolitis (Respiratory Syncytial Virus) Note: now acknowledged to be equal to influenza A in presentation/incidence/mortality in elderly and high-risk adult patient population 9/06 Leading cause of hospitalizations among all infectious agents (1% mortality) Most children infected once by 3 years old, recurrent infections common Most severe in infants 2 to 6 months old and/or underlying heart or lung disease Transmission: epidemics in winter and early spring, spread by secretions and fomites (some patients shed up to 20 days) Pathology: epithelial cell disruption, loss of cilia, disruption of neural control of airways (adrenergic mechanisms, cholinergic, ?noradrenergic?), CMI is important in clearing virus PE: fever and tachypnea CXR: air trapping, atelectasis Labs: rapid antigen testing or culture from nasal secretions Differential Diagnosis: HYPERLINK "micro.doc" \l "influenza"influenza, HYPERLINK "micro.doc" \l "parainfluenza"parainfluenza, HYPERLINK "micro.doc" \l "rhinovirus"rhinovirus, reactive airway disease (may mimic wheezing of RSV bronchiolitis) Treatment: outpatient with O2 saturation above 94%, bronchodilators and corticosteroids use is controversial,  HYPERLINK "micro.doc" \l "parainfluenza" Ribavirin may shorten duration (efficacy remains unclear), Synagis (Palivizumab) is a human IgG now recommended for high risk prophylaxis (given with heart or lung disease) Croup (Parainfluenza) Parainfluenza accounts for 4.3-22% of childhood respiratory illness (more on  HYPERLINK "micro.doc" \l "parainfluenza" parainfluenza) Presentation: fever, chills, hoarseness, barking cough (dry), inspiratory stridor, extrapulmonary symptoms Incubation: 3-6 days (maybe less) Course: onset is either sudden (overnight) or gradual (1-2 days) Mild Croup: acute, febrile illness, most children recover in 1-2 days (no hospitalization) Severe croup: continued fever, coryza, sore throat, may progress to severe stridor with tachypnea, wheezing, intercostal retractions Complications:  HYPERLINK \l "tracheitis" bacterial tracheitis, bronchiolitis or pneumonia / acute or chronic (airway fluoroscopy (probably more practical than ultrasound) Diagnosis: clinical findings, can sometimes be distinguished from epiglottitis using chest radiography, but direct laryngoscopy is definitive, PE: nasopharyngeal discharge, oropharyngeal injection, rhonchi, wheezes, coarse breath sounds CXR: air trapping, interstitial infiltrates, edema, fixation of chords, functional narrowing of glottis, sucks tracheal walls in on inspiration, Steepling sign (edema rounding out vocal cords also may be seen with congenital or vocal cord paralysis Differential Diagnosis: Influenza A (winter), RSV (young, immunocompromised), measles, VZV, epiglottitis from H influenza (type b), foreign body aspiration, severe food allergy, angioneurotic edema Treatment: treat secondary bacterial pneumonia acute respiratory distress: humidified O2, epinephrine, systemic glucocorticoids may help HYPERLINK "pharm.doc" \l "ribavirin"Ribavirin under investigation, effective vaccine not yet developed Bacterial tracheitis H. influenza super-infection following croup Findings: normal epiglottis, subglottal narrowing (but only visible from lateral view) (view of tracheal bifurcation on HYPERLINK "more/endoscopy\\mi_tr_01.htm"endoscopy) Pertussis (Whooping Cough) Organism: HYPERLINK "micro.doc" \l "pertussis"B. pertussis Catarrhal phase: 1 to 2 weeks of low-grade fever, cough, coryza Paroxysmal phase: 3 to 8 weeks of whooping cough, stridor, emesis Convalescent phase: 3 to 12 months Presentation: more severe in infants (may not have whoop), usu. have post-tussive emesis Treatment: HYPERLINK "pharm.doc" \l "erythromycin"Erythromycin useful in catarrhal phase (given in paroxysmal phase anyway to reduce duration of infectivity) Labs: WBCs over 30,000 (high lymphocyte fraction) / fluorescent antibody staining or culture (requires special medium) HYPERLINK \l "dtap"Vaccine: 95% effective in preventing severe disease, 1/3 experience mild infections anyway Bacterial Pneumonia in Children [HYPERLINK "micro.doc" \l "agepneumonia"age breakdown] Up to 50% have concurrent viral infection Etiology remains elusive in 1/3 of cases (no sputum, blood negative, no pleural fluid?) Risk Factors: BPD, CF, CNS impairment, GE reflux/aspiration, anatomical defects, hemoglobinopathies, immunodeficiencies Presentation: Typical sudden, fever, cough, sputum, chest pain, consolidation S. pneumo, H. influenza, mixed anaerobic and aerobic Atypical gradual, dry cough, extrapulmonary symptoms, CXR abnormalities despite minimal signs on physical exam Physical Exam: dullness to percussion, decreased breath sounds indicates bacteria (not always prominent) / crackles, wheezing, rales indicates virus or mycoplasma, cyanosis only in severe disease Labs: WBC over 15,000 might be a cause for concern about bacteremia Differential Diagnosis: congestive heart failure, chemical pneumonitis, pulmonary embolism, some connective tissue disorders, malignancy Radiology: pleural effusions (severe cases) or mild pleural effusions (mycoplasma), consolidation (bacterial), aspiration (right middle, upper), streaky interstitial (viral)  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus primary cause in previously healthy patients  HYPERLINK "micro.doc" \l "mpneumoniae" Mycoplasma common cause in children (over 5 years) and adults HYPERLINK "micro.doc" \l "chlamydia"Chlamydia usually presents 2 to 3 months after birth due to maternal HYPERLINK "micro.doc" \l "trachomatis"C. trachomatis Complications: pleural effusion, empyema, lung abscess (anaerobic, type 3 pneumo) Treatment: HYPERLINK "pharm.doc" \l "cefuroxime"Cefuroxime or penicillin given IV for bacteria Augmentin or 2/3rd generation cephalosporin for H. influenza and S. aureus (B-lactamase)  HYPERLINK "pharm.doc" \l "macrolides" Macrolides for Mycoplasma or Chlamydia (HYPERLINK "pharm.doc" \l "erythromycin"Erythromycin has poor activity against H. influenza; Azithromycin and Clarithromycin better Misc: H. influenza can cause bronchiectasis Parainfluenza: IgA, IgG, cell-mediated all implicated HIV/Leukemia pseudomonas and S. aureus / PCP Bacterial Meningitis in Children (HYPERLINK \l "meningitis"see adult) Most common at 6 to 12 months CSF leak (otorrhea, rhinorrhea following trauma, pneumococcus, Hib) Presentation: usually no prodrome, very high fever (60%), may have mental status changes, ataxia, seizures, shock Physical Exam: bulging fontanelle (28%), jaundice (38%), cranial nerve palsies, papilledema (increased ICP), nuchal rigidity (15%), diarrhea (17%), positive Kernigs (flex hip, pain on extension) and Brudzinskis (leg flexion on passive neck flexion), subdural effusion (rarely fatal), facial cellulitis (10% also have meningitis, usu. Hib), widespread purpuric skin lesions with  HYPERLINK "micro.doc" \l "nmeningitis"  HYPERLINK "micro.doc" \l "nmeningitis" N. menigitidis [HYPERLINK "pics/purpurafulminans.gif"purpura fulminans] Causative Agents: Neonatal: HYPERLINK "micro.doc" \l "strepb"Group B Strep (and preemies longer), HYPERLINK "micro.doc" \l "ecoli"E. coli,  HYPERLINK "micro.doc" \l "listeria" Listeria, citrobacter Children/adult:  HYPERLINK "micro.doc" \l "pneumococcus" Pneumococcus, HYPERLINK "micro.doc" \l "hinfluenza"H. influenza,  HYPERLINK "micro.doc" \l "nmeningitis" N. meningitidis / E. coli, Klebsiella, Listeria, Enterococcus, Salmonella Basilar meningitis (ataxia, incontinence): TB, fungal, Listeria, syphilis, sarcoid Post-surgical: S. aureus and another one? Treatment: please see pediatric reference Urinary Tract Infections in children Klebsiella, E. coli, enterobacter, Enterococcus, proteus, S. aureus Congenital Infectious Diseases  HYPERLINK "micro.doc" \l "toxoplasma" Toxoplasmosis ~20% mortality / periventricular lesions (vasculitis, fibrosis, calcification) leptomeningitis, myocarditis, eye lesions / pseudocysts (organisms at edge of necrosis) Treatment: bactrim Listeriosis (see micro) generalized granulomatous response / meningitis CMV (see micro) Acquired: to 2 yrs / very common, low mortality, many have maternal Abs already Congenital: cytomegalic inclusion disease (CID) - thrombocytopenia, purpura, hemolysis, jaundice, low birth weight, HSM, cerebral calcifications / causes microcephaly, blindness, retardation Coxsackie B (see micro) newborns - myocarditis, encephalopathy mature patients (relatively mild disease) - pleurodynia, meningitis, pericarditis HSV (see micro) jaundice, thrombocytopenia, pneumonia, meningitis, encephalitis hepatic, adrenal necrosis w/ intranuclear inclusions Pneumocystis carinii (immunocompromised infants) (see micro) foamy, eosinophilic pulmonary infiltrate / minute bodies (little Oreos on GMS stain) / premature, failure to thrive, immune disorders / Treatment: bactrim Congenital Rubella (see micro) growth retardation, cardiovascular malformations (A-V septal defects, patent ductus, pulmonary arterial stenosis) / scarring in liver, lungs, brain / arteriolosclerosis / blindness, deafness, myocardial, liver necrosis / bone malformation / placental infection Childhood Exanthems ( HYPERLINK "micro.doc" \l "exanthems" see micro)  HYPERLINK "micro.doc" \l "measles" Measles (Rubeola) Kopliks spots / can cause pneumonia, encephalitis (1:1000) Mumps parotitis, orchitis, pancreatitis German Measles (Rubella) morbilliform exanthem / congenital rubella Chicken Pox (VZV) Tzanck / shingles Fifth (B-19) slapped face / congenital can be fatal Roseola ( HYPERLINK "micro.doc" \l "hhv6" HHV-6) fever, rash Other Infectious Causing Exanthems Diptheria pseudomembrane / myocardial damage Hepatitis ( HYPERLINK "micro.doc" \l "hepatitis" see micro) Herpes Pelvic Inflammatory Disease Human Papillomavirus Vulvovaginal Infections HIV and AIDS in children Rocky Mountain Spotted Fever Lyme Disease Opportunistic infections  HYPERLINK "micro.doc" \l "mtb" MTB < 400 INH, clarithromycin, rifampin or see ( HYPERLINK "pharm.doc" \l "hrze" HRZE)  HYPERLINK "micro.doc" \l "pcp" Pneumocystis carinii < 200 bactrim / pentamidine / dapsone  HYPERLINK "micro.doc" \l "toxoplasmosis" Toxoplasmosis < 200 TMP/SMX  HYPERLINK "micro.doc" \l "cryptococcus" Cryptococcus neoformans < 100 amphotericin B / fluconazole  HYPERLINK "micro.doc" \l "cmv" CMV < 50 ganciclovir, foscarnet  HYPERLINK "micro.doc" \l "mai" MAI < 50 ethambutol, macrolide / may add aminoglycoside  HYPERLINK "micro.doc" \l "hbv" HBV (HYPERLINK "pharm.doc#hbv" \l "hbv"vaccine available) interferon alpha / protease inhibitors  HYPERLINK "micro.doc" \l "candida" Candida Splenectomy Reasons: Hodgkins, agnogenic myeloid metaplasia,  HYPERLINK \l "pnh" PNH, hereditary spherocytosis, thalassemia, and a variety of autoimmune disorders Increased risk for: S. pneumoniae, H. influenzae, Salmonella, Neisseria sp,  HYPERLINK "micro.doc" \l "df2" DF2 Note: must be vigilant about early (on the way to being overwhelming) sepsis even when only sign is fever Gastrointestinal [HYPERLINK "ddx.doc" \l "abdominalpain"Abdominal Pain] [ HYPERLINK \l "diarrhea" Diarrhea] [ HYPERLINK "ddx.doc" \l "gibleed" GI Bleed Ddx]  HYPERLINK \l "oral" Oral /  HYPERLINK \l "salivary" Salivary  HYPERLINK \l "esophagus" Esophagus  HYPERLINK \l "givarices" varices, HYPERLINK \l "zenkers"diverticula, HYPERLINK \l "esophagealwebs"webs/ HYPERLINK \l "esophagealrings" rings,  HYPERLINK \l "hernias" hernias,  HYPERLINK \l "esophagealinjury" burns/tears/infections  HYPERLINK \l "gerd" GERD,  HYPERLINK \l "achalasia" achalasia,  HYPERLINK \l "transferdysphagia" transfer dysphagia,  HYPERLINK \l "sdes" SDES,  HYPERLINK \l "sclerodermaesophagus" scleroderma,  HYPERLINK \l "esophagealcancer" esophageal cancer  HYPERLINK \l "stomach" Stomach  HYPERLINK \l "pud" PUD,  HYPERLINK \l "gastricvarices" gastric varices,  HYPERLINK \l "gastriccarcinoma" gastric carcinoma,  HYPERLINK \l "gastriclymphoma" gastric lymphoma  HYPERLINK \l "pancreas" Pancreas  HYPERLINK \l "liver" Liver  HYPERLINK \l "gallbladder" Gall Bladder  HYPERLINK \l "appendix" Appendix  HYPERLINK \l "peritoneum" Peritoneum  HYPERLINK \l "intestine" Small and Large Intestine  HYPERLINK \l "pedintestinal" Congenital Malformations Meckels, Hirschprungs, etc.  HYPERLINK \l "intestinevascular" Vascular  HYPERLINK \l "varices" Varices,  HYPERLINK \l "mesentericischemia" Ischemic Bowel Disease, HYPERLINK \l "avmintestinal"AVMs  HYPERLINK \l "diverticulitis" Diverticulitis  HYPERLINK \l "diarrhea" Diarrhea  HYPERLINK \l "ibd"  HYPERLINK \l "ibd" IBD  HYPERLINK \l "crohns" Crohns,  HYPERLINK \l "uc" ulcerative colitis  HYPERLINK \l "malabsorption" Malabsorption  HYPERLINK \l "celiacsprue" celiac disease,  HYPERLINK \l "whipples" Whipples, bacterial overgrowth, lactase deficiency  HYPERLINK \l "obstructions" Obstruction  HYPERLINK \l "intestinetumor" Tumors  HYPERLINK "#colonca" Colon Cancer,  HYPERLINK \l "fap" FAP,  HYPERLINK \l "carcinoidtumors" carcinoid,  HYPERLINK \l "gilymphoma" GI lymphoma [GI surgery] Abdominal Pain Work-up Rectal Exam always check internal/external hemorrhoids / can get idea of whether there is melena, hematochezia and grossly positive stool guaiac (but weakly positive could just be from performing exam itself) Fecal Occult Blood False positives: obtained by rectal exam (false positive due to trauma), red meat (has blood in it), ASA and NSAIDs cause non-malignant GI bleed, iron may darken test card, rehydration of card increases sensitivity but decreases specificity False negatives: peroxidase containing vegetables (cauliflower) interfere with peroxide developer, vitamin C Abdominal plain film (KUB) free air (perforation), bowel obstruction (distension: small > 2.5 cm, large > 9-10 cm), edema (infarction), renal stones (80% sensitivity), gall stones (15% sensitivity) Abdominal CT pancreatitis, diverticulitis, splenic rupture/laceration, bowel ischemia (edema) / examples: [HYPERLINK "pics/paracolicabscess-ct.jpg"paracolic abscess] Ultrasound abdominal aortic aneurysm, dilated ureter (nephrolithiasis), cholecystitis, appendicitis Colonoscopy may or may not be needed to make diagnosis / normal appearing colon [HYPERLINK "pics/normal-colon.jpg"pic] Labs dont forget hCG to rule out pregnancy Antibiotics: take blood cultures and start empirically pip/tazo ( better if Enterococcus involved cefepime/flagyl ( better if pen allergic or C. diff suspected Diarrhea [HYPERLINK "ddx.doc" \l "diarrhea"Ddx] History Tenderness, fever, wt loss ( IBD, neoplasm, amebiasis, Tb Wt loss despite good appetite ( malabsorption, hyperthyroid LLQ ( diverticulitis Bloody diarrhea ( HUS, TTP, 0157:H7, Shigella, mesenteric ischemia Diarrhea + PUD ( gastrinoma Arthritis ( IBD, Whipples Physical Flushing, bronchospasm ( carcinoid Arthritis, iritis, uveitis, erythema nodosum ( IBD Abdominal mass ( cancer, diverticular abscess, IBD Fever ( infectious, IBD, lymphoma Lymphadenopathy ( neoplasm/lymphoma, Tb, AIDS, Whipples Sx of hyperthyroidism ( hyperthyroidism Labs Occult blood Fecal WBC SSYC (and O157:H7) +/- N. gonorrhea O&P +/- E. histolytica C. difficile Cryptosporidium, Giardia ESR, CRP Hep A, Legionella Ur Ag Stool fat, Stool Osm ( HYPERLINK \l "stoolosmolality" see below) Fe, folate,  HYPERLINK \l "b12" B12, HYPERLINK \l "vitaminK"vitamin K,  HYPERLINK \l "vitamind" vitamin D Serum 5HT, urine 5HIAA, serum gastrin, VIP TSH, A1C Calcitonin, somatostatin, histamine, PG 24 hour stool protein Stool SO4 , PO4, Mg (and others) to detect factitious diarrheas H2 breath test (lactase or pancreatic deficiency, small intestinal mucosal Dz, bacterial overgrowth) Stool Osmotic Gap = Stool Osmolality (normal 290) 2 [StoolNa + StoolK] >125 ( caused by osmotically active particles (laxatives, sorbitol-containing foods, meds) No gap ( hyperthyroid, IBD, sprue, etc. Markers of intestinal inflammation  HYPERLINK "labs.doc" \l "inr" INR raised by vitamin K Malabsorption  HYPERLINK "labs.doc" \l "alkalinephosphatase" Alk phos elevated by vitamin D malabsorption  HYPERLINK "labs.doc" \l "albumin" Albumin lowered by malabsorptive/protein losing inflammation Stool a1-AT raised by malabsorptive/protein losing inflammation ESR/CRP Radiography (in general, not that helpful for watery diarrhea) KUB obstruction, toxic megacolon, pancreatic calcifications, mesenteric ischemia (esp. w/ perforation) UGI Series previous surgery, fistulas, blind loops, strictures, abnormal motility Wall thickening Uniform thickening ( amyloidosis, lymphoma, Whipples Uniform or patchy ( lymphoma Sprue may show characteristic small bowel dilatation Tagged WBC scan can sometimes detect IBD not seen on endoscopy Endoscopy Malabsorption or Steatorrhea? EGD w/ duodenal biopsy ( malabsorption (Whipples, Sprue, etc) Severe watery or elusive diarrhea? Colonoscopy to rule out villous adenoma, microscopic or collagenous colitis, mastocytosis, IBD (terminal ileum is best) Treatment of Acute Infectious Diarrhea 1st FQ (macrolides for Campylobacter) / 2nd bactrim / 3rd tetracycline or metronidazole Note: Campylobacter often resistant (must use macrolide)FQ and Bactrim Do Treat: Shigella, Salmonella, Yersinia, Campylobacter, cholera, travelers diarrhea = E. coli (ETEC not 0157:H7), pseudomembranous enterocolitis (C. difficile), parasites, sexually transmitted (N. gonorrhea) Do not treat: viral diarrhea, cryptosporidiosis (because it doesnt help) or E. coli 0157:H7 (because it may increase incidence of HUS) Exceptions: immunocompromised, very young, very old, prosthetic + (valvular, vascular, orthopedic), congenital hemolytic anemias Travelers diarrhea ETEC (50% in Latin America, 15% in Asia) / Mexico (ETEC > E. histolytica and V. cholerae / Campylobacter more common in Asia and in winter in subtropics / Giardia common in Northern American wilderness and in Russia General Treatment of Diarrhea Bulk-forming agents cholestyramine useful with bile acid diarrhea but can worsen fatty acid malabsorption by depleting bile salt pool Medium-chain fatty acids for short gut syndrome Anti-peristaltics: bismuth salicylates, opiates*, loperamide, clonidine**, PZ, SS Good for reabsorption Bad for assessing fluid replacement needs (fluids trapped in intestine) Bad because stasis may enhance bacterial invasion and delay clearance opiates can precipitate megacolon in IBD ** clonidine good for HYPERLINK "pharm.doc" \l "opioidwithdrawal"opiate withdrawal and diabetic diarrhea (sometimes) Somatostatin (Octreotide) Good for carcinoid syndrome and neuroendocrine tumors NSAIDs* Always ( acute radiation, AIDS, and villous adenomas Sometimes ( neuroendocrine tumors, irritable bowel, food allergy may be harmful in IBD Steroids IBD et al. Note: if no diagnosis made and diarrhea persists, can give empiric trial of FQ or bactrim or metronidazole or tetracycline Oral cavity Infectious origin HSV Syphilis Candida [HYPERLINK "pics/oralcandidiasis.jpg"pic] Histoplasmosis Oral hairy leukoplakia [HYPERLINK "pics/oralhairyleukoplakia.jpg"pic] hyperkeratotic thick tongue / lesions are more lateral tongue (usu. not involving other parts of oral mucosa) / precancerous lesion, requires biopsy (homogeneous and non-homogeneous; homogeneous more likely malignant) / associated with EBV / respond to high-dose acyclovir / may recur after treatment / may have super-imposed Candida (esp. in HIV patients) Ddx: smokers leukoplakia, erythroplakia (SCC), candida, warts Immunologic dysfunction aphthous ulcers chancre sores / tiny ulcers in mouth  HYPERLINK \l "behcets" Behets syndrome mouth, GU ulcers  HYPERLINK \l "reiters" Reiters arthritis, urethritis, conjunctivitis, oral ulcers  HYPERLINK \l "sle" SLE can produce oral lesions Systemic disease hypertrophic gingiva scurvy, pregnancy, leukemia, polycythemia oral pigmentation melanotic -  HYPERLINK \l "peutzjeghers" Peutz-Jeghers, Addisons Disease heavy metals dark line along gingival margin / lead (blue), bismuth (gray), mercury (purplish) enlarged tongue cretinism or amyloidosis atrophic tongue loss of papillae, atrophic glossitis / vitamin B or iron deficiency [HYPERLINK "pics/glossitis1.jpg"pic][HYPERLINK "pics/glossitis2.jpg"pic] xerostomia Sjogrens (destruction of salivary, lacrimal, conjunctival) / lymphocytic and plasma cell infiltrate / radiation therapy / anticholinergic agents Malignancies mature to old white men / multiple primary lesions / precursor lesions are leukoplakia (white) and erythroplakia (red) carcinoma of lip (better) lower lip / wedge resection, irradiation, nodal dissection if necessary carcinoma of mouth (worse) aggressive / resection, irradiation, dissection / tongue (worse), cheek (better) verrucous carcinoma large, fungating / tobacco / slow growth, locally aggressive, recurs Salivary glands Sialoadenitis mumps, Sjogrens, Mikuliczs (salivary, lacrimal inflammation w/ xerostomia), stones Pleomorphic adenoma (benign mixed tumor) most common / benign / superficial parotid / painless, movable / epithelial and myoepithelial proliferation / pseudopodia extend into surrounding / parenchyma complete excision / malignant transformation uncommon monomorphic adenoma only epithelial proliferation Warthins tumor (papillary cystadenoma lymphomatosum) smoking / parotid gland / second most common / double layer of columnar over lymphoid tissue 10% multicentric or bilateral malignant 20% of salivary gland tumors / most arise de novo (not from benign tumors) Adenoid cystic carcinoma (worse) common / all gland types / nests or cords / invades perineural spaces Mucoepidermoid carcinoma (variable) common / all gland types / children / radiation induced / mucous and epidermoid cell mixture Acinic cell carcinoma (variable) uncommon / usually parotid / females 2:1 / sheets of acinic cells / 7th nerve involvement resection, frequent recurrence Esophagus Congenital atresia with fistula Pulsion diverticulum false diverticulum from mucosal weakness / Zenkers diverticulum (hypopharynx esophagus junction) / obstruction may result from incomplete emptying / only large ones treated surgically Traction diverticulum adherence to mediastinal structures / mid-distal esophagus / associated with inflammation (Tb, etc.) Epiphrenic diverticulum Distal esophagus above LES / usually asymptomatic Esophageal Webs upper 1/3 / may be associated with  HYPERLINK \l "plummer" Plummer-Vinson (Paterson-Kelly) Esophageal Rings Schatzkis rings occur mainly at squamocolumnar junction Hernias Sliding most common / congenital predisposition / hiatal junction / increases with age Paraesophageal pouch of stomach alongside esophagus / more likely to strangulate, hemorrhage Esophageal injury iatrogenic, chemical (corrosives, KCl, doxycycline, Fosamax), infection, radiation, neoplasm, mechanical injury Burns: give steroids and broad spectrum antibiotics / increased risk of stricture, carcinoma Tears: Boerhaaves spontaneous rupture surgical emergency Mallory-Weiss mechanical injury from forceful emesis / initial nonbloody vomitus followed by hematemesis (surgery required in 10%) Infections: Candida diabetic, immunocompromised, poor emptying / odynophagia / nystatin, ketoconazole, fluconazole, (resistant cases amphotericin B) HSV immunocompromised / acyclovir CMV large ulcerations / ganciclovir HIV treat with steroids Pill Esophagitis Aspirin, NSAIDS, KCl, Fe, quinidine, antibiotics (may cause erosions/strictures) GERD (Gastroesophageal Reflux Disease) General: prevalence roughly 30-40% Presentation: heartburn (pyrosis) and regurgitation; atypical ( chest pain, dysphagia, water brash, globus (constant sensation of lump in throat), odynophagia (suggests ulcer or severe esophagitis), hoarseness, nausea (sometimes responds to acid suppression) Extraesophageal manifestations: asthma (GERD exacerbates, does not cause asthma), chronic cough, nocturnal cough, sinusitis, pneumonitis, laryngitis, hoarseness, hiccups, dental disease Complications: peptic stricture,  HYPERLINK \l "barretts" Barretts esophagus Ddx: cardiac, esophageal neoplasm, infectious esophagitis, NSAID-induced, caustic exposure, pill esophagitis, esophageal hypersensitivity (visceral hyperalgesia), achalasia, esophageal motility disorder, stricture, gastritis, eosinophilic gastroenteritis, peptic ulcer disease, non-ulcer dyspepsia, hepatobiliary disease, cholelithiasis, bile acid reflux Diagnosis: therapeutic trial of PPI (sensitivity ~80%); this is the more popular, cost-effective and easiest method esophageal pH monitoring (sensitivity 60-100%); to evaluate equivocal endoscopic findings on patients refractory to PPI (i.e. to see why the PPI isnt working, still sure of the diagnosis do while on PPI) or with atypical symptoms and need for diagnosis; when considering anti-reflux surgery with negative endoscopy (i.e. you want to do surgery but have to prove the pt really has GERD, do while off PPI x 1 wk) double contrast barium swallow (sensitivity 25%) Indications for endoscopy: dysphagia/odynophagia, refractory to therapy, immunocompromised, presence of mass, stricture or ulcer on barium study, GI bleeding or iron deficiency anemia, screening for Barretts after 5 yrs of symptoms (especially white men > 45; prevalence of Barretts similar with or without GERD symptoms (1-2%) Treatment: antacids, H2 blockers (50% effective),  HYPERLINK "pharm.doc" \l "ppi" proton pump inhibitors (80% effective, BID dosing may make a difference, switching agents have been reported to make a difference) can also try  HYPERLINK "pharm.doc" \l "reglan" metoclopramide surgery / post-op complications include perforation, acute gastric herniation (<1%) Note: may take 2-3 months to achieve resolution even with correct treatment / there is discussion over whether medical management only treats the symptoms and does not prevent the risks of esophageal cancer Achalasia Primary causes: idiopathic LES dysfunction, Chagas disease Epidemiology: 20 to 40 yrs / 1 in 20-100,000 in U.S. (30-50s) Pathology: degeneration of Auerbachs plexus, Wallerian degeneration of vagus, and dorsal vagal nucleus / supersensitivity to cholinergics and gastrin ( tonic narrowing of LES Presentation: dysphagia for solids/liquids, weight loss (90%), severe chest pain (60%), nocturnal cough (30%), recurrent bronchitis, pneumonia (8%) Diagnosis: r/o carcinoma (secondary achalasia) Radiography: beak-like tapering over LES (birds beak) Manometry: absence of peristalsis, elevated LES pressure, incomplete LES relaxation (although there is a rare form of vigorous achalasia with large-amplitude prolonged contractions Treatment: Drugs: nitrates, anticholinergics, -agonists, Ca channel blockers are 50% effective prostaglandins under investigation Pneumatic dilation 70-90% effective (0.2% mortality, 2-3% perforation) Endoscopic injection of botulinum toxin helpful in 70-80% Heller myotomy 65-90% success rate (3-4% complications) / increased reflux years later in 25-30% Endoscopic myotomy under investigation Transfer Dysphagia CVA (transient brainstem edema), myasthenia gravis, myotonic dystrophy, polymyositis, bulbar poliomyelitis, Parkinsons disease, multiple sclerosis, amyotrophic lateral sclerosis, hypothyroidism Diffuse Esophageal Spasm (SDES) Primary idiopathic or secondary (collagen vascular disease, radiation, diabetes) Presentation: dysphagia, odynophagia (esp. after hot or cold liquid/solid), spontaneous chest pain (actually relieved by nitroglycerin) Diagnosis: radiography corkscrew-shaped esophagus esophageal manometry 30% of basal state with spastic contractions / nutcracker esophagus (contractions associated with chest pain) 30% with incomplete LES relaxation / some normal contractions present balloon distension of lumen lower threshold of pain upon insufflation Treatment: 50% success rate with anticholinergics, nitrates, calcium channel blockers, bougienage, hydralazine (decreases amplitude), surgery in severe cases (longitudinal myotomy) Scleroderma ( HYPERLINK \l "scleroderma" see connective tissue) Pathology: early neural degeneration / late atrophy of circular smooth muscle Clinical findings: dysphagia, severe reflux/heartburn (50%), stricture (25%) Radiography poor emptying Manometry decreased LES pressure / weak contractions in distal 2/3 Treatment: anti-reflux therapy Esophageal Cancer (very bad prognosis) Epidemiology: male 4:1 / blacks 4:1 / incidence in U.S. 1 in 25,000 whites (50-70 yrs) / 1 in 8,000 blacks / worst in China and Iran / almost always malignant / esophagus has NO serosa / currently, in US, 50% adenocarcinoma, 50% squamous cell Risk Factors: alcohol, smoking, GERD (Barretts esophagitis; 10% risk, endoscopy q 2-3 yrs), hot liquids, burns, radiation, malnutrition (vitamin A and C deficiency), nitrosamines, burns (lye ingestion), achalasia (10% risk), Tylosis (hyperkeratosis of palms, soles; 80% develop squamous cell Ca of esophagus),  HYPERLINK \l "celiacsprue" celiac sprue, Plummer-Vinson syndrome Presentation: progressive dysphagia (1.2 cm narrowing), pain (extension beyond esophagus), dysphagia for liquids, cough, hoarseness, weight loss signify advanced esophageal cancer Diagnosis: barium swallow, endoscopy (90% sensitive; down to 1 cm), CT and bronchoscopy Treatment: surgery for distal lesions 5 yrs survival only 5-10%, radiotherapy for proximal lesions, stent placement or bougienage, laser therapy, chemotherapy regimens under investigation (currently no strong evidence for using chemotherapy in esophageal cancer 5/00) Complications: ruptured esophagus( thoracotomy and repair / antibiotics gastrograffin study later / 50% die if untreated / avoid mediastinitis, pneumomediastinum and pneumothorax Stomach [HYPERLINK "pics/stomach.gif"diagram] Physiology body chief cells pepsinogen body - parietal H+ ions / IF? antrum - G-cells gastrin solids empty in 2 phases over 3-4 hrs / initial lag period while particles broken to 2 mm or less followed by period of constant emptying Congenital Diaphragmatic hernias usually on the left Pyloric stenosis congenital hypertrophic pyloric stenosis - multifactorial / projectile vomiting / 1 in 300 acquired pyloric stenosis - gastritis, peptic ulcer, cancer Gastritis Acute gastritis NSAIDS, alcohol, chemo, infection, smoking, uremia, ischemia, mech. injury, etc. superficial erosion / may result in severe hemorrhage Chronic gastritis type A uncommon patchy autoimmune disease / occurs in body-fundus mucosa / 50% prevalence in elderly / associated with  HYPERLINK \l "pernicious" pernicious anemia, achlorhydria Risk factors: alcohol/smoking, antrectomy, radiation, granulomatous disease, etc. Pathology: regenerative change, metaplasia (glands become more antral/intestinal), atrophy (flattening, loss of glands) Complications: MAG and DCAG lead to Ca in situ type B common H. pylori (antral mucosa) / not invasive, Giemsa or Warthin-Starry stain, serum Ab, urease in biopsy, histology/culture, breath test diffuse (DAG) only antrum / 50% over 60 population multifocal (MAG) intestinal metaplasia / hypochlorhydria Diffuse corporal atrophic gastritis (DCAG) antibodies directed against parietal cells / 10% get pernicious anemia / increased gastrin Gastric Ulceration (PUD) Do not have to biopsy if it heals with medical management Elective surgery for outlet obstruction, hypochloremia, hyponatremia Reactive (erosive) gastropathy has not yet perforated muscularis / requires pepsin and acid secretion Risk Factors: NSAID, smoking, alcohol, corticosteroids, stress, H. pylori (30-60% of non-NSAID-related gastric ulcers) ( HYPERLINK \l "hpylori" see below) Acute gastric ulceration penetration of muscularis / requires gastric acid / shock, burns (Curlings), sepsis, trauma, acidosis, CNS-mediated from ICP and hypothalamic changes (Cushings) / more severe version of acute gastritis / multiple lesions in any location / scarring and vessel thickening absent / 5 - 10 % of all ICU patients / radiating mucosal folds, sloping distal margin (benign) shock ulcers mostly fundus / bleed but do not penetrate Treatment: endoscopic coagulation, surgery (ligation or gastrectomy +/- vagotomy) Cushings ulcer (increased H+ secretion) solitary, antral, deep / may perforate Chronic peptic ulcer 5-10% lifetime incidence / DU more common, younger, (type O, nonsecretors, HLA B5), rapid gastric emptying, increased acid H. pylori colonizes duodenum in areas of gastric metaplasia / can synergize with NSAID to create DUC / can cause iron-deficiency anemia from (erosions with blood loss and malabsorption from atrophic gastritis) Diagnosis: serology (85-95% sensitive) / positive result usually indicates active infection (if symptomatic and not already treated; serology remains positive for years after treatment) C13 urease breath test (95% sensitivity, 95% specificity) ($200) / 30% false negative if on PPI (must hold PPI 2 wks before testing, hold any antibiotics 4 wks before testing) direct urease detection from EGD biopsy specimen 90% s/s ($15) stool cultures, tissue biopsy, dental plaque? 90% s/s ($15) Differential diagnosis: non-related lymphoma, Crohns, GERD, bile reflux gastritis Treatment: use of NSAIDS should not alter treatment / document eradication (also reduces risk of future bleeding) / Note: H. pylori found incidentally many would treat just to remove any future cancer risk (H. pylori is carcinogen( HYPERLINK \l "gastriclymphoma" gastric lymphoma) Treatment (various preparations) (initial efficacy 90%) metronidazole + PPI + other clarithromycin + PPI + other Note: resistance to clarithromycin and metronidazole is prevalent after previously given to patient although clarithromycin resistance is more frequently implicated in subsequent treatment failure Note: elevated pH has theoretical risk of affecting IgG and MIC for certain antibiotics Recurrence: 75% untreated, 25% treated, 5% with eradication (antibody titre falls 50% by 6 months) NSAID induced ulcers very common cause of recurrent GI ulcers / may affect any portion of GI tract / dyspepsia 15% / gastric erosions / reactive gastropathy can be differentiated from other chronic types / develop in 5% - even after just 1 week of NSAID use Risk Factors: pre-existing ulcer, higher age, females, cardiovascular disease, high dose/potency NSAID, duration of treatment, smoking, alcohol, steroids / advanced age associated with less pain (no warning symptoms), more rebleeding Prevention: use lowest possible dose, enteric coating, prophylactic adjuvant treatment / buffering appears ineffective Treatment: stop or minimize NSAID use, eradicate H. pylori if present proton pump inhibitor (work faster,  HYPERLINK \l "nnt" NNT 6 / may be better for maintenance), prostaglandin, H2 antagonists Duodenal ulcer 90% due to H. pylori / relieved by food / triple therapy for H. pylori / double (omeprazole, clarithromycin) / NO risk of malignancy (unlike gastric H. pylori) Other Acid hypersecretory states (hypertrophic gastropathy) Mechanism: gastrin stimulates gastric acid secretion / trophic effects regulating GI mucosal-cell proliferation / G17 ( more potent, shorter half-life / G34 ( less potent, predominates Zollinger-Ellison Syndrome (ZES) gastric gland hyperplasia (gastrinoma) / hypertrophic-hypersecretory gastropathy (parietal and chief cells) / gastrinoma triangle Presentation: epigastric pain, weight loss, vomiting, severe diarrhea/malabsorption / extra pancreatic tumors Clinical: gastrinoma, pancreatic tumor, PUD with diarrhea, recurrent following surgery, FH, multifocal PUD, distal duodenal or jejunal ulcer (may occur anywhere though), rugal hypertrophy, hypercalcemia or multiple endocrine abnormalities (MEA) ( of cases) Diagnosis: serum gastrin level / secretin challenge causes paradoxical increase in gastrin (> 200 pg/mL; often > 1000 pg/mL) (must have 2 negatives to r/o ZES) [$200 test] / find tumor with MRI, U/S, CT, venous sampling Treatment: H2, PPI, octreotide / confined to lymph nodes( resect nodes (good prognosis) Prognosis: very good if resected early / debulking also prolongs survival Gastric Carcinoma (see below) 5th most common worldwide, 10% greater than 80 yrs / may present as GI ulcer confirm findings histologically (biopsy edge) Menetriers disease profound hyperplasia of rugal folds (epithelial cells/glands) / middle aged men / malignant transformation / protein-losing may cause edema / linked with type A blood (less secretion/protection) Gastric Varices ( HYPERLINK \l "portalgastropathy" see GI bleed) associated w/ esophageal varices / portal hypertension / deep location, resemble enlarged rugae Treatment: endoscopic ligation (most effective treatment), B-blockers and nitrates are less effective (but still useful as single therapy and even more so when combined with ligation) Portal Gastropathy ( HYPERLINK \l "portalgastropathy" see GI bleed) Kassabach-Merrit Diabetic gastroparesis [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/8/820" NEJM] Presentation: fullness, bloating, nausea, vomiting, delayed or accelerated gastric emptying / may occur in absence of other overt diabetic complications (although usu. part of broad spectrum of autonomic dysfunction) Exacerbated by: may be worsened by acute hyperglycemia, medications (pramlintide, exenatide), calcium channel blockers, clonidine, anticholinergics (e.g. antidepressants) Diagnosis: delayed gastric emptying suggested by splashing sound on abdominal succession one hour after meal / EGD / barium swallow / scintiscanning (modified protocol with hourly scans often done; retention over 10% at 4 hours is abnormal; sensitivity 93%, specificity 62%) / CO2 breath test (sensitivity 86%, specificity 80%) Course: symptoms generally stabilize indefinitely; no increase in mortality Treatment: try dietary modifications / erythromycin or metoclopramide or domperidone (not FDA approved), cisapride (requires special authorization) / may need pain relief (antidepressants, Neurontin) / severe cases may require nutritional support including G or J-tubes (2% serious complication rate of J-tubes: bowel perforations, jejunal volvulus, major bleeding, aspiration) / gastric electrical stimulation (being developed; showing some promise 1/07) / tegaserod (5HT4 receptor antagonist) being studied Gastric Tumors Gastric polyps 90% non-neoplastic / 10% gastric adenomas / sessile or pedunculated / may become carcinoma Gastric carcinomas (very bad prognosis) 1 in 40,000 / onset in 50s / diet (early exposure most important) / geographic setting Presentation: many are asymptomatic or fullness/anorexia (1st) or steady RUQ pain +/- anorexia, nausea, weight loss, iron deficiency anemia, B12 deficiency? / N/V ( pylorus, dysphagia ( cardiac / upper GI bleeding (hematemesis or melena) Risk factors: pernicious anemia, chronic atrophic gastritis Associations: migratory thrombophlebitis, microangiopathic hemolytic anemia, acanthosis nigricans Pathology: lesser curvature, antropyloric / exophytic, flat, excavated / invasion most important factor linitis plastica (diffuse, leather bottle appearance) Location: 30% distal / 20% mid / 40% proximal / 10% total / ovary mets (a.k.a. Krukenberg tumors) Method of Spread: direct, lymphatic (supraclavicular, L>R, Virchows node), hematologic Prognosis: very bad unless tumor is limited to submucosa/submucosa ( 80% survival (so get biopsy on all ulcers) intestinal diminishing in frequency in U.S. (may change with use of H2-blockers) / chronic gastritis / gastric adenoma / antrum, lesser curvature / expanding growth pattern / fungated, ulcerated diffuse prevalence unchanging in U.S. / younger onset / infiltrative growth pattern worse prognosis / signet-ring appearance, linitis plastica / mucin lakes reactive fibrosis Treatment: resection radiation only palliative taxol + radiation under investigation for advanced gastroesophageal CA post-op radiation + chemo under investigation as is pre-op (to increase respectability) early 50% 5 yr survival average 10% 5 yr survival Gastric lymphomas (good prognosis) MALT/B-cell or high grade/large cell / hard to distinguish clinically from gastric carcinoma / associated with H. pylori Diagnosis: gastric biopsy to look for  HYPERLINK \l "hpylori" H. pylori and tissue histology (make sure gastric biopsy is deep enough!) Treatment: 2 wks antibiotics for H. pylori, recheck breath test; if (-) observe for improvement (usu. by 2-18 months, 75% regress by 6 months, longest 2 yrs) and follow-up any gastric lesions with EGD or U/S; if no improvement, rebiopsy; if more aggressive histology seen, consider combination chemotherapy (50% cure rate) Other gastric tumors gastric sarcoma neuroendocrine cell (carcinoid) tumors mesenchymal (stromal, lipomas, neurofibromas) breast and lung mets may cause linitis plastica Trends: gastric bypass surgery more effective than nonsurgical treatments for morbid obesity (BMI > 40 kg/m2) Small and Large Intestine Causes of intestinal hyperpermeability: celiac sprue, IBD (CD>UC), Trauma/Burns/Sepsis, other (chemotherapy, diabetes, schizophrenia, sarcoidosis, cystic fibrosis, major surgical operations) Labs: increased lactulose/mannitol ratio (small molecules absorbed less, larger molecules absorbed more) Vascular GI Disorders Gastroesophageal Varices [ HYPERLINK "http://content.nejm.org/cgi/content/full/345/9/669" NEJM] 40-60% of patients with cirrhosis / 33% will bleed Ddx: gastric varices may occur from splenic venous thrombosis (consider in non-cirrhotics) Treatment: Prevention: propranolol or nadolol reduce risk of bleeding from 30% to 20% / goal is to reduce portal pressure by 20% or hepatic gradient < 12 and HR to 55 (or 25% reduction) / happens in 10-30% on propranolol (non-selective b-blockers reduce splanchnic flow / addition of Imdur (debated) / Note: sclerotherapy is not for primary prevention / TIPS (transjugular intrahepatic portosystemic shunting) is more as a bridge to OTL because risk of encephalopathy offsets reduction in bleed risk Acute Treatment: somatostatin or octreotide are effective in 80% of cases, mechanism unclear, reduces GI blood flow, side effects include hyperglycemia, abdominal cramping / vasopressin as continuous IV infusion, may require use of nitroglycerine for systemic BP increase / terlipressin (not in U.S.) has longer half-life, can be given as bolus Endoscopy for ligation or sclerotherapy (ligation preferred due to fewer complications) Antibiotics (ceftriaxone) in acute cases due to risk of co-existent infection Balloon tamponade: Minnesota tube (only if you know what youre doing) Ischemic Bowel Disease (mesenteric ischemia, ischemic colitis) Causes: atheromatous disease > cardiac disease > colonic surgery, DM, arrhythmias embolic arterial occlusion - usually more SMA nonocclusive ischemia - SMA-IMA (splenic flexure) and IMA-hypogastric watershed areas Presentation: acute mesenteric thrombosis ( acute bloody diarrhea chronic mesenteric ischemia ( bloody or watery diarrhea Diagnosis: often delayed due to more common appendicitis, peptic ulcer, cholecystitis Pathology: transmural infarction - often splenic flexure / hemorrhagic / gangrene and perforation at 1-4 days mural and mucosal infarction - hemorrhage and exudate absent from serosa / secondary acute and chronic inflammation / bacterial superinfection (pseudomembranous inflammation) / presents with intermittent bloody diarrhea chronic ischemia - submucosal chronic inflammation may cause stricture / segmental and patchy Note: colonoscopy appearance may resemble IBD [ HYPERLINK "pics/ischemiccolitis.jpg" pic] Course: most often resolve without intervention Angiodysplasia (intestinal AVMs) tortuous dilatations / cecum, right colon / 20% of lower intestine bleeds / 50s Hemorrhoids varices of anal, perianal venous plexi / 40s / 5% of population / may reflect portal hypertension Enterocolitis (Infectious Diarrhea) Differential Diagnosis: malabsorption, antibiotic use, cystic fibrosis, inflammatory bowel disease, thyrotoxicosis Labs: electrolytes and renal function, abdominal radiographs usually non-specific, blood, mucus, fecal leukocytes indicate bacterial causes Rapid antigen for rotavirus Treatment: quinolones are good (except campylobacter ( macrolide) Viral Gastroenterocolitis HYPERLINK "micro.doc" \l "rotavirus"Rotavirus HYPERLINK "micro.doc" \l "norwalk"Norwalk HYPERLINK "micro.doc" \l "adenovirus"Adenovirus - 1 wk incubation / 7-10 day duration HYPERLINK "micro.doc" \l "astrovirus"Astrovirus and HYPERLINK "micro.doc" \l "calicivirus"Calicivirus - mostly children / systemic symptoms as well Bacterial, Enterocolitis [ HYPERLINK "pics/infectiouscolitis.jpg" pic] Preformed toxins HYPERLINK "micro.doc" \l "saureus"S. aureus, Vibrio sp., C. perfringens Toxigenic organisms HYPERLINK "micro.doc" \l "difficile"C. difficile (invasion, hemorrhage) cause of antibiotic-associated colitis ( HYPERLINK "micro.doc" \l "cdifficile" pseudomembranous colitis; fibrinopurulent necrotic debris forms the pseudomembrane) ETEC (LT/ST) Vibrio (cholera toxin) (no invasion) HYPERLINK "micro.doc" \l "ehec"EHEC (shiga-like, hemorrhage, but no invasion) HYPERLINK "micro.doc" \l "shigella"Shigella (shiga toxin, hemorrhage, invasion) C. botulinum (neurotoxin) C. perfringens (no invasion) some strains produce severe necrosis or pigbel HYPERLINK "micro.doc" \l "salmonella"Salmonella (invasion) ileum, colon / bacteremia 5 - 10% / S. typhi causes chronic typhoid fever  HYPERLINK "micro.doc" \l "campylobacter" Campylobacter jejuni small intestine, colon, appendix, villous blunting, superficial ulcers, purulent exudate HYPERLINK "micro.doc" \l "yersinia"Yersinia enterocolitica pseudotuberculosis / hemorrhage and ulceration / necrotizing granulomas systemic spread with peritonitis, pharyngitis, pericarditis Chlamydia trachomatis Fungal and Parasitic Note: it takes 3 negative O/Ps to seriously r/o parasitic GI infection.  HYPERLINK "micro.doc" \l "giardia" Giardia  HYPERLINK "micro.doc" \l "cryptosporidium" Cryptosporidium Isospora belli like cryptosporidium / bactrim Entamoeba histalyticum bloody / metronidazole or Necrotizing Enterocolitis (NEC) < 3 months, usu. 2-4 days old / higher prevalence in formula-fed / mild or fulminant (gangrene, perforation, sepsis, shock) / fluid, electrolyte replacement or massive surgical resection Other inflammatory HIV enteropathy - opportunistic vs. direct (unproven) bone marrow transplantation - blunting, degeneration due to pre-transplant radiation or chemo. Graft versus host disease of GI tract ( HYPERLINK \l "gvhd" see GVHD) severe, acute secretory diarrhea / crypt cell necrosis / may progress to fluid, electrolyte derangement, sepsis, hemorrhage / chronic course may include dysphagia or malabsorption Malabsorption Syndromes Manifestations GI diarrhea, flatus, abdominal pain, weight loss, mucositosis (vitamin deficiencies) Hematologic anemia from iron,  HYPERLINK \l "b6" pyridoxine, folate, B12 deficiency, bleeding from vitamin K deficiency Muscle/Bone osteopenia and tetany from calcium, magnesium, vitamin D, and protein malabsorption Endocrine amenorrhea, impotence, infertility from general malnutrition, hyperparathyroidism from calcium and vitamin D deficiency Skin purpura, petechiae from vitamin K deficiency, edema from protein deficiency dermatitis, hyperkeratosis from vitamin A, zinc, essential fatty acids and niacin def. Neuro peripheral neuropathy from vitamin A and B12 deficiency Ddx Celiac (Sprue), Whipples Bacterial overgrowth Lactase deficiency, allergy/hypersensitivity Abetalipoproteinemia Radiation-induced enterocolitis [HYPERLINK "pics/radiation-stenosis-jejunum.jpg"pic] Eosinophilic Gastroenteritis Short gut syndrome Work-up collect all stools / r/o emotional causes Lab Tests 72 hr  HYPERLINK "labs.doc" \l "fecalfat" fecal fat - >6 g/day / 20-30g/day on 100g/day fat diet suggests pancreatitis xylose absorption test (measured by 14CO2 in breath) decrease indicates injury to intestinal mucosa / increase indicates bacterial overgrowth (also suggested by abdominal radiography of fistula, blind loop, stasis) decreased stool pH suggests lactase deficiency or celiac disease Schilling test (rarely done) positive test when urine B12 is only increased by combination of B12 and IF (suggests gastritis/pernicious anemia) Celiac sprue [HYPERLINK "http://content.nejm.org/cgi/content/full/344/7/510"NEJM] General: diffuse enteritis (mostly upper intestine) Epidemiology: 1 in 250 / whites only / any age, bimodal (4 yrs and 20s to 30s) Risk Factors:  HYPERLINK \l "dermatitisherpetiformis" dermatitis herpetiformis, type I diabetes, autoimmune thyroid, IgA deficiency, connective tissue diseases, Downs, collagenous or lymphocytic colitis, neurological or neuromuscular disorders, FH of celiac disease Mechanism: gluten sensitivity (from wheat and other grains) / Genetics: HLA B8 or Dqw2 Pathology: flat mucosa, tortuous crypts, villous atrophy [ HYPERLINK "pics/celiacdisease.jpg" pic] / lymphocytes (+) / mucosal thickness remains constant / often reversible Presentation: malabsorptive syndrome and diarrhea, vomiting, flatulence, fatigue, short stature, delayed puberty, weight loss and failure to thrive (can occur even without the diarrhea/steatorrhea) / severe abdominal pain usually from complications of refractory/untreated celiac disease Extraintestinal arthritis (25%) may precede GI symptoms (polyarticular, oligoarticular, or spondylitis)  HYPERLINK \l "dermatitisherpetiformis" dermatitis herpetiformis Diagnosis: IgA for gliadin (85% sensitivity, 90% specificity) / IgG for gliadin (80%, 80%) Anti-endomysial Ab (more expensive) gold standard (95%/95%) if high suspicion ( endomysial Ab testing and small-bowel biopsy if low suspicion ( endomysial Ab testing and gliadin Ab testing Other: malabsorption and decreased stool pH, biopsy, gluten-free improvement / sucrose screening test (absorbed mostly in proximal intestine) / may want to r/o  HYPERLINK \l "meckels" Meckels, enteroclysis Complications: ulcerative jejunitis, small bowel intussusception, colonic volvulus NHL of small intestine (T-cell lymphoma with poor prognosis) (2x risk, but worse celiac disease does mean worse risk for lymphoma), intestinal adenocarcinoma,  HYPERLINK \l "esophagealcancer" esophageal CA, oropharyngeal CA Extra-intestinal GI findings: lymphocytic gastritis, lymphocytic colitis, collagenous colitis, Treatment: remove gluten from diet (can take from just days to up to 6 months to see benefits, efficacy can increase up to a year) / IgA against gliadin can be used to assess clinical response and compliance with gluten-free diet Tropical sprue (post-infectious) megaloblastic changes in epithelial cells from  HYPERLINK \l "b12" B12 deficiency Treatment: broad spectrum antibiotics Whipples disease (intestine, CNS, joints) HYPERLINK "http://content.nejm.org/cgi/content/full/356/1/55"[NEJM] [ HYPERLINK "http://www.google.com/search?hl=en&q=whipple%27s+disease" G] rare / white males in 40-60s (not always) / affects small bowel, rarely large bowel micro: gram-positive, family actinomyces Presentation: malabsorption, diarrhea (watery/semi-formed, sometimes bloody), anorexia, malaise, weight loss, abdominal pain, fever (50%), increased skin pigmentation, arthritis (66%, often precede GI, migratory or axial), anemia, lymphadenopathy (50%) / extra-intestinal symptoms can precede GI symptoms by many years Lungs: chronic cough, pleuritis Heart: pericarditis, valvular endocarditis CNS (10%): ocular, CNS symptoms / common triad of dementia, opthalmoplegia, myoclonus [ HYPERLINK "pics/whipples-mri.jpg" MRI] Malabsorption: loss of calcium, fat, protein / muscle wasting, osteopenia, glossitis, skin pigmentation, clubbing, purpura Labs: low albumin and immunoglobulin levels (from GI loss), steatorrhea, defective xylose absorption, low cholesterol, anemia (chronic disease, B12, or iron deficiency) Radiography: thickened mucosal folds of small intestine proximal > distal on SBFT [HYPERLINK "pics/sf-whipples.jpg"pic] Diagnosis: PCR of small intestinal biopsy for causative organism (Tropheryma) / macrophages contain PAS and rod-shaped bacilli / characteristic changes in small intestine mucosal (changes usu. reverse immediately after treatment, but occasionally persist even years after successful treatment), PAS-granules sometimes seen in normal large bowel specimens (non-diagnostic) / PCR has identified organisms (but organisms do not grow) in various extra-GI body fluids like CNS, CVS, joints, blood Ddx: celiac sprue, seronegative arthritis, intestinal MAI in AIDS Treatment: several antibiotic choices (PCN +/- bactrim, others); give at least 4 wks (more like 6 months to a year) (1/3 relapse, sometimes years later) Bacterial Overgrowth Syndrome luminal stasis (autonomic disorders, scleroderma/MCTD), hypochlorhydria, immune deficiency Labs: low albumin and prealbumin Diagnosis: ask your GI fellow if they can do the hydrogen breath test Treatment: 2 week course of tetracycline, augmentin or flagyl / can use on-off periods (if predisposing condition is permanent, then multiple courses will be required indefinitely) Lactase deficiency congenital is rare / acquired is common follows mucosal damage (watery diarrhea, acidic stool from bacterial byproducts) / also a late-onset form that occurs following lactation Abetalipoproteinemia rare AR / apolipoprotein B deficiency / cannot make chylomicrons, VLDL, LDL / TGs accumulate and vacuolate enterocytes / symptoms: fat malabsorption (diarrhea, steatorrhea), failure to thrive, acanthocytosis, ataxia, retinitis pigmentosa Short gut syndrome Treatment: low-fat diet reduced steatorrhea and improves nutrient absorption, supplement diet with medium chain fatty acids (absorbed even without bile salts) / cholestyramine may worsen condition by depleting bile acid pool Hypersensitivity abdominal pain NOT usually a feature of hypersensitivity to nuts Eosinophilic Gastroenteritis Presentation: N/V, abdominal pain, wt loss, steatorrhea, protein-losing enteropathy Effects any segment of GI tract, peripheral eosinophilia in 75% Treatment: steroids Inflammatory Bowel Disease  HYPERLINK \l "crohns" Crohns Disease /  HYPERLINK \l "uc" Ulcerative colitis Differential: radiation, ischemia, infections, antibiotics (pseudomembranous colitis), other causes Genetics: HLA B27, B5-DR2, AW24, BW25 / 10% have positive family history (15-20% of healthy relatives with intestinal hyperpermeability) / inflammation is the common pathway Crohns Disease General: entire GI tract (33% small bowel alone, 20% colon involvement, generally does NOT affect rectum) / transmural inflammation, creeping fat, granulomas, fistulas, obstructions, psoas/hepatic abscesses (must be drained), systemic manifestations Epidemiology: Jews >> whites > blacks, developed countries, northern US / bimodal 15 to 25 yrs (more) and 55 to 65 yrs (less) Pathology: intestinal strictures / sharp demarcations, skip lesions, linear ulcers (may have fistula to bowel, bladder, vagina, rectum, skin, retroperitoneum), non-caseating granuloma (20%), granuloma (crypt abscesses), colon (crypt atrophy, paneth or pyloric metaplasia), lymphoid aggregates/granulomas (50%, may occur in uninvolved regions) Presentation: insidious or abrupt onset of pain, fever, diarrhea (symptoms may or may not mirror mucosal pathology) / chronic pain, intestinal obstruction, acute inflammation (mimics acute appendicitis) / Pediatric presentation: fever, anemia, arthritis / children also more likely to present with upper GI symptoms Ddx: appendicitis, Yersinia, lymphoma, intestinal tuberculosis, Behets Diagnosis: colonoscopy KUB: ileitis, string sign, skip lesions Labs: anemia, thrombocytosis, increased ESR, increased CRP orosomucoid, decreased albumin, increased fecal a1AT (not available in all labs), leukocyte scan/excretion / P-ANCA (not MPO) positive in 30% Systemic Complications: GI: malabsorption, iron deficiency anemia, steatorrhea (bile malabsorption may also cause oxalate renal stones and cholesterol gall stones) / pathos stomatitis (more common in children) / perianal fistulae and abscess / increased incidence of gallstones (supersaturated biliary cholesterol, not enough bile acids) Urologic:  HYPERLINK \l "renalstones" renal stones (10%, usually after small bowel resection or ileostomy), fistulae, hydronephrosis, amyloidosis (fat malabsorption leads to calcium being taken away to saponify acids, which leads to build-up of oxalic acid) Liver: hepatic involvement, fatty liver, sclerosing cholangitis (10% in adults, 3% in children) and autoimmune hepatitis (may need to do liver biopsy to differentiate as sometimes involvement is solely intra-hepatic ductal) Joint: polyarthritis (10-20%, associated with flare-ups, can happen w/out GI Sx / destructive changes not seen), sacroiliitis (20%, progresses independently, similar to  HYPERLINK \l "ankylosingspondylitis" ankylosing spondylitis) Skin: erythema nodosum (!5%), clubbing fingertips, pyoderma gangrenosum (rare) Eye: uveitis (common) (photophobia, blurred vision, headache) Cancer risk: minimal (2.5 x normal risk) / insurance wont pay for annual flexible endoscopy in Crohns (2.5 risk) Treatment: Medical:  HYPERLINK \l "ibdtreatment" see below (steroids) / antibiotics, anti-diarrheal, cholestyramine (for steatorrhea), see (treatment of  HYPERLINK \l "psc" PSC) Surgical: operate only when necessary (obstruction, fistula) / recurrence after operation is 50% by 10 years (occurs most at site of anastomosis) / liver transplant only cure for PSC and autoimmune hepatitis Pediatric: consider surgery in kids to let them go through puberty before recurrence Prognosis: 10% spontaneous remission, most relapse eventually Measuring disease status: diarrhea, abdominal pain, nausea/vomiting, rectal bleeding (hematochezia only from colonic affects / obstruction), weight loss, fever, growth retardation, fistula, more Ulcerative Colitis Epidemiology: Jews >> whites > blacks, developed countries, northern US / bimodal 15 to 25 yrs (more) and 55 to 65 yrs (less) / 1 in 20,000 / 20% will have 1st degree relative Presentation: may have more diarrhea than Crohns due to circulating secretagogues released from colonic inflammation Course: continuous inflammation begins in rectum and proceeds proximally, pseudopolyps, normal thickness, serosa / dysplasia / leads to carcinoma (stricture) Labs: 15% have elevated ESR/CRP during attack (mod-sever > 30), P-ANCA (not MPO) positive in 30% Complications: Colonic: toxic megacolon (> 6cm) (follow closely with serial KUB), lead pipe, usually does not have severe bleeding [note: steroids can mask pain of acute abdomen] // Note: start broad spectrum antibiotics (before perforation!, not after!) Arthritis: monoarticular, asymmetrical, large > small joints, no synovial destruction, NO subcutaneous nodules, seronegative (no RF) / do not treat like RA with NSAIDS / does not resolve with remission of GI disease /  HYPERLINK \l "ankylosingspondylitis" ankylosing spondylitis, which may progress even after colectomy Skin:  HYPERLINK "ddx.doc" \l "erythemanodosum" erythema nodosum (10-50%), pyoderma gangrenosum (1-10%), HYPERLINK \l "erythemamultiforme"erythema multiforme, maculopapular eruptions [skin conditions resolve with treatment of GI disease] Eye: episcleritis, iritis, uveitis (urgent ophthalmology consult, can cause blindness) Liver: fatty liver (common),  HYPERLINK \l "psc" sclerosing cholangitis (15%) (85% of sclerosing cholangitis due to UC / indication for liver transplant), cholangiocarcinoma (no liver transplant) Cancer risk: 10-20% by 20 yrs of disease (increases 1% per year after 7-10 yrs) [not always removed immediately; some say yearly colonoscopy starting 8 yrs after disease begins] Diagnosis: colonoscopy [ HYPERLINK "pics/ulcerativecolitis.jpg" pic] Indications for surgery: Emergent: hemorrhage (exsanguinations), toxicity and/or perforation (toxic megacolon) Neoplastic: suspected/confirmed cancer, significant dysplasia General: growth retardation, systemic complications, intractability Colectomy with mucosal proctectomy and ileo-anal anastomosis small bowel mucosa replaces removed colonic mucosa - better than bag, only an increased number of bowel movements, preserves sexual function, complications: infection of pouch (Rx: metronidazole) Treatment of IBD: Avoid: anticholinergics, anti-diarrheal, antibiotics (may use metronidazole Crohns for overgrowth) corticosteroids mainly useful in acute attacks, not for long term prevention oral prednisone 20-60 mg parenteral corticosteroids parenteral ACTH topical steroids corticosteroids enema 80-200 mg/d 5-asa compounds Onset: several weeks / not helpful in acute attacks, but give anyway to get them on board / can maintain remission for variable amount of time using oral-ASA agents HYPERLINK "pharm.doc" \l "sulfasalazine"sulfasalazine (best agent, cheaper) olsalazine (2 5-asa bound) 1.5-3 g/d oral 5-asa (mesalamine) 1.5-4.8 g/d topical 5-asa & 4-asa (rectal prep) mesalamine enema 1-4 g/d Immunosuppressives: cyclosporin, tacrolimus, MMF, 6-MP / Il-10 (under investigation) Collagenous colitis Usually benign chronic watery diarrhea / middle-aged women / some say it can progress to ulcerative colitis Microscopic colitis Irritable Bowel Syndrome  HYPERLINK "http://content.nejm.org/cgi/content/full/344/24/1846" [NEJM] Brainerds diarrhea Irritable bowel syndrome lasting up to 6 months induced by prior case of infectious diarrhea / some patients respond to cholestyramine / up to 25% of cases of infectious diarrhea Acute Radiation-Induced Enterocolitis (see chronic below) With 40 Gy or more / friability, ulceration, edema / similar to IBD Chronic Radiation-Induced Enterocolitis [HYPERLINK "pics/radiation-stenosis-jejunum.jpg"SBFT] [ HYPERLINK "pics/radiationproctopathy.jpg" radiation proctopathy] Occurs 6 to 12 months after treatment (5% of those receiving radiation therapy) 1. radiation-induced chronic inflammation (fibrosis, endarteritis, angiodysplasia) 2. radiation-induced small bowel strictures ( bacterial overgrowth in terminal ileum ( bile acid malabsorption and bile acid diarrhea Treatment: For chronic inflammation ( sulfasalazine, steroids, cholestyramine For bleeding angiodysplasia ( endoscopic thermal ablation is only effective treatment (anti-inflammatory therapy does not help) For strictures, fistulas, etc ( surgery Colonic Diverticulosis sigmoid most common (but cecum most likely to bleed) / 50% of people >70 yrs in U.S. Mechanism: focal weakness, increased pressure / 1 cm diameter atrophic mucosa, attenuated muscularis Presentation: only 20% manifest symptoms (some say 90% have pain, LLQ > RLQ), diarrhea, constipation, fever (70%) / young patients < 40 yrs often present with a more fulminant course, can mimic appendicitis with sigmoid on the right, requiring surgery in majority of cases / also consider elective surgery after 1st episode in young patients Labs: elevated WBC (70%) Diagnosis: Note: DO NOT perform barium enema (may perforate bowel, gastrograffin is less harmful than barium if spillage occurs) Abdominal CT: (pericolic fat stranding, thickening > 4 mm, abscess [HYPERLINK "pics/paracolicabscess-ct.jpg"CT]) Colonoscopy: may cause perforation, but direct visualization is good for colon cancer and r/o bleeding from rectal causes (ulcers, hemorrhoids) Ultrasound: can do similar things as CT (even detect some abscesses, etc) Acute diverticulitis (20%) Presentation: as above (pain, fever, ! WBC) with risk of obstruction, stricture, hemorrhage, perforation (peritonitis), fistula formation (colovesical > colovaginal, coloenteric > colocutaneous), but can have fistulization to just about anything, localized pericolic or intramesenteric or peritoneal abscess formation / colovesical more in males (because uterus shields bladder) Treatment: outpatient: ciprofloxacin/flagyl inpatient: amp/gent/flagyl and bowel rest (delay invasive diagnostic measures for as long as permissible up to several weeks to minimize risk of perforation) CT guided or surgical abscess drainage if no improvement by 48 hrs or if large obstruction usually can be resolved with medical management strictures (result from recurrent attacks): trial of endoscopic therapy (bougienage, balloon, laser, electrocautery or blunt dilating endoscope) / surgery if cannot exclude neoplasm resection for 2nd attack as complications will recur (60%) with each attack rarely requires colostomy and/or surgical resection, however, this may be a better option for younger patients Arteriovenous Malformations Common cause of lower GI bleeding / cecum and right colon / affect 25% of elderly / present with massive bleeds 10% / 80% will rebleed Treatment: endoscopy with ablation, electrocoagulation, segmental colectomy Bowel Obstruction Presentation: vomiting, abdominal pain Findings: high-pitched bowel sounds Radiography: air-fluid level in distended loops, no air in rectum SBO Adhesions (1st) Hernia (2nd) Neoplasms Obturation/strictures ischemia, radiation, Crohns, gallstone, bezoar Intussusception Meckels diverticulum (2 feet from IC) Volvulus SMA syndrome Intramural hematoma LBO* Primary colorectal cancer (50%) Volvulus (15%) Diverticular disease (15%) Extrinsic obstruction from metastatic carcinoma (5%) Other: stricture, hernia, fecal impaction, adhesions * pseudo-obstruction (more common, but above for complete obstruction) Paralytic Ileus (very common) Causes: trauma, abdominal surgery, peritonitis, hypokalemia Radiography: intestinal gas is diffuse, air may be present in rectum Mechanical Obstructions Adhesions surgery, infections, endometriosis may lead to intestinal adhesions (internal hernias) Hernias visceral segments often protrude and become entrapped (external herniation) / may infarct Tumors (see below) Gallstone Ileus (HYPERLINK "more/endoscopy\\mi_gs_01.htm"endoscopy) Intussusception children: idiopathic (or hypertrophic Peyers patches) / 60% from 4-12 months, 80% by 2 yrs / occurs from terminal ileum to ascending colon Diagnosis: currant jelly stools / ACT show RLQ mass [ HYPERLINK "pics/intussusception.jpg" pic], but empty on palpation (Dances sign) Treatment: barium enema may be curative (85%), laparotomy with massage or resection Ddx: childhood tumor ( HYPERLINK \l "nhl" non-Hodgkins lymphoma) Adults: tumor, Meckels, polyps or other intraluminal mass / almost always with N/V, morphine usually relieves pain Volvulus Rare, 1 in 50,000 / order of frequency: sigmoid (75%) > cecum (25%) >> small bowel, stomach, transverse colon / crampy abdominal pain, distention / KUB shows birds beak at point of obstruction / Treatment: sigmoid volvulus can be reduced by rectal tube enemas, proctoscopy / cecal volvulus requires surgical resection Ogilvies syndrome acute colonic pseudo-obstruction / rare / may respond to conservative management Intestinal Tumors Small intestinal neoplasms (in general) only 1% of GI malignancies / usually benign Presentation: obstruction, bleed / often not symptomatic right away syndromes: NF, OWR, PJ benign include leiomyomas (ulceration of mucosa usually present), adenomas, lipomas (ileocecal valve), neurogenic, vascular, hamartomatous lesions adenocarcinomas - napkin-ring as in distal colon cancer / usually papillary / upper duodenum Diagnosis: usually disseminated by time of Dx / barium, CT, Tc-99 RBC (0.1/min sensitivity) Prognosis: fairly decent survival rate with en bloc excision Non-neoplastic polyps 90% of epithelial polyps in colon / 50% of population over 60 / < 5mm hyperplastic polyps: single or multiple / rectosigmoid / almost no malignant potential Juvenile Polyposis 80% in rectum / < 5yrs / 1-3 cm / hamartomatous (low risk of adenoma) / 90% bleed and most autoamputate / juvenile polyposis syndrome (multiple) / smaller version in adults (retention polyps) Peutz-Jeghers [HYPERLINK "pics/peutzjeghers.jpg"pic] AD / multiple hamartomatous polyps, entire GI tract melanotic pigmentation of lips, oral mucosa, face, genitalia, palmar surfaces increased risk of carcinoma of breast, lung,  HYPERLINK \l "ovary" ovary/testes, uterus Lymphoid polyps (focal lymphoid hyperplasia) common in rectum in children Neoplastic epithelial lesions 25% before age 40 / 50% after age 60 / size, architecture, level of dysplasia / CIS in the mucosa may still be benign (few mucosal lymphatics in colon) / once in the submucosa, polypectomy may be adequate for tubular variety, but surgical resection is necessary for sessile adenocarcinoma (remaining polyps should be considered pre-malignant or malignant) Note: if patient has one polyp, there is 30-50% chance of regrowing another (takes about 5 years, so repeat colonoscopy recommended at 3 yrs post-polypectomy) tubular (90%) (less invasive) rectosigmoid (50%) fibrovascular stalk (2.5 cm in diameter) / single or multiple dysplasia begins at polyp head and invades down into mucosa (CIS) or sub-mucosal stalk (invasive adenocarcinoma) villous(1%) (more invasive) sessile / rectosigmoid / up to 10 cm dm / 40% present w/ invasive carcinoma may secrete proteins and potassium (hypokalemia, hypoproteinemia) tubulovillous (10%) Familial Adenomatous Polyposis [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/22/2349" NEJM] AD inheritance (20% sporadic) / 100s to 1000s of tubular polyps / onset 20s and 30s with 100% progressing to cancer within 10-15 yrs / immediate colectomy Genetics: APC (5q21) or DP 2.5 present / hypomethylation of DNA / ras, myc, myb, trk, hst all increased / DCC decreased / p53 defect / instability of microsatellite DNA Associations: 1-2% lifetime risk of thyroid cancer (papillary>>follicular; ! women; S! thyroid precedes colon manifestations), fundic gland polyps, epidermoid cysts, osteomas, desmoids tumors, congenital hypertrophy of retinal pigmented epithelium Gardner s syndrome FAP variant with intestinal polyps and multiple osteomas, epidermal cysts, fibromatosis, also abnormalities of dentition, thyroid and duodenal cancer Turcots syndrome FAP variant plus CNS tumors (gliomas) Carcinoid tumors neuroendocrine origin / over 60 yrs / S! to of malignant small intestine tumors / appendiceal (most common) and rectal rarely metastasize / ileal, gastric, colonic usually have mets at Dx / stomach and ileum usually multiple lesions / cells usually differentiated and secrete a particular hormone Clinical: ZES (gastrin), Cushings (ACTH), hyperinsulinism, SS Carcinoid syndrome generally means liver mets from GI tumors (85% in intestine, 50% appendix) or bronchoalveolar adenoma Mechanism: lack of 1st pass metabolism of ( NE increased, 5HT increased occurs in 1% carcinoid tumors with hepatic mets or extra GI tumors (especially ovarian tumors) Presentation: headache, HTN, diarrhea, flushing [ HYPERLINK "pics/carcinoidsyndrome.jpg" pic], bronchospasm, personality change (anxiety, panic attacks) / can be exacerbated by general anesthesia (an emergency) Labs: elevated urine 5-HIAA (and other metabolites) / normally, 5-HT or kallikrein is metabolized by the liver (5-HT to 5-HIAA) Imaging: CT only for mets (primary tumors are too small) / barium may demonstrate resulting stricture Complications: subendocardial fibrosis and deposits on right heart valves (restrictive heart disease and TR; 3 yr survival) Treatment: octreotide, methysergide (anti-5HT) Intestinal lymphoma (see also HIV related) infiltration into muscularis leads to motility problems in advanced cases / small follicular center cells and immunoblasts 95% B-cell type ( high-grade) / T-cell type is high-grade Risk factors: chronic malabsorption, Mediterranean, HIV, immunosuppression Treatment: chemotherapy may cause acute perforation of large tumors / Sporadic lymphomas (Western type) arise in MALT - linked to chronic inflammatory states Sprue-associated lymphoma (bad prognosis) 10 yr of malabsorption or associated with diffuse malabsorption / T-Cell origin Mediterranean lymphoma (bad prognosis) young adults / chronic plasmacytosis / immunoproliferative / small intestine Mesenchymal tumors (GI stromal tumors) lipomas, leiomyomas, leiomyosarcomas, leiomyoblastoma of stomach (intermediate grade) Short Bowel Syndrome Complications: nutritional deficiencies ( HYPERLINK "pathology.doc" \l "shortboweldeficiency" see list), gastric acid hypersecretion, D-lactic acidosis, nephrolithiasis, cholelithiasis Colon Cancer Incidence: 1 in 20 / 15% of all cancer deaths / 2:1 male:female / occurs in elderly Screening: annual rectal over 40 yrs, over 50 yrs ( stool occult blood every year, one colonoscopy, if normal (hyperplastic polyps normal, adenomatous polyps abnormal) then flex sigmoidoscopy every 3-5 yrs Risk Factors: FH of colon CA, multiple polyps, ulcerative colitis / too much animal fat Presentation: left ( obstruction or anemia / right ( anemia / sigmoid/rectum (60%) / 30% invasive at presentation proximal polypoid masses on one wall of cecum, ascending colon / obstruction uncommon / clinical symptoms include fatigue, weakness, iron-deficiency anemia (in older men, iron-anemia is cancer until proven otherwise) distal annular, encircling growth, produce napkin-ring constrictions / clinical symptoms include occult bleeds, bowel habit changes, cramps in left lower quadrant / tend to be more invasive early Genetic Markers: APC (chr 5), K-ras activation in 50% (chr 12), DCC loss (chr 18), P53 in 75% (non-specific), BRCA (non-specific), CEA (also pancreatic) Diagnosis: biopsy from colonoscopy is gold standard / virtual colonoscopy by CT is available, but cannot remove polyps or take biopsies (would need to have colonoscopy after) Pathology: variable histological pattern for both right and left / mucin secretion into interstitium facilitates invasion / neuroendocrine differentiation in 10% / signet-ring / squamous component (especially in anorectal type) Dukes staging 5 yr survival Treatment Stage A 95% (A1) surgery Stage B 85% (B1) / 65% (B2) 5FU and leucovorin Stage C 55% (C1) / 25% (C2) 5FU and leucovorin + carboplatin with mets Stage D Treatment Surgery: in selected patients (~25%) with < 5 mets, lobectomy can offer long-term survival Chemotherapy can otherwise offer 14-18 months extended survival Begins with separation by EGFR/KRAS status (50/50 wild or mutant) (similar to breast cancer HER status; Abs work better if wild-type positive) MS-H (dMMR) (20% of cases) overall better prognosis / 5-FU may be harmful in stage II MSI-H (high) pts / trials underway 2009 VEGF/EGFR another marker (dual Ab inhibition seems harmful in most patients; studies ongoing) Bottom line = NCCN guidelines are changing / need a good oncologist  HYPERLINK "pharm.doc" \l "5fu" 5 Fluorouracil (5-FU) inhibits DNA / RNA synthesis Side effects: leukopenia, nausea (mild), skin erythema, melanin deposition in skin creases, rash, photosensitivity, conjunctivitis, alopecia (reduced with leucovorin rescue), angina (rare) Capecitabine (Xeloda) oral 5-FU  HYPERLINK "pharm.doc" \l "Irinotecan" Irinotecan Diarrhea Gemcitabine HCL (Gemzar, dFdC) Inhibits DNA/RNA Oxaliplatin Part of front-line regimens / decision to use as adjuvant to 5-FU based on stage III (yes) or stage II (maybe?) (cannot give too much, meaning repeatedly, or nerve toxicity accrues; co-administration of Ca/Mg may help reduce toxicity without reducing efficacy) Cetuximab / bevacizumab (Avastin) / Panitumumab Targeted Abs being added as well based on positive data and the EGFR/KRAS issue Side effects: diarrhea (20%), nausea, vomiting, HTN, thromboembolic (9%), neurotoxicity (8%), allergy (3%), bleeding (2%) Camptothecins topoisomerase inhibitors Follow-up: screening colonoscopy minimum every 3 yrs (regardless of stage) to look for new polyps Prevention: some debate over whether ASA or NSAID can decrease risk of colon cancer; current thinking 6/06 is that requires very high doses, and risk of bleed may outweigh benefit Rectal Cancer Treatment is different from other colon cancer ( resection alone can be curative if non-invasive, also radiation/chemotherapy can be curative even if invasive Solitary rectal ulcer syndrome usually in older adults / painful defecation, constipation, passage of mucous Appendix Acute appendicitis Most common cause of acute abdomen at any age / 10% lifetime incidence (15-35 yrs and elderly) Types: early acute, acute suppurative, acute gangrenous Pathology: neutrophilic infiltration, muscularis invasion Presentation: anorexia, pain (colicky, periumbilical then McBurney s point RLQ S! from right anterior iliac spine and umbilicus) then nausea/vomiting, mild fever / usually 24 hrs from onset of pain to perforation Exam: RLQ pain, peritoneal signs: obturator sign (pain on ext. rotation of flexed thigh), psoas sign (pain on right thigh extension), Rovsing sign, rectal exam may reveal tenderness or mass / if patient will eat (appendicitis unlikely) Note: malrotation may cause left sided appendix / retrocecal appendix may produce pelvic pain may also lead to pyelephlebitis with portal - Diagnosis: elevated WBC, pyuria (25%) / hard to diagnose in youngest and oldest Ultrasound: wall thickening, luminal distention, incompressibility / also r/o ovarian CT abdomen: more accurate Ddx: perforated ulcer may leak down and irritate RLQ, mesenteric lymphadenitis (e.g. Yersinia), fecalith (5%), acute PID or other ovarian, kidney stones, pneumonia, Mittelschmerz / 10-20% of cases are falsely diagnosed / mild hematuria and pyuria common from urethral irritation Complications: ruptured appendix (10% mortality), peritonitis, thrombosis, liver abscess, bacteremia Risk of perforation: 25% by 24 hrs / 50% by 36 hrs / 75% by 48 hrs Treatment: non-perforated: antibiotics (1 day) then appendectomy / perforated: triple antibiotics (7 days), appendectomy, drainage / may only perform CT guided drainage w/ clinical improvement Tumors of appendix mucocele caused by obstruction, endometriosis non-neoplastic hyperplasia mucinous cystadenoma common / 20% perforate / no neoplastic cells, surgical cure cystadenocarcinoma pseudomyxoma peritonei when cancer cells are in the peritoneum / see carcinoid tumor of appendix / treated by debulking and intraperitoneal chemotherapy (@UTMDA) CDDP, 5-FU, MMC Peritoneum Inflammation bile (green than suppurative), pancreatic enzymes (saponification then frank pus), surgical foreign body (granuloma, fibrous adhesions, obstruction, internal herniation) Peritoneal Infection Spontaneous bacterial peritonitis (SBP) occurs in 10-20% of cirrhotics nephrotic children and cirrhotic adults One bug: GNR: E. Coli et al (60%), Streptococcus (25%), Staphylococcus Secondary bacterial peritonitis Polymicrobial: gram negative coliforms, obligate anaerobes, localized abscesses Diagnosis: paracentesis [ HYPERLINK "http://content.nejm.org/cgi/video/355/19/e21/" video] ( >250 PMNs/mm3), cultures, CT, can do tagged WBC if CT unavailable Differential Diagnosis: pneumonia, sickle cell, herpes zoster, DKA, tabes dorsalis, porphyria, familial Mediterranean fever, plumbism, SLE, uremia, other intra-abdominal infections Treatment: ceftriaxone, Zosyn, Unasyn, imipenem, meropenem, trovafloxaxin, (some use cefotaxime, cefotetan, cefoxitin / vancomycin (esp. if you put it there w/ your previous paracentesis, any dialysis patient, nursing home patient, patient known to be MRSA carrier, others) Prognosis: often very serious, can be self-limited, persistent, relapsing or fibrosing Sclerosing retroperitonitis autoimmune disease of peritoneum / may cause hydronephrosis, etc. Mesenteric cysts developmental origin, infectious sequelae, associated with adenocarcinoma Tumors primary mesotheliomas rare / caused by asbestos exposure secondary metastases ovarian and pancreatic are most common Pancreas Acute pancreatitis ( HYPERLINK \l "chronicpancreatitis" see chronic) Presentation: abdominal pain, radiates posteriorly, nausea and vomiting, low grade fever, soft/tender abdomen, decreased/absent bowel sounds, Cullens sign (ecchymotic discoloration of anterior abdominal wall / less common), Grey-Turner similar? Mechanism: obstruction, autodigestion / trypsinogen to trypsin, which activates other enzymes, clotting, complement / chymotrypsin / lipase (PLA-2) (fat necrosis) / elastase (ruins vessels) / amylase Causes: 90% of cases from alcohol or biliary tract disease (1st) alcohol - young men, duodenal irritation causes sphincter spasm and obstruction (2nd) biliary tract disease -  HYPERLINK \l "gallstones" gall stones, women 2:1 / structural or functional obstruction (3rd) idiopathic (some say ! TG) Other causes: Trauma: children and teenagers / surgery / ERCP Obstruction: gallstones, pancreatic carcinoma EtOH Drugs: VPA, staduvine, (HYPERLINK "pharm.doc" \l "didanosine"didanosine (ddI) > ddC), thiazides, Immuran, furosemide, sulfonamides, steroids, tetracyclines, estrogens, metronidazole, L-asparaginase, methyldopa, pentamidine, ethacrynic acid, procainamide, Sulindac, nitrofurantoin, ACE inhibitors, danazol, cimetidine, diphenoxylate, piroxicam, gold, ranitidine, sulfasalazine, isoniazid, acetaminophen, cisplatin, opiates, erythromycin Hypercalcemia: renal failure, hyperparathyroidism elevates Ca (augments trypsin) Hyperuricemia leads to inspissated secretions Hypertriglyceridemia (as a cause, must be 1000-2000) can be cause or result of pancreatitis Infections (mostly viral) PUD (penetrating) Congenital (pancreas divisum) / hereditary pancreatitis Hyperlipoproteinemia (types I, IV, V) Exposure: methanol, cobalt, zinc, mercuric chloride, napthalenes, cadmium, cresol, lead, organophosphates Other: scorpion bite, ampullar obstruction (neoplasm, duodenal diverticula, Crohns) Vasculitis Ischemia (hypotension) Organ transplants / Post-operative Idiopathic: makes up 10-30% of cases Note: smoking accelerates progression of pancreatitis (independent of alcohol consumption) and resultant diabetes Ddx: PUD, acute cholecystitis, early appendicitis, perforation or penetration of duodenal ulcers, mesenteric vascular occlusion, small bowel obstruction, alcoholic hepatitis, cardiopulmonary event, DKA, lower lobe pneumonia, MI (inferior wall), renal stones, ruptured or dissecting aorta Labs: Amylase/Lipase resolution in 4-5 days for amylase (6 days for lipase) / amylase level does not correlate to severity of pancreatitis Note: hyperlipidemia can mask elevated amylase Note: up to 30% of acute alcoholic pancreatitis will have normal amylase Note: amylase 5 times upper limit suggests gallstones or drug-induced // see below other causes of elevated amylase urine amylase: to distinguish macroamylasia, hyperlipidemic cases and when serum amylase is normal but clinical suspicion is high elevated K (renal failure, acidosis) Other causes of hyperamylasemia: cancer, intestinal infarction, obstruction, acute appendicitis, ectopic pregnancy/salpingitis (normal lipase), DKA, renal failure (40% of pool normally excreted/day), macroamylasemia (oversized protein is not excreted, normal lipase) salivary gland disease (including vomiting) (should have normal lipase) / pulmonary disease Imaging: KUB pancreatic/biliary calcifications, localized ileus, blurring of psoas shadow, dilation of transverse colon CXR elevation of diaphragm(s), pleural effusion(s), basilar infiltrates, atelectasis Abdominal U/S enlargement, gallstones, pseudocysts Abdominal CT edema, necrosis or phlegmon, fluid collection / must use contrast to best detect areas of necrosis (30-50% infection which raises mortality from 10 to 30%) ERCP therapeutic/diagnostic try to avoid during acute attack, unless necessary to remove impacted stone / should do in patients > 45 yrs to r/o cancer Complications: GI: ileus, peritonitis, infarction, cholestasis Phlegmon necrosis ( may become abscess (usu. 2-3 wks) Abscess antibiotics +/- surgery Pseudocysts (granuloma, fibroma) may resolve in 6 wks, but if > 6 cm, painful, growing in size, infected ( must be drained Bleeding main hepatic or splenic emergent surgery Metabolic complications: hypocalcemia, hypoglycemia, hyperkalemia, hyperlipidemia, metabolic acidosis (normal anion-gap, leakage of bicarbonate) Pulmonary: atelectasis, pneumonia, pleural effusion, ARDS Renal manifestations Hematological: leukocytosis, anemia, DIC Prognosis: > 5 Ransons criteria (see below) ( 75% mortality Treatment: supportive care: watch, NPO (NG if necessary), IV fluids, nutritional support, pain management prophylactic antibiotics (carbapenems or pip/tazo or cefepime/flagyl) start when necrosis is suspected/observed ERCP for choledocholithiasis (see above) May need surgery for pancreatic sepsis Ransons criteria Initial: age > 55, WBC > 16, glucose > 200, LDH > 350, AST > 250 Within 48 hrs: Hct !10 pts, BUN ! > 5 after hydration, PO2 < 60, Ca < 8.0, base deficit > 4, est. fluid sequestration > 6 L Acute interstitial pancreatitis (mild cases) small foci of pancreatic and fat necrosis / peritonitis sudden onset epigastric pain, tender to deep palpation, may radiate to back / temporarily elevated serum amylase / prompt recovery / may relapse Acute hemorrhagic pancreatitis (severe cases - 50% mortality) liquefactive necrosis and hemorrhage / inflammatory cells not numerous / peritonitis sever epigastric, back pain / nausea and vomiting / shock / elevated serum amylase (3-5 days) / serum lipase rises later, elevated 10 days / jaundice (25%) / hypocalcemia (rare) with fat necrosis, DIC, ARDS Chronic pancreatitis Classic Triad ( abdominal pain, malabsorption, diabetes Causes: chronic alcoholism >> idiopathic (25%), autoimmune (10%), other / men > women / dilated ducts filled with fluid or calcium carbonate stones Complications: atrophy, fibrosis, chronic inflammatory cells / pancreatic pseudocysts, calcification early: chronic mild pain, nausea and vomiting late: pancreatic insufficiency (steatorrhea, secondary diabetes mellitus), malabsorption (40% with B12 deficiency), painful seizures Other: calcific pancreatitis of the tropics, hereditary, hyperparathyroidism, cystic fibrosis, pancreas divisum (2 ducts), miscellaneous Treatment: Endoscopic therapy with dilation, stone removal, long term stent placement stone extraction and drainage works in 80% of selected cases (dilation > 6 mm) initially, benefit lasts 5 yrs in 50% Pancreaticojejunostomy (current thinking 1/07 is surgery more effective [NEJM]) Pancreatic enzymes can induce feedback inhibition of meal-stimulated secretion in order to reduce pain (only marginally effective with normal pancreatic anatomy) / not effective with pancreatic calcifications, ductal stones or ductal dilation Autoimmune pancreatitis [HYPERLINK "http://content.nejm.org/cgi/content/full/355/25/2670"NEJM] 10% of chronic pancreatitis / men > women 2:1 / 50s Presentation: usually not like acute, jaundice and/or chronic symptoms / 15% will have IBD / can affect lungs, kidney also Diagnosis: idea is to exclude pancreatic cancer (may even need surgical biopsy if clinical and lab picture not convincing; including response to steroids) and alcoholic pancreatitis CT shaped enlargement with homogeneous attenuation, moderate enhancement, and the peripheral rim of a hypoattenuation halo [ HYPERLINK "pics/autoimmunepancreatitis-ct.jpg" CT] MRI/MRCP diffusely enlarged gland, may see hypointense halo and/or diffuse attenuation of the main pancreatic duct or a small, strictured main pancreatic duct ERCP focal, diffuse or segmental attenuation of the main pancreatic duct and the disappearance of right-angled branches FNA biopsy pathological specifics still being worked out 12/06 Labs: elevated IgG4 Treatment: prednisone 40 mg qd x 1 week then taper (repeat imaging in 2-4 weeks; should show regression in some and eventually most if not all of lesions) Hereditary pancreatitis: loss of autodestructive regulatory process Pancreatic Cancer (Carcinoma of Pancreas 5th leading cancer death / 50-60s / men 2:1 / smoking is risk factor adenocarcinoma in dense fibrous stroma / lymphatic and blood invasion frequent Labs: elevated CA 19-9, hemoccult positive (50%) Diagnosis: CT and ERCP Ddx: cancer of ampulla of Vater, distal common bile duct, duodenum Prognosis: 5 yr survival with Whipples (10-15%) / average 5 yr survival (3%) / body mostly fatal Head involves bile duct early (Courvoisiers law ( with jaundice and palpable gall bladder), causes death before mets / distal region / obstructed, fibrotic (islets last to go) Labs: average bilirubin 18 mg/ml (much higher than with gall stones) Body, Tail peritoneal implants, lymph mets, liver mets / constant LUQ pain unrelated to eating, worse at night and supine / depression, weight loss, anorexia, ascites / Trousseaus sign (migratory thrombophlebitis; also caused bother other mucin producing carcinomas) Treatment: 15% of cases (mostly those starting in head of pancreas) are operable ( Whipple procedure has 1% mortality rate, and in patient w/ only nodal involvement ( 5 year survival 20% For unresectable or advanced pancreatic carcinoma, chemotherapy and/or endoscopic stenting is palliative only (average survival < 6 months) Note: do not need tissue diagnosis to undertake surgery if tumor is resectable (no vena caval involvement, pt is otherwise a surgical candidate), otherwise consider FNA to r/o lymphoma and/or guide chemotherapy Islet cell tumors Insulinoma most common / beta-cell tumor / hypoglycemia / Treatment:  HYPERLINK "pharm.doc" \l "streptozocin" streptozocin Zollinger-Ellison Syndrome (ZES) gastrinoma / causes hypersecretion of HCl and recalcitrant peptic ulcer disease / suspect gastrinoma with ulcers in distal duodenum or jejunum, refractory (even to surgery), concomitant diarrhea, other evidence for MEN I Diagnosis: secretin and calcium infusion tests cause paradoxical rise in  HYPERLINK "labs.doc" \l "gastrin" gastrin levels Glucagonoma causes weight loss, intertriginous erosive dermatitis, angular cheilitis Multiple Endocrine Neoplasia (MEN) MEN 1 (Wermers) Parathyroid hyperplasia Pituitary, adrenal cortex Pancreatic islets (gastrinoma ( gastric hypersecretion +/- peptic ulceration or calcitonin-secreting tumor) MEN 2 (Sipples) Parathyroid hyperplasia Medullary carcinoma of thyroid Pheochromocytoma Exam: thick lips, kyphosis, pectus excavatum MEN 3 thyroid pheochromocytoma and/or ganglioneuroma (mucosal neuroma syndrome) Other Pancreatic Situations Annular pancreas most commonly presents with vomiting from duodenal obstruction Schwachman syndrome rare / pancreatic insufficiency and neutropenia METASTATIC DISEASE TO THE PANCREAS AND PERIPANCREATIC REGIONS uncommon - 3% to 11% of all pancreatic cancers Lymphatic, direct >> hematogenous (lung, kidney (RCC), breast, / rarely - melanoma, sarcoma, stomach, ovary, uterus) Ultrasound, CT, and ERCP MRI and CT for diagnosing hypervascular tumors (neuroendocrine neoplasms or renal cell carcinoma) Gall Bladder Diagnostic Tests RUQ U/S MRI or MRCP Excellent sensitivity (95%) and specificity (97%) for presence and level of obstruction; less sensitive for stones (92%) or telling malignant from benign (88%) ERCP 1-9% of post-ERCP pancreatitis (1% severe); advantage is you can remove stones, place stents, etc. Cholelithiasis (gall stones) Very common / 10-20% of patients > 65 yrs (only 10% develop symptoms within 10 yrs) Acute calculus >>> chronic calculus >> acute acalculus > chronic acalculus Presentation: biliary colic (epigastric pain, often after meals, may radiate to right shoulder, last about 1-4 hrs) Labs: elevated alk phos, elevated bilirubin (> 3g/dL suggests common duct stone) Complications: obstruction (cystic or common bile duct) ( may lead to gallstone pancreatitis,  HYPERLINK \l "cholangitis" cholangitis biliary fistula (necrosis) gallstone ileus (erosion into bowel 98% caused by gall stones) Treatment (see acute cholecystitis): do not treat asymptomatic gallstones (if symptomatic, consider cholecystectomy, lithotripsy is 2nd line) / 40% recur within 6 weeks Cholesterol (Fat ((cholesterol), Female 3:1, Fertile, > Forty, Familial, Hispanic) Risk factors: women 3:1, increasing age, obesity, Hispanic, familial mixed type (cholesterol, bile, Ca, protein)  most common stone(s) aggregate, smooth / chronic cholecystitis / growth by accretion supersaturation 7 -hydroxylase deficiency (! bile salt pool) / obesity (cholesterol secretion nidus, nucleation secreted glycoprotein as nidus / deficiency of anti-nucleating factor calcium pigment calcium and bile / normal gall bladder / multiple, small, sharp black hemolysis, increased unconjugated bilirubin in bile brown bacterial cholangitis, increased unconjugated bilirubin in bile (due to bacterial hydrolysis) often in intra/extra hepatic ducts / malnourishment Acute cholecystitis less common than chronic (often superimposed on chronic) Presentation: severe RUQ pain (Murphys signpain with inspiration on palpation of RUQ), fever, leukocytosis, enlarged gallbladder, prior h/o pain Imaging: Ultrasound: 90% with stones, gallbladder wall thickening, distended gall bladder, pericholecystic fluid  HYPERLINK \l "mrcp" MRCP ERCP, IOC or PTC (percutaneous transhepatic cholangiography) KUB shows 20% of stones HIDA scan (hepatoimminodiacetic acid) for tagged bile output (gall bladder does not fill if cystic duct is obstructed) Complications: hemorrhage, ulceration, gangrene if inflammation subsides, may leave hydrops (thin wall, clear fluid) or empyema (calcium carbonate rich secretion, not pus) / asymptomatic stones have a 2% complication rate/yr Organisms: E. coli, klebsiella, bacteroides, Enterococcus, pseudomonas Emphysematous cholecystitis: Clostridium perfringens and diabetics / may perforate (5%) Treatment: antibiotics (e.g. Unasyn) to allow patient to cool down for a few days until can have gall bladder removed; see cholangitis below Cholecystectomy in pregnancy (4 indications) acute cholecystitis (operate after antibiotics and decreased temperature) ascending cholangitis (very serious, STAT operation) pancreatitis (usually from small stones) obstruction (pt with jaundice) Treatment: cefoxitin (anaerobes), gentamicin (GNR) Chronic cholecystitis 90-95% with stones / rarely typhoid fever / mucosal atrophy or ulceration, fibrosis, Rokitansky-Aschoff projections, calcification or porcelain gall bladder / can happen in people who dont have gall bladder (stones formed in ducts) Presentation: chronic indigestion, large fatty meals aggravate (CCK stimulated contraction) Treatment: symptomatic cases treated with cholecystectomy, (rarely) shock-wave lithotripsy, litholytic drugs Acute cholangitis Presentation: Charcots triad ( fever, jaundice, RUQ pain / Raynauds pentad: add hypotension, mental status changes / and elevated WBC Ultrasound: may see evidence of obstruction CT scan CXR: may see sympathetic effusion (left) Treatment: if stable, can give abx such as Unasyn 3 g q 6 until patient is cooled off and then the obstruction must be relieved either by ERCP or IOC; if patient unstable, must do emergent ERCP or IOC (w/ sphincterotomy or tube placement) Carcinoma of gall bladder (usually incurable) 1 in 50,000 / if discovered incidentally, 5 yr survival 50%, if symptomatic, 1 year survival of 5% / associated with chronic cholecystitis / finding of porcelain gall bladder carries 25% risk of progression to carcinoma and requires open cholecystectomy (because cannot risk having it be malignant and rupture) / liver and lymph mets / adenocarcinoma (80%), anaplastic (10%), squamous (5%) Carcinoma of extra-hepatic biliary apparatus (usually incurable) men / 5yr survival of 10% ampulla of Vater (soft, papillary), common duct (hard, infiltrative), confluence of hepatic and common duct (Klatskin tumor) / obstructive jaundice (first sign), upper abdominal pain, hepatomegaly Risk factors: ulcerative colitis, sclerosing cholangitis, clonorchis sinensis infection Diagnosis: U/S, CT, ERCP or PTC Spleen 25% with accessory spleen Splenic Infarction Diagnosis: DPL (diagnostic peritoneal lavage), U/S, CT Treatment: repair or remove based on amount damaged / observe (especially in children, who get post-splenectomy sepsis) Note: dont forget to give the  HYPERLINK "pharm.doc" \l "vaccine" vaccines for Hib vaccine, pneumococcus and N. meningitis Indications for splenectomy  HYPERLINK \l "#itp" ITP + spherocytosis, bleeding and diseased states ( HYPERLINK "micro.doc" \l "#ebv" EBV, malaria, trauma) distal pancreatectomy failed medical therapy of autoimmune hemolytic anemia GI Surgery (more) Anastomoses of bowel segments / must remove bacteria (bowel prep solutions) in order to increase wound healing (some authors suggest decontamination with polymyxin, tobramycin, vancomycin, and amphotericin B) Pimp anatomy: Marginal artery of Drummond, anastomosis of Riolan Liver [ HYPERLINK \l "liverlabs" Liver Function Tests]  HYPERLINK \l "hepatitis" Hepatitis HYPERLINK "micro.doc" \l "hepatitis"Viral Hepatitis (HYPERLINK "micro.doc" \l "hepatitisa"HAV, HYPERLINK "micro.doc" \l "hepatitisb"HBV, HYPERLINK "micro.doc" \l "hepatitisc"HCV) ( HYPERLINK "micro.doc" \l "viralhepatitislabs" hepatitis labs)  HYPERLINK \l "alcoholichepatitis" Alcoholic hepatitis  HYPERLINK \l "autoimmunehepatitis" Autoimmune hepatitis  HYPERLINK \l "nash" Non-alcoholic fatty liver disease Biliary System  HYPERLINK \l "gallbladder" Gall Bladder ( HYPERLINK \l "cholelithiasis" cholelithiasis,  HYPERLINK \l "cholecystitis" cholecystitis,  HYPERLINK \l "cholangitis" cholangitis)  HYPERLINK \l "biliary" Biliary Cirrhosis (PBC), Sclerosing Cholangitis (PSC)  HYPERLINK \l "alpha1liver" alpha-1-antitrypsin,  HYPERLINK \l "wilsons" Wilsons, HYPERLINK \l "hemochromatosis"Hemochromatosis Cirrhosis ( HYPERLINK \l "ascites" ascites,  HYPERLINK \l "sbp" SBP)  HYPERLINK \l "portalcirrhosis" Portal cirrhosis /  HYPERLINK \l "pncirrhosis" Post-necrotic cirrhosis /  HYPERLINK \l "portalvenous" Portal venous hypertension  HYPERLINK \l "liverneoplasia" Liver Neoplasia  HYPERLINK \l "livertransplant" Liver Transplant  HYPERLINK \l "fnh" focal nodular hyperplasia  HYPERLINK \l "hca" hepatocellular adenoma  HYPERLINK \l "hcc" hepatocellular carcinoma Lab evaluation of liver disease Lab error rate usually about (3-4%) serum bilirubin ( HYPERLINK \l "pedbilirubin" see pediatric) jaundice when serum bilirubin above 3mg/dL / high serum levels may correlate to severity of chronic liver disease / G-6-PD patients (black) may have disproportionately high bilirubin (hemolysis) 5mg/dl and PT > 4 seconds (50% mortality) in patients with acute alcoholic hepatitis causes of unconjugated bilirubinemia include hemolysis, impaired hemoglobin synthesis, genetic defect of bilirubin transport into hepatocyte urine bilirubin unconjugated BR is bound to albumin and cannot be filtered / early indicator for liver disease (even before jaundice / pyridium and phenothiazide give false positive results urine urobilinogen absence on dipstick indicated biliary obstruction / elevation may mean liver injury (impaired re-uptake of serum urobilinogen) or hemolysis / can be an early marker for liver damage fecal urobilinogen rarely used / antibiotics may suppress bacterial conversion of bilirubin to urobilinogen albumin not early or sensitive due to 14-20 day half-life, large stores / can be decreased from renal loss great marker for severe, chronic liver disease / good response to therapy will see a rise above 3g/dl prothrombin time (PT) [11-13] useful in assessing prognosis of severe acute/chronic liver disease / 2, 7, 9, 10 / PTT may also be elevated in severe liver disease Hepatocellular aminotransferase (AST/ALT) [10-40] absolute level of no prognostic value (mainly used as an early indicator) / AST (heart, liver, muscle, kidney, some pancreas/spleen) / ALT (many tissues, highest in liver, some in kidney) / AST reaches higher levels than ALT in non-hepatic injury / AST over 400 units/liter is liver or skeletal muscle, an MI above 200u/l would be severe and obvious / acute liver injury may reach 400-1000u/l, obstruction will not be over 400u/l / values may drop from 1000 to 300 in just 3-5 days (masking previously high levels) 80% alcoholic liver disease (AST > ALT) alcoholics are PBP deficient (this is a false-phenomenon also seen with fatty liver associated with pregnancy) ALT cytosol / injured cell releases enzymes into circulation male > female, higher in winter, Hispanic/native American higher, increased weight, married > single / ALT reaction measures activity (step 1 requires PBP, step 2 uses NADH, measures NAD production) / test results can vary based on many factors (including drugs and solutes in the patients blood sample) AST in organelles? Similar reaction, but not dependent on PBP Only T! of increased AST with liver disease (type B and O blood has increased activity) Cholestatic Alkaline phosphatase (AP) [75-125] Liver (80%), bone (20%), GI (1%), placenta / AP also elevated in growing children / but in the presence of jaundice, large increases (3-20 fold) suggest obstruction, infiltration and mild increases (1-3 fold) suggest hepatocellular injury / normal AP argues strongly against liver disease / local increase in bile acids increases de novo AP synthesis / if anyone asks, liver AP is heat-labile, GI AP is heat-stabile Gamma-glutamyl transferase (GGT) very sensitive, not selective (pancreas, heart, lungs, kidney) / elevated by drugs (ethanol, phenobarbital, phenytoin) and diabetes, some drugs increase hepatocyte membrane (releases GGT into circulation) / may confirm AP / inhibited by gestational hormones (non-informative in pregnant women) Other enzymes LAP and 5-NT only in liver and placenta (not bone) / may confirm AP / many false negatives LDH may rise moderately in several liver diseases (mild in obstructive) / marked increases may result from liver mets Other tests (not often used) bromosulphopthalein BSP, indocyanine green, meg-x, aminopyrine, caffeine Hepatitis Labs Viral Hepatitis Labs ( HYPERLINK "micro.doc" \l "viralhepatitislabs" see micro) [HYPERLINK "pics/hbv1.jpg"diagram] [HYPERLINK "pics/hbv2.jpg"diagram] Autoimmune Hepatitis Labs ANA, ASMA, LKM-1, AMA lab values can show large variability even from the same lab anti-ANA used with SMA to diagnose lupoid hepatitis (unrelated to SLE) ASMA chronic active hepatitis (60%), biliary cirrhosis (10%) / transient rise with EBV LKM-1 rare type of autoimmune hepatitis (not having ANA or SMA) type II AMA 100% of primary biliary cirrhosis (M2 fraction) 25% chronic active hepatitis (M4) alpha-fetoprotein endoderm derived (peak at 12 weeks gestation) / malignant  HYPERLINK \l "hcc" HCC or  HYPERLINK \l "yolksactumor" germ cell tumors (>1000ng/ml) others include pancreas, gall bladder / used to follow progression, not for diagnosis Complications/Findings of Liver Failure/Cirrhosis Decreased hepatic function neurological: encephalopathy (confusion, somnolence, coma) from elevated ammonium coagulopathy: increased PT (lack of clotting factors) hypoglycemia lactic acidosis jaundice estrogen metabolism decreased (spider angiomas, redistribution of hair, etc.) Ascites (see Ddx below) Presentation: dyspnea, umbilical hernia Mechanisms: hydrostatic, oncotic (decreased albumin) / SAAG usually high in mixed cases / portal vs. malignant (can tap more fluid off safely with malignant ascites because hemodynamics are less likely to be embarrassed) SAAG (serum ascites albumin gradient = serum albumin ascitic albumin) [ HYPERLINK "ddx.doc" \l "ascites" more Ddx] > 1.1 g/dL: cirrhosis, portal vein thrombosis, Budd-Chiari, CHF, constrictive pericarditis, urinary extravasation, hypothyroidism, Meigs, hydronephrosis < 1.1 g/dL: peritoneal infection, peritoneal carcinomatosis, pancreatic ascites, bowel obstruction or infarction, serositis (e.g. SLE), nephrotic syndrome Physical exam: JVD/pulsatile liver / KUB ( ground glass w/ centrally located bowel loops Note: all new or unexplained cases of ascites should undergo paracentesis (may rule in infectious/tuberculous, primary hepatoma or malignant seeding / you should inoculate cultures at bedside Hepatic hydrothorax Negative inspiratory pressure causes buildup of ascitic fluid through small diaphragmatic holes Treatment: same as ascites except avoid tube thoracostomy because this will just pull more fluid into pleural space / refractory cases can consider VATS to correct any defect or pleurodesis Nephrogenic ascites diagnosis of exclusion / intractable ascites with resultant cachexia / mechanism is multifactorial (i.e. unclear) / occurs from 20 months pre to 70 months post-initiation of dialysis from ESRD / dialysis associated hypotension may be a harbinger / M:F 2:1 / survival ~ 10 months / best treatment is bilateral nephrectomy with renal transplant / some benefit from CAPD, or peritoneovenous shunt Varices (see GI bleed) esophageal, hemorrhoidal, caput medusae (ammonia bypasses liver and reaches CNS causing  HYPERLINK \l "hepaticencephalopathy" hepatic encephalopathy) Treatment: meds/endoscopy (banding preferred over sclerotherapy), TIPS if endoscopy fails Portal Gastropathy (GI bleed) gastric mucosa is weakened by portal hypertension and more likely to bleed Peritonitis usually from perforation of abdominal viscus, but portal HT is the first cause of spontaneous peritonitis in adults (may have more insidious onset, lack of peritoneal signs) / 50% mortality / more than 250 PMNs/mL Hepatorenal syndrome Unrelenting renal failure because of liver failure Types of Cirrhosis Portal cirrhosis alcohol / portal tract to portal tract, tract to central vein / small, pseudo-lobules (regenerating tissue, no intralobular structures) Post-necrotic cirrhosis chronic active hepatitis and autoimmune hepatitis / patchy distribution (piecemeal necrosis) / irregular broad bands of fibrosis / variable sized nodules / also called portal triaditis Biliary Cirrhosis portal tract to portal tract / central veins are spared Portal venous hypertension [HYPERLINK "pics/portal.jpg"diagram of portacaval anastomoses] Pre-portal: portal vein thrombosis, schistosomiasis Sinusoidal: HCV, HBV, alcohol Post-portal: Budd-Chiari, pericarditis, renal failure Budd-Chiari occluded IVC/hepatic vein / polRV?, pregnancy, HCC / SAAG > 1.1 Fibrocongestive splenomegaly greater in post-necrotic, hemolysis, pigment gall stones Hepatitis (Hepatocellular) Viral: hepatitis  HYPERLINK "micro.doc" \l "hepatitis" virus A - G / CMV / EBV / Yellow Fever Bacteria: Coxiella, TB Parasites: Echinococcus Drugs: Antibiotics: rifampin, PZA, INH, macrolides CNS: phenytoin, VPA, carbamazepine, antipsychotics, pemoline, methyldopa, MAO inhibitors Other: PTU, indomethacin, diclofenac, halothane Toxins: EtOH, Neoplasms: Other:  HYPERLINK \l "alpha1liver" alpha-1-antitrypsin,  HYPERLINK \l "wilsons" Wilsons, HYPERLINK \l "hemochromatosis"Hemochromatosis Alcoholic hepatitis heavy alcohol consumption / Mallorys hyaline / neutrophilic infiltrate / fatty change, hydropic change, fibrosis around central vein / AST:ALT > 2 / < 300 AST Non-alcoholic fatty liver disease (NAFLD) 20% of US adults (1 in 30 develop cirrhosis or less commonly HCC, ESLD requiring transplant) Risk factors: obesity, type 2 DM, hyperlipidemia Diagnosis: biopsy is only way to tell prognosis and r/o other diseases / LFTs may not correlate / macrovesicular accumulation of fat (fatty deposits) Treatment: ?gemfibrozil, vitamin E, thiazolinediones (promising but trials underway 11/06) / too rapid wt loss is actually harmful Non-alcoholic steatohepatitis (NASH) progression/complication of NAFLD but when hepatocyte necrosis occurs Acute Fatty Liver of Pregnancy microvesicular fat Reyes Syndrome microvesicular fat Granulomatis hepatitis in AIDS may not be able to produce impressive granulomas Acetaminophen toxicity Ingestion of 10g or more Mechanism: increased p450 metabolism (NAPQI formation) and depletion of glutathione stores (leads to NAPQI persistence) Labs: LFTs reaction to normal dose ( markedly increased AST / moderately increased ALT / AST:ALT > 2 / increased to markedly increased PT / huge overdose ( normal initially, later markedly increased AST and ALT Treatment: N-acetylcysteine should be started within first 10 hrs, continued 72 hrs Ischemic hepatitis bile duct obstruction Hypotension Sudden, very high rise of AST 24-48 hrs peak Rapid normalization within 7-10 days after reperfusion Concomitant renal impairment Fatty change acute alcohol consumption, metabolic derangement (TPN) Total Parenteral Nutrition (TPN) Useful: critical illness, pre-BMT, liver failure, pancreatitis, severe IBD; with cancer cachexia, only really useful for short term just prior to surgery (otherwise the TPN will not overcome the net negative of cachexia; analogous to albumin loss issue in liver disease) Hepatic steatosis (25 to 100%) increase in LFTs with smaller increase in alkaline phosphatase peak ~2 weeks, then decline even with continued TPN / reversible Long-term TPN Chronic liver injury in adults steatohepatitis (common) / can lead to fibrosis (discontinue, cycle, reduce calories and/or supplement with small amount of enteral nutrition) cholestasis and hepatic fibrosis (uncommon) Biliary sludge (50% > 6 wks, ~100% > 3 months) Gallstones (acalculus and calculus cholecystitis) From decreased bile flow and gallbladder stasis (can try CCK, pulsed amino acids, small enteral feedings) Autoimmune hepatitis Diagnosis: piecemeal necrosis on liver biopsy, also correlate with serology Treatment: steroids +/- azathioprine, cyclosporine, tacrolimus, MMF, liver transplant Type 1 classic autoimmune hepatitis ANA, ASMA,  HYPERLINK "labs.doc" \l "ama" AMA (rarely) Type 2 LKM-1, ASMA (occasional), Type 3 generally seronegative, ASMA (occasional), AMA (rarely) Type 4 (PBC) ANA, ASMA, AMA (rarely) Primary biliary cirrhosis (PBC) autoimmune destruction of small intrahepatic bile ducts / females 35-60 / cholestasis late / Presentation: usu. begins with pruritis Labs: high  HYPERLINK "labs.doc" \l "ama" AMA (>1:40), elevated  HYPERLINK "labs.doc" \l "alkphos" alkaline phosphatase (2-5x !) Diagnosis: liver biopsy shows lymphocytic destruction of bile ducts Associations: T! have Sjogren s / 20% have CREST / 17% with autoimmune thyroiditis / can get various lung disease (IPF, granulomatous, lymphocytic interstitial pneumonitis, pulmonary HTN, pulmonary hemorrhage) Secondary biliary cirrhosis obstruction / edema, inflammation / portal tract lesions, but hepatocytes intact AMA (-), lower alkaline phosphatase Sclerosing Cholangitis Primary: 5% of ulcerative colitis Secondary: many causes / in AIDS pts CMV, cryptosporidium, PCP, MAI (some) Primary Sclerosing Cholangitis (PSC) [HYPERLINK "http://content.nejm.org/cgi/content/full/332/14/924"NEJM] men (70%), 75% of PSC and cholangiocarcinoma occur in IBD patients (UC >> Crohns) / 3 per 100,000 (1:100 as much as alcoholic cirrhosis) / 4th leading indications for liver transplant Mechanisms (speculated): chronic portal bacteria, toxic bacterial metabolites of bile, ischemic damage, genetic/immunological Location: mostly intra/extrahepatic ducts (15% with gall bladder/cystic duct too) Presentation: asymptomatic until obstructive liver disease signs develop, episodes of  HYPERLINK \l "cholangitis" acute bacterial cholangitis (fever, chills, lab abnormalities) / steatorrhea, vitamin A deficiency Course: may evolve over many years / mean age at diagnosis 40 yrs, survival 12 yrs from diagnosis Labs: hypergammaglobulinemia in 30% (elevated IgM 50%), pANCA (65%), ASMA (10%), ANA (20%), elevated obstructive liver enzymes, elevated urinary copper and serum ceruloplasmin Ulcerative Colitis: more with early age onset of UC / may precede symptoms of UC by many years (diagnosed with ERCP) / some say some degree of UC exists in all PSC / PSC does not correlate with activity of UC Other associations: thyroiditis, type I DM Complications: liver failure, cholangiocarcinoma (20% of PSC patients, even 20 yrs after colectomy, smoking and presence of IBD increases risk), vitamin K deficiency (rare, but happens with chronic jaundice, cholestyramine use), vitamin D deficiency (osteoporosis) Diagnosis: ERCP (fine ulcerations, dilatation, narrowing) with cholangiogram [HYPERLINK "pics/n-psc1.gif"pic] [HYPERLINK "pics/n-psc2.gif"pic] / transhepatic cholangiogram is the 2nd choice / percutaneous liver biopsy will probably miss lesions (concentric fibrosis around bile ducts) but can be used to follow disease Ddx: stricture/obstruction from previous surgery, cholangitis, bile duct neoplasms, choledocholithiasis, congenital biliary tree abnormalities Treatment:  HYPERLINK "pharm.doc" \l "ursodiol" ursodiol is of debatable utility, steroids are not helpful (other immunosuppressives under investigation), ERCP may diagnose and treat complications, liver transplant only proven cure (cholangiocarcinoma is relative contraindication to transplant); may experience sclerosing cholangitis (recurrence vs. rejection vs. bacteria from roux-en-Y) Pruritis: cholestyramine, colestipol binds bile acids / naloxone (elevated endogenous opiates implicated) / ursodiol, odansetron, m-testosterone, rifampin, phenobarbital, antihistamines, UV light, plasmapheresis Recurrent cholangitis: optimal antibiotic choice and use of preventative abx under investigation Alpha-1-antitrypsin ( HYPERLINK \l "a1lungs" see lungs) cholestatic liver disease in infancy, cirrhosis and/or portal hypertension / chronic liver disease / MM normal / ZZ abnormal Hemochromatosis [ HYPERLINK "http://content.nejm.org/cgi/content/full/350/23/2383" NEJM] Primary: inherited disorder / 5-10% frequency of gene in population [most common mutation can be tested, small minority have other mutations] / AR / most are homozygote for the C282Y mutation of the HFE gene increased iron absorption, progressive iron overload Pathology: increased Fe uptake (normal 3 g, increased to 20-40 g) / women lose 20-30 mg at menses / hemosiderin deposition (causes direct damage to liver, pancreas) Secondary: increased absorption (chronic liver disease, iron-loading anemias, porphyria cutanea tarda, dietary overload) or parenteral administration (multiple blood transfusions) of iron / secondary has much less total iron build-up (ferritin) Presentation: often diagnosed early with fatigue, arthralgias (25-50%) or increased AST/ALTs or ( fatigue, arthralgias (frequent), skin pigmentation (90%, gray or bronze color), liver disease (RUQ pain, hepatomegaly, cirrhosis, HCC), and diabetes Complications: micronodular cirrhosis, diabetes, skin pigmentation, restrictive cardiac failure, arthritis (may have CPPD, often 2nd and 3rd MCP (1st most-asked pimp question in history of mankind), impotence / 200 x risk of  HYPERLINK \l "hcc" HCC (30% incidence) Labs:  HYPERLINK "labs.doc" \l "ferritin" ferritin increased (proportional to iron burden), transferrin increased (Fe %sat) Diagnosis: liver biopsy can be useful to quantify iron overload and assess liver fibrosis (can also use genetic testing to risk stratify patients for development of fibrosis/cirrhosis (look for presence of the C282Y or H63D mutation) Ddx: can have falsely high ferritin levels from other diseases Treatment: phlebotomy, deferoxamine Course: life expectancy goes to normal if treated before cirrhosis Wilsons disease AR mutation in ATP7B gene / onset in 10s to 20s Mechanism: abnormal copper transport causes increased GI absorption and decreased clearance Liver: hepatitis, cirrhosis CNS: extrapyramidal signs (hypertonia, rigidity, tremors, clumsiness), range of psychiatric disorders Eyes: Kayser-Fleischer rings in cornea and sunflower cataracts Renal: hematuria, tubular dysfunction Hemolytic anemia: may be presenting finding (occurs in 10-50%), circulating Cu kills RBCs, may have elevated  HYPERLINK \l "a2" HgA2 Presentation: hepatitis 1st (jaundice, malaise, anorexia) that usually resolves / may effect only liver or various organ combinations Labs: serum ceruloplasmin < 20 ug/dl, urine Cu > 100 ug/24 hrs / elevation of serum copper can be a non-specific sign of cholestatic liver disease / low  HYPERLINK "labs.doc" \l "lap" LAP score Treatment:  HYPERLINK "pharm.doc" \l "penicillamine" penicillamine (given with pyridoxine) / restrict dietary intake (shellfish, legumes) / maintenance therapy with oral Zinc (decreases absorption) Liver Abscess Pyogenic: Organisms: E. coli, Klebsiella, Bacteroides, Enterococcus Diagnosis: CT guided sampling Treatment: antibiotics +/- drainage Amebic: 2-5 months after travel to endemic area / occurs in 3-25% of intestinal amebiasis (especially with HIV) /most common presentation: RUQ abdominal pain Diagnosis: positive antibodies in 98% of cases (indirect hemagglutinin test) / ultrasound 75-85% sensitivity Treatment:  HYPERLINK "pharm.doc" \l "metronidazole" metronidazole usually works +/- chloroquine, but drain if rupture is imminent Parasitic: echinococcus Diagnosis: U/S or CT (90% sensitive and direct aspiration may seed peritoneum), eosinophilia, positive heme agglutination Treatment: open resection (do not spill), instillation ethanol or 20% NaCl Liver Neoplasia 5% of liver tumors are benign Hemangioma most common benign liver tumor / incidence of 7% of population / usually clinically unimportant but can cause consumptive coagulopathy Presentation: pain (can rupture), jaundice (can obstruct) Diagnosis: do NOT biopsy (risk of bleeding) / peripheral enhancement on CT, arteriography Focal Nodular Hyperplasia central stellate scar / unencapsulated, but well-defined / central blood supply, not likely to rupture / 2 cells thick / females 2:1 / not related to OCPs / any age / 20% symptomatic from mass effects / not precursor to HCC Hepatocellular Adenoma (not HCC precursor) 1 per million / risk factors: females, reproductive years, birth control pills (40 x risk) Pathology: peripheral blood supply, may rupture (1/4 present with circulatory collapse) causing necrosis (increased ALT and CT findings) / portal tracts absent Presentation: pain (may not be present; can rupture), jaundice (can obstruct) / more common in right lobe Labs: LFTs usually normal, a-FP negative Treatment: remove hormones (stop OCPs, etc.) / tumor likely to regress spontaneously / however, may resect if symptomatic, > 10 cm or not regressing / patients should avoid pregnancy which increases likelihood of hemorrhage Hepatocellular carcinoma (HCC) very common worldwide / 3 per 100,000 in US (and rising) / males > female / 95% liver tumors are malignant Risk Factors: HBV,  HYPERLINK "micro.doc" \l "hcv" HCV (major cause in US), alcoholic cirrhosis, hemochromatosis, smoking?, vinyl chloride, OCPs Pathology: large mass with satellite lesions / may be green with bile / 50% with mets to regional nodes, lung Presentation: weight loss, RUQ, shoulder pain, weakness Physical Signs: hepatomegaly, portal hypertension, ascites, jaundice (50%) Diagnosis: often positive  HYPERLINK "labs.doc" \l "afp" AFP (elevated in germ cell tumors; >500 suggestive, >1000 almost diagnostic) Ultrasound: cystic v. solid / radiography: benign v. malignant / CT or MRI: multiplicity and anatomical / hepatic arteriography to diagnose hemangioma Treatment: wedge resection (often difficult due to underlying liver disease) / entire lobectomy does not improve survival transplant can be curative in selected patients (must have single lesion < 5 cm or 3 or fewer < 3 cm) Prognosis: no treatment ( 3 month survival / with resection ( 3 yr survival / 5 yr survival rate is 10-50% / with successful transplant survival same as nonmalignant liver transplant patient Liver metastases most common malignant liver tumor / one source( colon > stomach > pancreas > breast > lung / another source ( lung > colon > pancreas > breast > stomach Treatment: liver mets from colon cancer (up to 3 lesions) should be resected (some say 4-5) Liver Transplant [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/15/1545" NEJM] Child-Pugh rating system: must have >= 7 to qualify for liver transplant / get points for INR, low albumin, ascites, hepatic encephalopathy Must demonstrate (in rehab) no alcohol/drugs for 6 months Malignancy develops in 2%-7% of transplant recipients (from immunosuppression) (100 fold > than normal) / transitional cell Ca of UG tract and renal cell Ca, skin and lips, lymphomas (esp. CNS), cervical, lung, head and neck, colon / onset time 1-158 months (avg. 40) / lymphomas develop faster Hematology [ HYPERLINK \l "oncology" onc] [ HYPERLINK \l "transfusionmedicine" transfusion medicine]  HYPERLINK \l "anemia" Anemia ( HYPERLINK \l "anemiaworkup" work up) [ HYPERLINK \l "anemiaddx" Ddx]  HYPERLINK \l "hemolyticanemia" hemolytic anemia,  HYPERLINK \l "hellp" HELLP,  HYPERLINK \l "aplasticanemia" aplastic anemia HYPERLINK \l "hemoglobinopathy"Hemoglobinopathy  HYPERLINK \l "sicklecell" sickle cell,  HYPERLINK \l "thalassemia" thalassemia  HYPERLINK \l "thrombocytopenia" Thrombocytopenia [ HYPERLINK "ddx.doc" \l "thrombocytopenia" Ddx] HYPERLINK \l "hit"HIT,  HYPERLINK \l "ttp" TTP,  HYPERLINK \l "itp" ITP,  HYPERLINK \l "apa" APA  HYPERLINK \l "coagulation" Coagulation Bleeding disorders  HYPERLINK \l "hemophilia" Hemophilia,  HYPERLINK \l "vonwillebrands" Von Willebrands  HYPERLINK \l "hypercoagulability" Hypercoagulability  HYPERLINK \l "apa" APA,  HYPERLINK \l "apc" factor V,  HYPERLINK \l "prothrombin" G20210  HYPERLINK \l "renalthrombotic" Thromboembolic  HYPERLINK \l "renaldic" DIC,  HYPERLINK \l "hellp" HELLP,  HYPERLINK \l "ttp" TTP,  HYPERLINK \l "hus" HUS,  HYPERLINK \l "hsp" HSP  HYPERLINK \l "leukemia" Leukemia  HYPERLINK \l "all" Lymphoblastic  HYPERLINK \l "all" ALL,  HYPERLINK \l "aml" AML,  HYPERLINK \l "cll" CLL,  HYPERLINK \l "hairycell" Hairy Cell  HYPERLINK \l "myeloproliferative" Myeloproliferative  HYPERLINK \l "cml" CML,  HYPERLINK \l "myelofibrosis" myelofibrosis,  HYPERLINK \l "thrombocythemia" thrombocythemia,  HYPERLINK \l "prv" PRV,  HYPERLINK \l "leukemoid" leukemoid reaction  HYPERLINK \l "plasmacell" Plasma cell dyscrasias  HYPERLINK \l "multiplemyeloma" MM,  HYPERLINK \l "wm" WM,  HYPERLINK \l "heavychain" heavy chain disease,  HYPERLINK \l "monoclonal" benign monoclonal gammopathy HYPERLINK \l "histiocytoses"Histiocytoses  HYPERLINK \l "lymphoma" Lymphoma  HYPERLINK \l "hodgkins" Hodgkins  HYPERLINK \l "nhl" NHL  HYPERLINK \l "lymphomab" B-cell  HYPERLINK \l "smalllymphocytic" small lymphocytic,  HYPERLINK \l "cleavedcell" cleaved cell,  HYPERLINK \l "largecelllymphoma" diffuse large cell,  HYPERLINK \l "burkitts" Burkitts  HYPERLINK \l "lymphomat" T-cell  HYPERLINK \l "adulttcell" adult T-cell,  HYPERLINK \l "lymphoblastic" lymphoblastic,  HYPERLINK \l "sezary" Sezary Basic Principles Clotting Cascade [HYPERLINK "pics/h-clottingcascade.jpg"diagram][HYPERLINK "pics/f-clottingcascade.jpg"diagram] [HYPERLINK "pics2\\hematology.html"hematology lab slides] Hb conc. in whole blood RBC count hematocrit Male 14-18 g/dL male 4.7-6.1 e6/ul male .42 - .52 Female 12-16g/dL female 4.2-5.4 e6/ul female .37 - .47 Mean corpuscle volume (MCV) hematocrit/RBC count (use fudge factor) normal 80-94 fL (normocytic may include high degree of variation - anisocytosis) false elevation with  HYPERLINK \l "coldagglutinins" cold agglutinins Mean corpuscular Hb Hb/RBC count (fudge factor) MCHC Hb/hematocrit (normo, hyper or hypochromic) Neutrophils Dohle bodies (vague, blue cytoplasmic inclusions) blacks may have lower low end (1160 vs. 1700) Eosinophils Eosinophilia: AEC > 500-750 / NAACP (Neoplasm, Allergy, Addisons, Connective tissue diseases, Pancreatitis) / Other: atheroembolic vasculitis, IBD, sarcoidosis, TB, parasitic infection Eosinophiluria: caused by eosinophilia and BPH/prostatitis, RPGN Basophils no mitotic potential Mast cells mitotic potential Lymphocytes dont confuse activated lymphocytes with leukemic blasts Platelets number in one oil immersion field x 20K Other plasma cells, endothelial cells, histiocytes, nucleated RBCs, myeloblasts Anemia [ HYPERLINK \l "anemiaddx" causes of anemia] Hb < 12 Hb < 15 in neonate Hct < 37 Hct is 50 in neonate, then drops to 30 and gradually increases to puberty levels Physiology anemia in tissue produces more 2,3-DPG, shifts Hb curve to the right redistribution of blood flow away from kidneys and skin increased cardiac output (in severe anemia) physiologic anemia in young infant 2o shift in oxygen dissociation curve clinical signs of acute anemia: syncope, orthostatic hypotension, orthostatic tachycardia very acute hemorrhage ( normal Hct and Hb (corrects with fluid intake) clinical signs of ongoing anemia: tachycardia, pallor (conjunctiva, lips, oral mucosal, nail beds [ HYPERLINK "pics/pallor-nails.jpg" pic], palmar creases), jaundice, petechiae, purpura (TTP), glossitis (pernicious anemia, iron deficiency), systolic ejection murmur, S3, splenomegaly (hemolysis, neoplasia, infiltration), LAD Anemia Work-Up Consider: age, sex, color, ethnic, neonatal, nutrition/diet, drugs, diarrhea, inflammation, infection, pica, prosthetic valves, guaiac status, Initial workup:  HYPERLINK \l "reticulocytecount" reticulocyte count iron studies (TIBC, ferritin, %sat) haptoglobin, LDH, direct/indirect Bilirubin serum or RBC folate, B12 More workup:  HYPERLINK \l "peripheralsmear" peripheral smear, Coombs, Hgb electrophoresis,  HYPERLINK \l "bonemarrow" bone marrow Classification of Anemia Normochromic, Normocytic Marrow hypoplasia (drugs, radiation)  HYPERLINK \l "aplasticanemia" Aplastic anemia Marrow infiltration (myeloma, lymphoma, leukemia) Myelofibrosis Renal insufficiency  HYPERLINK \l "hemolyticanemia" Hemolytic anemia Acute hemorrhage Anemia chronic disease Hypochromic, Microcytic  HYPERLINK \l "ida" Iron deficiency (most common)  HYPERLINK \l "thalassemia" Thalassemia  HYPERLINK \l "porphyria" Porphyria? Sideroblastic anemia (lead, INH, EtOH, congenital) Anemia of chronic disease (?rarely) Normochromic, Macrocytic Folate, Vitamin B12 Drugs (AZT, TMP, pentamidine, phenytoin, primidone, phenobarbital [mild], chronic nitrous oxide) Myelodysplasia Liver disease Note: elevated MCV (reticulocytes have increased diameter) Reticulocyte count reticulocytes live about 1-1.5 days then circulate 120 days absolute reticulocyte count (normal 50-70,000/mm3) reticulocyte production index (normal 1.0 to 2.0) reticulocyte x [patients Hct / normal Hct] x [1/RBC maturation time] <1 % is inadequate production, > 4% RBC destruction corrected reticulocyte count accounts for any anemia Peripheral Smear Cell Types  HYPERLINK \l "spherocytosis" Spherocytes hereditary/secondary (autoimmune-mediated hemolysis) Tear drop cells (extramedullary hematopoeisis) myeloproliferative disease (e.g.  HYPERLINK \l "myelofibrosis" myelofibrosis), pernicious anemia, thalassemia Helmet cells microangiopathic hemolysis, severe iron deficiency Schistocytes microangiopathic hemolysis [ HYPERLINK "pics/schistocytes.jpg" pic] Sickle cell HbSS Findings Hypochromic lead, iron deficiency Hyperchromic B12, Folate, spherocytosis Basophilic stippling lead, hemolysis, thalassemia Pappenheimer bodies postsplenectomy, hemolytic, sideroblastic, megaloblastic Rouleaux formation multiple myeloma, Waldenstroms, other conditions Parasites Malaria, Babesiosis Nucleated RBCs extramedullary hematopoeisis, hypoxia, hemolysis Target cells hemoglobinopathies, iron deficiency, liver disease Heinz bodies (denatured Hgb) (requires supravital stain) unstable hemoglobinopathies, some hemolytic anemias Howell-Jolly Bodies (nuclear fragments) - hemolytic, megaloblastic, asplenia Cabot ring (nuclear remnants) megaloblastic Bone marrow exam myeloid/erythroid or M:E ratio / hyporegenerative, aplastic anemia / diagnosis of leukemia aspirate Wright smear / more painful core biopsy stained biopsy (and aspirate clot) for neoplasm, granuloma Dx Ineffective Hematopoeisis Causes: metabolic deficiency, primary stem cell defect (e.g.  HYPERLINK \l "mds" MDS), abnormal bone marrow microenvironment (autoimmune, infectionsHIV, Tb, histoplasmosis) Pathology: hypercellular marrow with thrombocytopenia, anemia, low reticulocyte count Iron metabolism There is no excretory pathway for iron (only through skin and GI loss) menstruating women may lose 7 mg/day (30 mg/month) vs. 1 mg/day other males/females Fe2+ absorbed in duodenum (1-2 mg of 15 mg total intake), transferrin takes Fe3+ in cell and blood, stored as ferritin (Fe3+/apoprotein) in equilibrium between blood and marrow histiocytes hemosiderin in histiocytes in erythron (iron > apoprotein) Iron deficiency anemia (IDA) [ HYPERLINK "http://www.nejm.org/content/1999/0341/0026/1986.asp" NEJM] Epidemiology: black females have slightly decreased Hgb in general / women > 50 (2%), < 50 (5%), men (~1%) Causes: Blood loss (GI bleeds): ulcer, cancer, angiodysplasia, IBD, hookworm Uterine blood loss: menstruation, fibroids Malabsorption: gastrectomy, celiac disease, IBD Intake problem: bovine milk-fed infants (not enough Fe), pregnancy, vegetarian diet Clinical: fatigue, shortness of breath, may have cravings for dirt or paint (pica) or ice (pagophagia), glossitis, cheilosis, koilonychias / rare/advanced cases: postcricoid esophageal web (Plummer-Vinson syndrome) Labs: TIBC and FEP increase, decreased Fe saturation (<10%) decreases may precede other findings / low RPI, increased TIBC (transferrin), decreased ferritin, absent iron stores in marrow, increased protoporphyrin and zinc-protoporphyrin / may have elevated RPI and thrombocytosis due to bleeding (caused by iron deficiency) Peripheral smear: hypochromic, microcytic [ HYPERLINK "pics/microcytic-irondeficiencyanemia.jpg" pic] / anisocytosis, poikilocytosis when severe Note: peripheral smear may distinguish from thalassemia minor / RDW > 15 supports Fe deficiency (because marrow is producing a lot of erythrocytes; lower RDW suggests stable thalassemia) 2-3 months minimum age of onset Treatment: oral ferrous sulfate / parenteral iron (use cautiously because of increased risk of anaphylaxis) / transfusion (see other) Anemia of chronic disease (new term is anemia of chronic inflammation) inflammatory cytokines (hepatic synthesis of hepcidin) ( decreased RBC lifespan, impaired iron metabolism (including absorption), refractoriness to erythropoietin / slightly decreased MCHC / normo/macrocytic Labs: decreased TIBC and Fe saturation (10-20%) but increased ferritin (usually) and Fe in macrophages [note: ACD may co-exist with IDA and make these labs difficult to interpret] Treatment: can you use Epogen? Sure! Patients with ACD can have a so-called relative deficiency in erythropoietin levels (elevated but not enough for degree of anemia, in spite of normal kidneys) Sideroblastic Anemia (microcytic) Lead (Pb), alcohol,  HYPERLINK "pharm.doc" \l "inh" INH toxicity / congenital form (sex-linked) Labs: increased Fe, increased Fe saturation, increased ferritin Smear: dimorphic population of microcytic and normocytic cells [ HYPERLINK "pics/microcyticanemia.jpg" pic] / may have basophilic stippling / ringed sideroblasts (developing RBCs with engorged mitochondria due to faulty heme synthesis) in bone marrow Aplastic Anemia or Pure Red Cell Aplasia (normocytic) Infections: HBV, EBV,  HYPERLINK "micro.doc" \l "b19" B19, HTLV, HIV Drugs: Ara C, chloramphenicol, phenylbutazone, TMP-SMX, Dilantin) Other: precursor to leukemia, autoimmune (SLE, RA), thymoma, lymphoma, hereditary, pregnancy Labs: giant pronormoblasts on peripheral smear, ! erythropoietin Treatment: if cause can be determined, sometimes immunologically active meds (prednisone, cyclosporin, IVIG) can be helpful Anemia of Renal Failure Mechanism: decreased RBC lifespan with inadequate erythropoietin response (this may actually be more complicated than just this, studies suggest increased CHF if over-normalized by Epogen 11/06) Labs: BUN > 36, Cr 3-5, Hg may be < 7 / Fe labs are normal (may become Fe deficient following hemodialysis losses) Exceptions: HUS (increased erythropoiesis), polycystic (normal erythropoiesis), diabetes mellitus (decreased erythropoiesis relative to state of renal failure) Anemia of liver disease Chronic: impaired LCAT leads to burr cells and stomatocytes Alcoholic: bone marrow suppression, folate deficiency, dietary inadequacy, blood losses Megaloblastic anemia (leukopenia, thrombocytopenia) problems making DNA, so precursors get held up in marrow, macrocytic Folate made into THF by DHF reductase / FIGlu (histidine metabolite) is a marker for folate deficiency / malnourished, milk-fed, pregnant, drugs (phenytoin, isoniazid, phenobarbital, primidone, cycloserine) B12 Molecular: important in reversing the folate trap / methylmalonic acid is a urine marker for folate deficiency (folate helps metabolize odd-chain fatty acids) Diagnosis: > 2 hypersegmented PMNs/HPF [HYPERLINK "pics/hypersegmentedneutrophil-b12deficiency.jpg"pic], macrocytic anemia, decreased WBC, decreased platelets / direct B12 / Schilling test (not needed now) / consider doing one EGD to r/o adenocarcinoma Presentation: you can have CNS Sx without hematological findings Causes: pernicious anemia (see below) dietary deficiency - only in vegans because body stores last several years malabsorption IF not produced by parietal cells (gastrectomy) terminal ileum lesions - Crohns, celiac disease, etc. bacterial overgrowth or D. latum (fish tapeworm) Pernicious anemia [ HYPERLINK "http://www.nejm.org/content/1997/0337/0020/1441.asp" NEJM] B12 deficiency / Ab to IF or gastric mucosa (anti-parietal Ab positive in 90%) / young blacks, old whites / 20-30% with family history disease Presentation: jaundice (hemolysis), cheilitis, glossitis (burning tongue, atrophy of papillae, deep/red mucosa, cobblestone appearance) Neuropathy paresthesias, weakness (demyelination in posterior columns) CNS: megaloblastic madness - constellation of symptoms Associations (autoimmune): vitiligo, thyroid Treatment: 1 mg SC x 3 d and check reticulocyte count Pediatric Anemias birth 12 months Blackfan-Diamond Syndrome 12 mo 5 yrs transient erythroblastopenia of childhood (TEC) follows viral infection, like childhood ITP, usually self-limited any age transient erythroid aplasia in hemolytic disease follows viral infection, exacerbates underlying hemolytic disease late childhood on pure red cell aplasia Blackfan-Diamond Syndrome congenital macrocytic anemia due to (lack erythropoietin receptors?) / presents within months of birth / associated with Turners and thumb abnormalities / may see urinary, cardiac, skeletal anomalies / Treatment: corticosteroids may help Transient Erythroblastopenia of Childhood (TEC) normocytic / 6 months 4 yrs / usually only one episode per life / may require transfusion Hemolytic anemia Dx RPI to establish bone marrow response / look for erythrocyte detritus / increased unconjugated bilirubin, increased urobilinogen in urine (dark urine), free serum decreased haptoglobin / can measure haptoglobin, free serum Hb, urine Hb, hemopexin, methemalbumin / Note: haptoglobin, serum and urine Hb not as altered with extravascular hemolysis Mechanical Intravascular artificial heart valves,  HYPERLINK \l "dic" DIC,  HYPERLINK \l "ttp" TTP, malignant HTN (microangiopathic) produces hemosiderin in urine, Hb in serum/urine, and schistocytes (broken cells) Extravascular RES enlargement produces spherocytes/chopped cells (could be considered immune-mediated by macrophages eating RBCs) Autoimmune mechanisms Warm agglutinins (occurs at any temperature) IgG against certain universal Rh component (more extravascular, i.e. RES plucks RBCs out of circulation, gives spherocytes, not schistocytes) [ HYPERLINK "pics/microspherocytes-hemolyticanemia.jpg" pic] may be drug-induced ( HYPERLINK "pharm.doc" \l "methyldopa" methyldopa), autoimmune (SLE et al) or alloimmune (erythroblastosis fetalis, transfusion reaction) Treatment: remove offending agent and/or steroids / also consider cyclophosphamide, azathioprine, danazol, IVIG, rituximab) / splenectomy in refractory cases Cold agglutinins IgM against I antigen on RBC / paroxysmal cold hemoglobinuria - anti-P antigen Causes: HYPERLINK "micro.doc" \l "mpneumoniae"Mycoplasma pneumoniae and (rarely) EBV Labs: same as other hemolytic anemias (! haptoglobin, ! MCV, erythroid hyperplasia) Treatment: steroids, splenectomy, replacement, other? Infectious C. perfringens sepsis (and other GP/GN sepsis), malaria (and other protozoa), Bartonella, Tb (local and disseminated), Borrelia, Leptospirosis, malaria, mumps Chemical Agents, Drugs, and Venoms Oxidant Drugs and Chemicals Oxygen (high pressure) / Vitamin E deficiency in infants Nitrates, cisplatin, naphthalene (mothballs), nitrofurantoin, sulfonamides, ASA, sodium sulfoxone Dapsone and phenazopyridine (Pyridium) also are associated with Heinz body hemolysis triamterene, methyldopa, rifampin Nonoxidant Mechanisms PTU arsine (metal industry, transistor, gold refining) give exchange transfusions Trimellitic Anhydride (plastic industry) lead copper (see Wilsons disease) Water (drowning with entry of > 0.6 L) Hemodialysis (contaminants) Other Agents Venoms spiders ( HYPERLINK "micro.doc" \l "brownreclusespider" brown recluse, hobo spider), snakes (cobras, Australian king-brown, saw-scaled carpet viper), Bee Stings (very rarely), scorpions Physical Agents Thermal Injury, ionizing irradiation (debatable) Hypophosphatemia ( HYPERLINK "#hypophosphatemia" see lytes) Paroxysmal Nocturnal Hemoglobinuria (PNH) massive intravascular hemolysis / 4 to 6 per million Mechanism: acquired somatic mutation (H or I) in PIG-A gene on X chromosome (decay accelerating factor) / causes non-specific activation of complement ( hemolysis ( cell-free hemoglobin acts as NO scavenger ( decreased NO may cause most of symptoms Presentation: abdominal pain, esophageal spasms, erectile dysfunction, venous thrombosis (esp. European descent) Findings: bone marrow hypoplasia with up to 13% aplastic anemia; thus may have anemia and/or  HYPERLINK "ddx.doc" \l "thrombocytopenia" thrombocytopenia without positive urine Hb), tea or cola-colored urine (or bright red in up to S!) Labs: Prussian blue will stain urine for hemosiderin / low  HYPERLINK "labs.doc" \l "lap" LAP score Treatment: oral iron supplementation if iron-deficient, BMT may be used as last resort for aplastic anemia, eculizumab (antibody against C5 complement factor) is under investigation 9/06 Glucose-6-phosphate dehydrogenase deficiency (G6PD) XLR / most common metabolic disorder ([! of world s population) / 100 different variants / variable predominance and expressivity across ethnic groups (ranges from mild to life-threatening) / A-type occurs in 15% of black males / Mediterranean variant is more severe Mechanism: glutathione peroxidase reduced peroxides to water / relies on reduced GSH, requires NADPH from hexose monophosphate shunt (first step is G-6-PD) neonatal hemolysis and jaundice only in premature infants / also less severe in blacks because young RBCs have more enzyme function and are not susceptible to drug-induced attacks, so the hematocrit does not fall as much Causes (of acute attacks): Drugs: many antibiotics (sulfamethoxazole, nitrofurantoin), anti-malarials, phenacetin, vitamin K, seizure meds, chemotherapy agents, HIV meds infection favism (severe Mediterranean variant) due to fava beans Labs: Heinz bodies / can have false negative G6PD levels during crisis (because decreased levels occur in older RBCs, not new ones being produced) Diagnosis: measure decreased levels of GPI anchors or GPI-linked surface proteins CD55 or CD59 Treatment: usually self-limited once offending agent removed Pyruvate kinase deficiency autosomal recessive / RBCs have impaired glycolysis, reduced ATP, and lyse Spherocytosis Primary hereditary spherocytosis: abnormal cytoskeletal protein (spectrin) (AD) Secondary: autoimmune hemolysis Findings:  HYPERLINK "ddx.doc" \l "splenomegaly" splenomegaly / increase in MCHC / may have normal appearing peripheral smear Diagnosis: osmotic fragility test Treatment:  HYPERLINK \l "splenectomy" splenectomy curative RBC infection malaria, Carrions disease, babesiosis, C. perfringens sepsis March hemoglobinuria massive intravascular hemolysis Hemoglobinopathy Hemoglobinopathy is abnormal structure of a globin chain Physiology Increased O2 affinity elevated erythropoietin, erythrocytosis Decreased O2 affinity blue Hb > 5 g/dL leads to cyanosis Methemoglobinemia Causes: oxidizing compounds (nitrites, dapsone, local anesthetics, some anti-malarials, various chemicals: anilines, nitrosohydrocarbons) Mechanism: O2 saturation curve shifted to left (too much Fe3+) or HbM / also caused by NADH-diaphorase deficiency (used to reduce circulating metheme) Labs: elevated blood levels of HbM, peripheral smear (Heinz bodies, bite cells) Presentation: cyanosis, gray-brown cyanosis or brownish discoloration of patients skin (at levels of 15-20%) and blood, hemolysis, tachycardia, tachypnea, lactic acidosis (levels > 45%) O2 sats or pulse oximetry will be in 80s (or normal) in spite of normal PaO2 (because the oxygen is in the blood, just not delivering to tissues properly) Treatment: 100% O2, can give IV methylene blue for levels > 30% or symptomatic or evidence of ischemia, in severe cases consider exchange transfusion and/or hyperbaric O2 Unstable Hb (Heinz body anemia) RBC becomes rigid, lysed by RE system / Heinz bodies seen with supravital dye Sickle Cell Disease (HbS) Genetics: valine as 6th amino acid on B-chain / masked for 6 months by HbF (a2d2) / alpha thalassemia carriers have lower MCHC and less severe course / HPFH (hereditary persistence of HbF) also lessens severity / electrophoresis (not solubility) to distinguish trait Mechanism: deoxy-HbS forms tactoids causing sickling, dehydration at cellular level (as well as circulatory), activated platelets release thrombospondin which binds sickled RBCs Triggers: deoxygenation, acidosis, dehydration, venous stasis, variations in body temperature / physical, emotional stress also a trigger Presentation: anemia, jaundice, cholelithiasis, aplastic crisis, hemolytic crisis, dactylitis, leg ulcers, priapism, renal papillary necrosis, infarctive crisis, sequestration crisis (sudden pooling of RBC in RES, common COD in young patients / autosplenectomy usually complete before age 5, Sickle C and thalassemias may have splenic sequestration into adulthood Complications: Heme: hemolytic anemia, can have aplastic crisis, channel defects give target cells, congestive heart failure Renal: nephrotic syndrome, progressive renal failure (decreased erythropoietin), isosthenuria, mild nitrogen retention, inability to concentrate urine, painless hematuria (also sickle cell trait) GI: choledocholithiasis (mimic gall bladder pain), cholecystitis Infections/Immune compromise cellular immunity depressed, B-cell antibody production depressed, splenectomy (allows increased susceptibility to encapsulated organisms) increased UTI (commonly precipitates crises / UTI also increased with sickle trait) pneumonia (esp. mycoplasma) osteomyelitis (S. aureus, Salmonella) abscesses Infarcts/hemorrhages more common in children / can involve large veins Bone: fish-mouth vertebrae (biconcave), expansion of bone marrow, aseptic necrosis (head of femur), chronic leg ulcers CNS: stroke (can necessitate blood transfusion to decrease viscosity), cognitive (silent infarcts), sub-arachnoid hemorrhage and seizures (breakdown product of Demerol also causes seizures) Eye: retinopathy, vitreous hemorrhages, retinal detachment (blindness) / risk increases with age (vascular) hepatic infarcts, icterus [HYPERLINK "pics/eye-icterus.jpg"pic] papillary necrosis priapism Labs: CBC: Hgb 7-10 (rarely higher than 10) / 5 or less suggests associated G6PD or folate deficiency / total WBC 15-20 / reticulocytosis (except in aplastic crisis) / macrocytosis (many young RBCs) [ HYPERLINK "pics/sickledcells.jpg" pic] peripheral smear: splenic dysfunction ( sideroblasts, target cells, Howell jolly bodies [HYPERLINK "pics/sicklecellsmear.jpg"pic] LDH is useful to validate presence of hemolytic state Diagnostic studies: newborn screening / 99% of sickle cell patients present before age 1 anyway metabisulfite test: will show sickling in blood specimen of any patient with HbS or sickle cell trait or HbC monitor HBS levels (predict crisis frequency) monitor blood counts (based on clinical assessment) pulmonary function testing reduce ACS # / determine need for IS and -agonists transcranial Doppler (predict stroke risk) Treatment: Note: avoid use of CT contrast (may worsen crisis and cause major problems) Fluids: replace fluid liberally (rule out concentrating deficits) cellular hydration: Mg salts, Clotrimazole (small doses inhibit Gados channel) Other: bed rest, O2, ? steroids, IVIG Pain control: morphine, meperidine, hydromorphone Prophylaxis (with appropriate antibiotics) until ready for HYPERLINK "pharm.doc#pneumovax" \l "pneumovax"Pneumococcal vaccine folate / L-arginine (under investigation) ACE inhibitors reduce proteinuria, slow progression of renal failure [ongoing studies] Induction of HgF hydroxyurea (3-4 wk onset, also increases cell volume, decreases granulocytes) [usually only used in severe cases] 10-15 mg/kg/day q am 6-8 wks / check blood counts, increase dose if necessary / consider reasons for failure of HgF induction acceptable myelotoxicity plat > 80,000 WBC > 20,000 / 1/3 respond to hydroxyurea [6 months 1yr onset] short chain fatty acids (may work faster) Transfusion: acute/chronic anemia / renal failure / many other needs / do NOT transfuse just to elevate Hg/Hct unless indicated (uncomplicated surgery, pregnancy, anemia-induced end-organ ischemia, anemia-induced pain, to decrease viscosity with ongoing thrombosis, stroke) Course: 60% at least one episode per year / 1-2% have constant pain ( > 6 episodes/yr) Prognosis: peak mortality: 6 months 1 yr / late adolescent, young adults Acute chest syndrome Definition: new pulmonary infiltrate on CXR, fever, respiratory symptoms (can be due to pneumonia, PE, vaso-occlusion) Incidence: children and young adults (4 fold greater incidence), often occurs perioperatively Causes: bone marrow embolism, fat embolism, infection (14% bacteremic, chlamydia > mycoplasma > RSV) older patients w/ ACS ( more pain, more mortality Treatment: Oxygen (give oxygen even if sats okay because it reduces sickling of RBCs) Bronchodilators Antibiotics (must cover typical and atypicals, use macrolides or quinolones) Transfusion for PaO2 drop of more than 10% or PaO2 < 70 / exchange transfusion if Hct already e" 30 (Careful) hydration (give fluid, but not so much to cause pulmonary edema) Long term  consider hydroxyurea aplastic crisis most often from parvovirus B19 / usually self-limiting but may require transfusion HbC (excellent prognosis) mutation on B chain (lys(glu) / crystalloids (pathognomonic, rarely seen in smear) / many target cells (codocytes) / retinal vascular lesions worse in SC than SS patient / tend to have enlarged spleen rather than asplenia HbE SE Asians (not Chinese or Japanese) / microcytosis, hypochromia / may have target cells on peripheral smear but no clinically significant anemia Thalassemias Epidemiology: Mediterranean, SE Asia, Africa Mechanism: low supply of one chain(s) results in buildup of remaining chains / hypochromic/microcytic (normal RDW, uniform size) / severe forms lead to extramedullary hematopoeisis, splenomegaly, hypersplenism, folate deficiency and perhaps megaloblastic anemia, hyperuricemia Diagnosis: hemoglobin electrophoresis / totally iron levels usually normal Treatment: transfusions (see below for each subtype) A 22 normal Hb F 2y2 fetal Hb A2 2d2 microcytic anemia marker - ! in -thalassemia, ! in Fe deficient anemia H 4  -thalassemias / forms Heinz bodies / causes hemolysis Bart s y4  -thalassemias in fetus/infants Bo thalassemia (major) no B chains / only survive (until puberty) if they also inherit persistent HbF B+ thalassemia (B+ severe / B+ negro) increased HbA2, except in dB thalassemia / MCV < 80 heterozygotes ( thalassemia minor homozygotes ( thalassemia major (B+ negro homozygotes have thalassemia intermedia)  -thalassemia (each haplotype codes for 2 alpha chains, which do not cross over) (a-)  -thalassemia-2 gene (--)  -thalassemia-1 gene (a-/aa) 20% African Americans / lessens severity of HbS (a-/a-) or a-thalassemia trait / microcytic, slightly hypochromic / no significant anemia (--/a-) causes HbH buildup and minor to major thalassemia (--/--) causes severe anemia, CHF in utero leads to hydrops fetalis Peripheral smear shows high RBC, basophilic stippling (distinguishes from Fe deficiency) Transfusion Medicine  HYPERLINK \l "ffp" FFP,  HYPERLINK \l "cryoprecipitate" cryoprecipitate,  HYPERLINK \l "ivig" IVIG,  HYPERLINK \l "platelets" platelets, factor VIII Blood transfusions Indications: Hgb 7g/dL usually enough (except in cardiovascular disease where Hct > 30 desired) Labs: expect rise in Hct 3% for each unit of PRBCs (300cc; 250 mg iron) Risk of infections: HCV: 1 in 103,000 / HTLV I, II, HIV: 1 in 700,000 / HBV: 1 in 66,000 / B19 Bacterial contamination rare, parasites ruled out by screening questions Adverse reactions (see  HYPERLINK \l "hemolyticanemia" hemolytic anemia) Overall rare of occurrence: 1-4% ABO incompatibility Presentation: hypotension, hemoglobinuria, chills, fever, flank pain Treatment: stop transfusion, may even need dialysis to remove Ab complexes Milder, delayed hemolytic reactions Febrile non-hemolytic reactions (range from minor to major) Treatment (mild): Tylenol, Benadryl Treatment (severe): similar to hemolytic anemia TRALI: transfusion related lung injury (can mimic aspiration pneumonia; can cause severe pulmonary edema requiring mechanical ventilation) / caused by antibodies in donor blood against HLA on host WBCs Platelet transfusion Each unit increases platelet count by 5 to 10,000/mm3 Indications: < 50,0000 with bleeding or < 10,000 Fresh Frozen Plasma (FFP) Cryoprecipitate Precipitated FFP ( fibrinogen, some clotting factors / less volume than FFP Intravenous Immune Globulin (IVIG) Uses:  HYPERLINK \l "itp" ITP, hemolytic anemia, premature babies, autoimmune neutropenia, burn victims, leukemia, myeloma / works faster than other agents / can be useful for refractory autoimmune diseases including dermatomyositis, ITP, SLE, has been used in  HYPERLINK "micro.doc" \l "tsst" TSST (S. aureus), many more indications IV infusion over ~5 days / given in 3 month cycles? / very expensive / made from pooling many samples (watch out for BSE) Dosage: 400 mg/kg for 5 days (high-dose 1 g/kg over 5 days for acute chronic ITP) Note: avoid in patients with IgA deficiency (can get anaphylaxis from preformed Abs) Side effects: often causes aseptic meningitis (~bad headache lasting 24-48 hrs, give Tylenol before IVIG) Factor VIIa (recombinant) Being studied for use in acute ICH to limit expansion of hemorrhage (optimal guidelines being worked out 1/07) Factor VIII Highly purified form may not have enough vWF in it to treat  HYPERLINK \l "vwd" vWD Thrombocytopenia [ HYPERLINK "ddx.doc" \l "thrombocytopenia" Ddx] HYPERLINK \l "hit"HIT,  HYPERLINK \l "ttp" TTP,  HYPERLINK \l "itp" ITP,  HYPERLINK \l "apa" APA,  HYPERLINK \l "dic" DIC ITP (Idiopathic Thrombocytopenic Purpura) [ HYPERLINK "http://content.nejm.org/cgi/content/full/355/16/1699" NEJM] General: platelet destruction by RES / NO splenomegaly / occurs more in women 20-40 yrs / 85% acute, 15% chronic / harbinger of SLE Childhood: acute post-viral event (weeks later, IgG mediated), may last up to 6 months because IgG is distributed throughout all ECM (33% of body water) / chronic ITP of childhood similar to chronic ITP of adulthood Labs: normal clotting time, prolonged bleeding time / Ab unhelpful because of many false positives Ddx: other causes of  HYPERLINK "ddx.doc" \l "thrombocytopenia" thrombocytopenia Treatment:  HYPERLINK "pharm.doc" \l "ivig" IVIG works fast, may last for weeks (give when platelets < 10,000) prednisone 1-2 mg/kg platelet transfusion often consumed immediately splenectomy and immunosuppressants are last resort Prognosis: children ( 3-6 months then resolves spontaneously Adult ( insidious, subacute to acute / uncommon spontaneous remission Heparin-induced thrombocytopenia (HIT syndrome) Incidence: 1-5% of heparin exposees Early (type I): day 2 to 3, usu. not severe, not mediated by IgG Late (type II): one week, antibodies that aggregate platelets in presence of heparin (bind to complex of platelet factor 4 and heparin), can persist for 6 wks, causes thrombosis / formation of antibodies influenced by type of heparin, dose, and circumstance (2% baseline, 15% ortho patients, 50% CABG patients) / only some HIT-patients become thrombocytopenic Note: risk of thrombosis (white-clot syndrome) is higher than risk of bleeding at 5-10% per day even first few days after heparin discontinued (including patients w/ HIT and normal platelet counts) / mean platelet drop to 60,000 / only 5% drop to < 15,000 Findings: red/necrotic lesions at sites of SC injection, decreased platelets by 30% Labs: check HIT Abs or PF4 antibodies (takes several days to come back; high sensitivity but this test only has moderate specificitybecause there can be anti-PF4 antibodies which are not clinically pro-thrombotic) Treatment: avoid heparin (including heparin flushes), avoid warfarin and ancrod (during the acute phase) because they may exacerbate prothrombotic state / if thrombosis present or other indication for anticoagulation, must use  HYPERLINK "pharm.doc" \l "lepirudin" lepirudin or  HYPERLINK "pharm.doc" \l "argatroban" argatroban (direct thrombin inhibitors) or possibly danaproid and/or long-term warfarin / thrombolysis, thrombectomy, IVIG, plasmapheresis, antiplatelet agents as indicated Coagulation ( HYPERLINK \l "Hypercoagulability" see hypercoagulability) [HYPERLINK "pics/h-clottingcascade.jpg"diagram of clotting cascade] [HYPERLINK "pics/thrombin.gif"thrombin] Pro-coagulants Initiating pathway (extrinsic) PT defective VII (tissue factor) has clinical bleeding Maintenance pathway (intrinsic) aPTT defective VIII, IX, XI have clinical bleeding Defective V, X, prothrombin/thrombin both PT and aPTT are increased All sorts of cells secrete tissue factor (stimulated by Il-1B) Binds 7a and then 10 forms 10a (inhibited by  HYPERLINK "pharm.doc" \l "lovenox" LMWH) Regulated V and VIII is important (they act as scaffolds for reactions) Anti-coagulants Plasminogen to plasmin, which competes with thrombin for the same sites on the clot Thrombin-thrombomodulin-nice closed loop with protein C, which inactivates V and VIII Inhibitors can sometimes be diluted 400/500 fold with normal plasma and still prevent clotting Protein C and Protein S regulate coagulation Antithrombin III (stimulated by HYPERLINK "pharm.doc" \l "heparin"heparin) inactivates IIa and Xa TFPI acts at Xa to prevent unnecessary coagulation Liver disease (II, VII, IX, X) early liver/warfarin/vitamin K deficiency: PT rises before PTT because factor VII has shorter half-life (although that doesnt make sense to me looking at the diagram) Prolonged Thrombin Time inhibitors of thrombin heparin, fibrin degradation products (FDP) elevated in DIC / also elevated in renal failure, liver disease (see D-dimer) low fibrinogen abnormal fibrinogen - late liver disease, inherited Other tests: Fibrinogen decreased in DIC other conditions D-dimer is most specific  HYPERLINK \l "dic" test for DIC Bleeding time (unreliable due to poor technicians) Starts increasing at < 100,000 Platelet aggregometry Secretion tests Prothrombin consumption test Hemophilia [section in progress] Note: synovial cells tend not to produce tissue factor (rely on intrinsic pathway) Note: epistaxis should last less than 5 minutes (recurrent epistaxis may be benign) Hemophilia A XLR / 1 in 10,000 males / bleeding into soft-tissue, muscle, weight bearing joints / bleeding usu. occurs when levels < 5% / may occur hours or days after trauma / may involve any organ / elevated aPTT Treatment: factor VIII levels must reach 25-50% to control bleeding into joints / half-life of factor VIII only 8-12 hrs / must be given twice daily as  HYPERLINK \l "ffp" FFP,  HYPERLINK \l "cryoprecipitate" cryo (contains factor VIII activity of FFP in one tenth the volume / DDAVP (causes release of vWF from tissue and may help in very mild cases) / purified factor VIII or Humate-P (for severe cases; may be needed for weeks) Factor VIII inhibitor can be acquired (post-transfusions) or idiopathic/autoimmune Treatment: prothrombinase complexes, porcine factor VIII (may resist the anti-VIII antibodies), treat with factor VIII transfusions, factor VIIa (activates factor X), immunosuppression (steroids, chemotherapy, rituximab), human recombinant factor VIII (can give but will get used up quickly) Von Willebrands disease (vWD) most common inherited bleeding disorder / 1 in 1000 (1 in 250 have mild form) / AD variable penetrance / causes platelet dysfunction (vWF is sub-type of factor VIII which helps platelets cross link) Type I (classic) all multimers present problem is with secretion Type II (variant) large multimers absent problem with vWF or its binding site on VIII / other types Type III (severe; rare) multimers absent totally absent/defective vWF / AR Treatment: may not be adequately replaced with purified factor VIII (should give product mixtures instead)  HYPERLINK "pharm.doc" \l "ddavp" DDAVP (causes release of stored vWF; usu. adequate for treatment of type I mild disease; wont help Type III) estrogen/progesterone increase primary and constitutive secretion of vWF (increased 50% during pregnancy) Osler-Weber-Rendu [ HYPERLINK "http://dermis.net/dermisroot/en/25652/diagnose.htm" dermis] AD inheritance with incomplete penetrance / endoglin Presentation: epistaxis, skin telangiectasias, visceral AVMs / continuous bruit in systole and diastole / high-output cardiac failure GI: blood loss in 10-40% (later age) small bleeds, not hematemesis CNS: strokes, migraines, seizures (2/3 from paradoxical embolus) / 5-11% have CVMs Lungs: ~ Liver: hepatomegaly, hepatic encephalopathy, cirrhosis of HHT Kidneys: hematuria Diagnosis: contrast echocardiography, ABG, IV digital subtraction / MRI/angiography of brain and lungs (more sensitive than CT), CBC (r/o anemia) Treatment: surgical correction of AVMs Re-check patients every 5-10 yrs / children must be re-examined after puberty / screen relatives Factor XII Christmas disease? generally not clinically significant Hypercoagulability [ HYPERLINK "pics/h-clottingcascade.jpg" diagram of clotting cascade] [ HYPERLINK "pics/hypercoagulable-prevalance.jpg" prevalence chart] Congenital:  HYPERLINK \l "apc" Factor V Leiden >  HYPERLINK \l "prothrombin" prothrombin G20210A,  HYPERLINK \l "homocystinuria" hyperhomocysteinuria, HYPERLINK \l "Dysfibrinogenemia"dysfibrinogenemia Acquired: malignancy (Trousseaus), myeloproliferative, HYPERLINK \l "pnh"PNH, CTD (HYPERLINK \l "sle"SLE), HYPERLINK \l "behcets"Behets, HYPERLINK \l "buergers"Buergers Vasculitis, HYPERLINK \l "prv"PRV, HYPERLINK \l "thrombocythemia"primary thrombocythemia, HYPERLINK \l "ttp"TTP, HYPERLINK \l "dic"DIC,  HYPERLINK \l "diabeteshypercoagulable" DM Congenital or Acquired: HYPERLINK \l "antiphospholipid"APA syndrome,  HYPERLINK \l "proteinc" protein C deficiency,  HYPERLINK \l "proteins" protein S deficiency,  HYPERLINK \l "antithrombin" antithrombin deficiency III Work-up: for unexplained DVT/PE, you might start with a PCR for factor V and prothrombin mutation, presence of LA and cardiolipin Ab and check functional assay for protein C, S, ATIII Treatment: current thinking is 1 year full anticoagulation / PREVENT study supports lifelong low-dose  HYPERLINK "pharm.doc" \l "warfarin" coumadin (INR 1.5 to 2.0) (study included most types of hypercoagulable patients except not APAS) [ HYPERLINK "http://content.nejm.org/cgi/content/full/348/15/1425" NEJM] APC resistance (Factor V Leiden) most common cause (25%) of 1st idiopathic DVT / whites >> blacks, Asian / 20x risk for homozygotes (7x risk for heterozygotes) / 3-4% incidence of gene in general population / worsened by contraceptives Genetics: mutated factor V APC cleavage site (Arg 506 ( Glu 506) Labs: modified APCR assay < 2.0 aPTT / this test can be done while pt is on heparin/coumadin Treatment: heterozygotes heparin + 6 months oral anticoagulation / lifelong with 2nd episode (lifelong with 1st episode for homozygotes and in some other circumstances) Prothrombin G20210A most common cause of recurrent DVT / increased plasma prothrombin / venous/arterial thrombosis Labs: PCR / this test can be done while pt is on heparin/coumadin Treatment: heparin + 3 months coumadin and lifelong anticoagulation Anti Phospholipid Syndrome (APS or APA) antiphospholipid antibody / incidence 2-4% / causes 5-7% of strokes / 9-28% with positive anticardiolipin labs will have thrombotic complications (some say much higher) associated with  HYPERLINK \l "sle" SLE vs. primary APS (PAPS) / PAPS has higher incidence of  HYPERLINK \l "tma" TMA Other: test anyone w/ SLE who has a first thrombotic event / link between elevated IgM and elderly stroke patients Complications: strokes/TIA, seizures, chorea, dementia, migraine headaches, left sided endocarditis (Libman-Sacks) Renal: can cause a progressive kidney damage (PAPS ( TMA more common than SLE/APA ( TMA) similar but different to angiosclerosis of aging and HTN Pathology: activates platelets via Fc receptor / antibody affects X-V-Ca complex [HYPERLINK "pics/h-clottingcascade.jpg"diagram] / clotting, miscarriage, thrombocytopenia (40%), neuropsychiatric Labs: almost any combinations of labs can exist with APA, 2 positive tests > 8 weeks apart (trying to avoid false positives) prolonged aPTT does not correct with normal serum APS pts usu. have baseline platelets of 100-160 anticardiolipin antibody (IgG elevated ~30%, IgM ~20%, both decreased ~50%, and IgA not considered important) Russell viper venom test (RVVT), but you have to make sure the lupus anticoagulant is there as well (can get elevated RVVT but not significant) low titre false positive RPR anti-B2-glycoprotein Abs (B2GPI), can be the only positive lab (and tends to correlate more directly with actual disease activity, so definitely get this test if others are negative and clinical suspicion is high [this is a send-out lab] Pregnancy: 20-40% develop pre-eclampsia / 3 or more spontaneous abortions or late fetal demise Treatment: ASA (antiplatelet agents may elevate platelet counts, and a 2 week trial should be given),  HYPERLINK "pharm.doc" \l "heparin" heparin then 6 months oral anticoagulation (this may be lifelong in confirmed cases because risk of repeat event too high) / if not associated w/ SLE, could recheck in 6 months and base decision to terminate coumadin on results, sometimes disease associated positive ACL Abs disappear (lymphoma, parvovirus, other) / can give heparin, ASA to pregnant patient with APA syndrome (full dose if h/o thrombosis) Snedden syndrome livedo reticularis [ HYPERLINK "pics/livedoreticularis.jpg" pic] and CNS ischemic events (usu. associated with APA syndrome) with broken circles, its livedo racemosa [ HYPERLINK "pics/livedoracemosa.jpg" pic] Binswangers disease CNS lesions (association with APA syndrome) / diffuse white matter (WM) lesions and a scattering of lacunar infarcts in the basal ganglia and WM Treatment: antithrombin under investigation Protein C deficiency 160+ mutations / Type I vs. Type II / decreased degradation of V, VIII / decreased clot/fibrinolysis / nephropathy form / also decreased in acute clotting / because C and S also dependent on vitamin K, levels can decrease before other factors leading to warfarin induced skin necrosis [HYPERLINK "pics/proteinc1.jpg"pic][HYPERLINK "pics/proteinc2.jpg"pic] Labs: initial screen with functional Protein C assay / antigenic assay (when patient free of warfarin > 10 days) Treatment: heparin + 3 months oral anticoagulation / lifelong with 2nd episode Protein S deficiency Cofactor for APC / same mechanism as Protein C / nephropathy form Labs: initial screen with functional Protein S assay / free total antigen assay Treatment: heparin + 3 months coumadin and lifelong with 2nd episode Antithrombin deficiency 1 % prevalence / can be from nephrotic syndrome in children (but is usually only symptomatic in children, adults) / can also occur secondary to massive thrombus with APA syndrome / congenital form? / long term use of heparin (increased clearance of heparin-ATIII complexes) Mechanism: decreased inhibition of thrombin and Xa, IXa, XIIa, kallikrein (needed by both heparin and LMWH to function) Labs: initial screen with functional ATIII assay / antigenic assay Treatment: heparin + 3 months coumadin and lifelong anticoagulation / FDA has approved replacement of ATIII in nephrotic children Dysfibrinogenemia AD or acquired (liver disease, hepatoma, AIDS, lymphoproliferative / < 1 % prevalence / dysfunctional or deficient fibrinogen (a constellation of different defects) / even a severe deficiency produces mild, rare bleeding episodes (usu. noticed after surgery) Labs: prolongation of thrombin time suggests disorder, PT, reptilase time, functional vs. antigenic assay Treatment: heparin + 3 months coumadin and lifelong anticoagulation Hyperhomocystinuria ( HYPERLINK \l "homocystinuria" see other) Acquired causes (some of them) Elevated Factor VIII or IX 10-50% prevalence / impractical to measure because normal range varies a lot Renal failure some say loss of anti-clotting factors (several smaller molecular weight ones) others say activation of platelets Leukemia acute leukemia anemia, infection, hemorrhage / 30% or more blasts in bone marrow high or low peripheral WBC / identical twins have 1 in 20 chance chronic leukemia indolent course Acute Lymphoblastic Leukemia (ALL) (good prognosis) children and young adults / 85% of childhood leukemias up to 85% remission (not with adult ALL) 85% L1 / 15% L2 / L3 (Burkitts - worst) / CNS common site of relapse / 80% B-cell origin (CALLA marker) / T-cell present in thymus / 60% have cytogenetic abnormalities hyperdiploidy (good) / Philadelphia chromosome (poor prognosis) and others (t8:14, c-myc) Complications: 10-30% rate of hyperleukocytosis or blast crisis Treatment: chemotherapy with allopurinol to prevent renal calculi Blast crisis oncological emergency / elevated blood viscosity from increased circulating blasts CNS: stupor, headache, dizziness, tinnitus, visual changes, confusion, coma Lungs: respiratory distress, hypoxemia, progressive respiratory failure Treatment: admit to ICU / decrease blast cell count with leukapharesis / proceed with other diagnostics (bone marrow) and treatments Chronic Lymphocytic Leukemia (CLL) (~not rapidly progressive) most common chronic leukemia in U.S. / 50 - 70 yrs / males 2:1 95% B-cell origin [ HYPERLINK "pics/cll-bcells.jpg" pic] / incompetent lymphocytes in marrow, nodes, spleen Presentation: usually type B symptoms (weakness, fatigue, etc.), lymphadenopathy (66%), enlarged liver/spleen (10-40%) Diagnosis: 40% in marrow required for Dx (historically, not sure if still true) / can now do flow cytometry on blood and detect monoclonal B-cell line (e.g. CD5+ B-cells) / bone marrow biopsy gives prognostic information (nodular, interstitial, mixed, diffuse) Labs: may or may not have absolute lymphocytosis at diagnosis (usu. 40-150K) [ HYPERLINK "pics/cll.jpg" pic], anemia (15-20%), thrombocytopenia (10%), Coombs positive (10%), may have increased M fraction Course: usually indolent but can develop number of late complications bone marrow failure or pure red cell aplasia (slow progression) fulminant transformation (Richters syndrome) severe adenopathy obstructing esophagus, ureters, GI tract, lymphatics pleural effusions, ascites, leg edema opportunistic fungal, viral, gram negative and encapsulated organisms (due to low IgG) increased incidence of MALT or mantle cell leukemia (also has translocation of chromosome 11 and 14 and expression of cyclin D1) Treatment: no treatment for asymptomatic or early stage / can treat late 10-20 yrs later ( steroids if low blood components (RBC, WBC, plat) from various autoantibodies / advanced disease can give monoclonal antibodies, nucleosides, chemotherapy (goal to reduce lymphadenopathy and WBCs) Prognosis: 10-20 yrs from stage O (RAI system) or A (Binet system) / 4-5 yrs average survival when advanced Prolymphocytic leukemia (Richters syndrome) fulminant prolymphocytic form of CLL / marked splenomegaly, minimal lymphadenopathy Hairy Cell Leukemia (good prognosis) rare / mature B-cells / CD25+ Presentation: middle aged males present with pancytopenia, splenomegaly (rarely lymphadenopathy) / main problem is susceptibility infection Labs: cytoplasmic projections causing fried egg appearance [HYPERLINK "pics/hairycellleukemia-cytoplasmicprojections.jpg"pic] / tartrate resistant acid phosphatase (TRAP+) / may have dry bone marrow aspirate Treatment: 7 day course of 2-chlorodeoxyadenosine (remission in 80%) / other options: splenectomy, interferon-alpha, Pentostatin (deoxycoformycin) Myeloproliferative Disorders Acute Myelocytic Leukemia (AML) onset 15 - 40 yrs / only 15-20% of childhood leukemias Histology: myeloblasts contain Auer rods [ HYPERLINK "pics/aml-auerrods.jpg" pic] and myeloperoxidase / lymphocytes contain TdT Markers: Philadelphia chromosome 9:22 - poor prognosis for M1 / 8:21 is good prognostic sign for M2 Complications: 3-13% incidence of hyperleukocytosis Treatment: chemotherapy with allopurinol to prevent renal calculi, bone marrow transplant Chloroma [HYPERLINK "pics/chloroma1.gif"pic][HYPERLINK "pics/chloroma2.gif"pic][HYPERLINK "pics/chloroma3.gif"pic] leukemic infiltrate of skin / reddish-blue (the green is usually hidden by the blood) Maturation (M1-M3) Acute promyelocytic leukemia (M3) greater risk for  HYPERLINK \l "dic" DIC with hemorrhage / this may be the rare time when heparin is given to treat DIC Differentiation (M4-M7) Monoblastic component (M4-M5) tissue infiltration / increased muramidase and hypokalemia erythroleukemia Radiation and toxin-induced leukemia (M6) Megakaryocytic leukemia (M7)  HYPERLINK \l "downs" Downs / follows myeloproliferative disorders Chronic Myelogenous Leukemia (CML) (poor prognosis) 7-20% of leukemias / onset in 40s (but children can get it too) / mutated tyrosine kinase (unregulated signal transduction) / Philadelphia chromosome (95%) (9:22 translocation), BCR, ABL Presentation: 40% asymptomatic at time of diagnosis / fatigue, weight loss, weakness, fever, splenomegaly (50%), hepatomegaly / rarely has CNS invasion or lymphadenopathy Diagnosis: bone marrow full of WBCs (high M:E), basophilia very indicative, wide variety of myeloid precursors [ HYPERLINK "pics/cml-granulocytes.jpg" pic] / very low leukocyte alkaline phosphatase (low  HYPERLINK "labs.doc" \l "lap" LAP), distinguishes from leukemoid reaction (such as with Tb in marrow) / elevated B12 due to increased transcobalamin I Labs: leukocytosis, thrombocytosis, 10% blasts with promyelocytes / can follow therapy by testing quantitative t(9;22) BCR-ABL by PCR(7/09) Course: chronic phase 3-5 yrs / acute phase (blast crisis) 3 to 6 months with > 30% blasts in marrow, myeloid crisis does not respond to chemotherapy Treatment:  HYPERLINK "pharm.doc" \l "imatinib" Imatinib (Gleevec) ( preliminary findings show response of 60-90% rIFN-a plus low-dose cytarabine( early stage / low response rate (5-20%), but some survival benefit HU ( alternative conventional chemotherapy with reduced benefit but less toxicity; response rate following IFN roughly 50% BMT ( best within 1-2 yrs of diagnosis, increased short term risks, increased chance of remission, lack of evidence based support / previous chemotherapy may reduce success of subsequent BMT; only 30% find donors Under Investigation: anti-RAS drugs Primary Thrombocythemia or Essential Thrombocytosis primary thrombocytosis causes severe bleeding or thrombosis / secondary thrombocytosis common in CML and PRV / rarely may be associated w/ myeloid metaplasia Treatment: ASA + platelet pheresis when count exceeds 1 M / HYPERLINK "pharm.doc" \l "hydroxyurea"hydroxyurea, alkylating agents, 6-MP Diagnosis: historically diagnosis of exclusion but JAK2 V617F PCR now available (high sensitivity, very specific in distinguish reactive/secondary thrombocytosis from myeloproliferative disorder) Secondary thrombocytosis: infection, inflammatory conditions, malignancy, iron deficiency, hemorrhage, post surgical states, other myeloproliferative (CML, myelofibrosis), myelodysplastic syndromes (e.g. 5q syndrome), rebound (correction of B12 or folate deficiency or cessation of chronic alcohol use) Polycythemia Rubra Vera (PRV) Presentation: ruddy cyanosis, headache, dyspnea or orthopnea, dizziness, eye complaints, epigastric discomfort / thrombosis (because of erythrocytosis, not thrombocytosis) / high Hb, dark, viscous blood / accompanied by leukocytosis and thrombocytosis (releases K causing spurious hyperkalemia) Complications: 20% get CML Diagnosis: JAK2 V617F PCR Treatment: phlebotomy (can give ASA but no evidence that ASA reduces incidence of thromboses if asymptomatic and normal Hct 1/07) chemotherapy for symptomatic splenomegaly (increased risk of leukemogenesis with use of hydroxyurea) Secondary PRV due to low oxygen saturation state (lung disease, intracardiac shunt, hypoventilation, AV malformation, altitude), elevated carboxyhemoglobin (smoking, CO poisoning), high-affinity hemoglobinopathy, some tumors (RCC, HCC, uterine leiomyoma), hormonal disorders high erythropoietin / usually not splenomegaly and immature cells in peripheral blood Leukemoid Reaction usually no anemia, thrombocytopenia as in leukemia / mature WBCs / transient / high LAP Myelodysplastic syndrome clonal proliferation (can affect any of three cell lines) / 5 subtypes (RA, RARS, RAEB, RAEB-T, CMML) / elderly / male>female / macrocytic anemia, mild thrombocytopenia or neutropenia may precede diagnosis of MDS for years / 20% have splenomegaly / development of secondary AML (30% of de novo MDS and 50% of chemo-related MDS) is highly refractory to chemotherapy (poor prognosis) Presentation: based on affected cell lines Diagnosis: must distinguish CMML from CML Labs: may have dimorphic RBC populations, macrocytosis, punctate basophilia, WBCs with pseudo-Pelger-Huet abnormality or hypersegmentation and/or Dohle bodies, increased or decrease platelet count, neutropenia / %myeloblasts distinguishes RA 50 yrs, 10% > 75 yrs) Usually > 50 yrs, median age 70 yrs, blacks > whites, men > women Primary monoclonal: IgG (70%), IgM (20%), IgA (10%) Secondary causes: chronic liver disease (esp. due to hepatitis C virus), rheumatologic diseases, CML, chronic neutrophilic leukemia, lichen myxedematosus, pyoderma gangrenosum. Presentation: often asymptomatic (diagnosed incidentally) or may cause neuro (usu. symmetric, distal, IgM instead of IgG), cardiac disease (transient or chronic) or other symptoms of paraproteinemias Labs: level of M component relatively small (< 3g), many normal immunoglobulins present, light chains > 1g/24 hrs is significant (should consider bone marrow biopsy; can have light chain disease with normal serum monoclonal component; if normal hemoglobin, creatinine, calcium ( may still be able to avoid) [ HYPERLINK "pics/mgus-workup.jpg" table] Note: 10-30% have falsely decreased HDL due to paraproteins binding to HDL in assay (also occurs with bilirubin, phosphate, LDL, glucose) Risk for progression (to MM, WM, amyloidosis, etc): 1% per year (16% lifetime; median lifetime survival only 2 yrs shorter than age-matched controls) [ HYPERLINK "pics/mgus-comparisons.jpg" table] higher g/dL protein (M component > 3g/dL is MM) IgM or IgA higher plasma cells in bone marrow (> 5% is bad; > 10% is MM) higher free light chain ratio (normal .26 to 1.65) presence of Bence-Jones proteinuria, renal failure, lytic bone lesions, ! M-fraction or ! plasma cells Treatment: none other than follow up // measure SPEP, UPEP, other labs 1 x year // every 4 months if  smoldering MGUS is seen Multiple Myeloma (Plasma Cell Myeloma) Presentation: bone pain (hurts with movement), slowly progressive renal failure (see below), Raynauds (cryoglobulins) / overlap with  HYPERLINK \l "amyloidosis" amyloidosis / non-neoplastic plasmacytosis is common in AIDS Diagnosis: >10% plasma cells in bone marrow [ HYPERLINK "pics/multiplemyeloma-plasmacells.jpg" pic] + monoclonal spike (75%) in serum [ HYPERLINK "labs.doc" \l "spep" SPEP] (levels often > 3000) or light chains (25%) in urine [ HYPERLINK "labs.doc" \l "upep" UPEP] or lytic lesions on plain films (or MRI, but bone scan does not show lesions) Labs: anemia (normochromic, normocytic; 80%), thrombocytopenia (10%), leucopenia, low anion gap from positively charged immunoglobulins / purely lytic malignant bone lesions do not raise  HYPERLINK "labs.doc" \l "alkalinephosphatase" alk. phos. Complications: majority have punched-out, lytic lesions (compression fractures, hypercalcemia) / spinal cord compression in 5% from local mass (try radiation) Immunologic compromise: lack of useful IgG (increased infection from S. pneumo, S. aureus, H. flu, etc.), WBC dysfunction Renal: Bence-Jones proteins (light chains): deposition, tubular toxicity / tubular casts with foreign body reaction [prevention with lots of hydration] ( Fanconis hypercalcemia (15-20%): vasoconstriction + deposition of Ca-salts in tubules amyloidosis (10-15%): deposition ( nephrotic syndrome hyperuricemia: deposition/tubular damage (treat with allopurinol) hyperviscosity: vascular occlusion (5%) cryoglobulinemia (type I): can cause glomerulopathy (rarely) dehydration: prerenal failure pyelonephritis: also an important cause of renal failure CNS: neuropathy secondary to amyloidosis Platelets: M protein or amyloid coats platelets causing prolonged bleeding time (can sometimes have paradoxical hypercoagulability) Note: ?pneumococcal/H influenza vaccine useful? Treatment: Chemotherapy: steroids, thalidomide, alkylating agents,  HYPERLINK "pharm.doc" \l "Bortezomib" bortezomib (new) followed by autologous hematopoeitic-cell transplant is standard of care in patients < 65 yrs / few patients remain disease free beyond 10 yrs Opiates Bisphosphonates Control of tumor bulk Allogeneic stem cell transplantation / transplant-related mortality 30-60% but only option for long-term cure / different protocols evolving 1/07 Non-secretory myeloma (<1%): diagnose with bone marrow biopsy Solitary plasmacytoma of bone uncommon Local collection of plasma cells without marrow plasmacytosis / M component usually absent (presence suggests dissemination) / responsive to local radiation therapy (good long-term prognosis) Extramedullary plasmacytoma most common in sub-epithelial, upper airways / 35% disseminate (likely to have M component) Waldenstroms Macroglobulinemia monoclonal IgM gammopathy / 10x less common than multiple myeloma / mean age 63 yrs Presentation: hepatomegaly (20%), splenomegaly (15%), lymphadenopathy (15%), fatigue (from anemia) Manifestations:  HYPERLINK "ddx.doc" \l "hyperviscocity" Hyperviscosity (50%; when serum viscosity > 4 CP): headache, blurred vision, dizziness, neuropsychiatric symptoms, hemorrhage (including retinal hemorrhage, subarachnoid hemorrhage) / may see sausage shaped vessels (from venous congestion) / rouleaux formation Bleeding diathesis: cryoglobulins et al interfere with platelet function ( may cause purpura Anemia: normochromic, normocytic / DO NOT transfuse, because the blood volume may already be too high, and this will make it worse leading to high-output heart failure Tumor infiltration bone marrow, lymph, spleen / lytic bone lesions ( < 20%) Peripheral neuropathy: IgM attacks myelin components creating picture similar picture to Guillain-Barr (distal, symmetrical, legs > arms) / also from associated amyloidosis / cranial nerve palsies, mononeuropathy, mononeuritis multiplex from infiltration, hyperviscosity or bleeding diathesis Cryoglobulins (7-20%): undergo reversible precipitation at cold temperatures (grossly visible in blood stain) / can cause vasculitis (WM, along with lymphocytic lymphoma, is one of the few lymphoproliferative disorders that not uncommonly causes vasculitis Cold agglutinins: Raynauds, cyanosis / cold T changes surfaces (affects presentation of Ag to IgM creating an acquired von Willebrands (effect) / can lead to infarctions Lungs: infiltrates (plasma cell interstitial pneumonia), isolated masses, pleural effusions Infection: double rate / PCP, CMV, HCV Amyloidosis (less common): see  HYPERLINK \l "amyloidosis" amyloidosis Renal failure (less common): more chronic than acute / amyloidosis, Bence- Jones proteinuria (33%), IgM deposition, IgM occlusion Labs: Coombs positive, cryoglobulins, hyponatremia (from dilution), hyperproteinemia (total protein and albumin), hypercalcemia, normocytic anemia (decreased RBC survival, Fe deficiency, increased plasma volume, not so much hemolytic anemia but there is some extravascular causing spherocytosis), azotemia, elevated inflammatory markers (ESR, RF, C3/C4, CPK), ?hepatitis immunity, normal WBC (but with lymphocytosis or monocytosis) Diagnosis:  HYPERLINK "labs.doc" \l "spep" SPEP with monoclonal spike (IgM always elevated, IgG decreased in 60%, IgA decreased in 20%), bone marrow biopsy Treatment: plasmapheresis for immediate benefit (based on symptoms, not labs), followed by proper chemotherapy (cladribine, fludarabine and 2-deoxychloroagenosine are accepted agents) /  HYPERLINK "pharm.doc" \l "rituximab" rituximab (anti-CD20) / high-dose autologous hematopoeitic stem-cell transplantation / bisphosphonates unnecessary because no bone/lytic lesions Survival: 80% response to chemotherapy / median survival 3-5 years Schnitzlers syndrome Urticarial vasculitis with macroglobulinemia / nodular, macular infiltration of tumor cells or pruritic papules from IgM deposition / can get urticaria and crusted, hemorrhagic lesions from type I cryoglobulinemia Heavy chain disease age 10 - 30 / heavy chain fragments, do not react with anti-lambda or anti-kappa Angioimmunoblastic lymphadenopathy with dysproteinemia Widespread, rapidly progressive (weight loss, hepatosplenomegaly, fevers), usu. polyclonal Castlemans Disease (angiofollicular lymph node hyperplasia) often associated with  HYPERLINK "micro.doc" \l "hiv" HIV/AIDS, but can occur by itself /  HYPERLINK "micro.doc" \l "hhv8" HHV-8,  HYPERLINK "micro.doc" \l "ebv" EBV Hyaline vascular type fever, anemia, hypoalbuminemia (~100%), organomegaly (90%), edema, pleural/pericardial effusions or ascites (50%), rash (33%), pancytopenia (35%) Labs: polyclonal SPEP, elevated ESR Plasma cell type  only 10% / neuropathy POEMS syndrome (T! will have Castleman s plasma cell type) Polyneuropathy, Organomegaly, Endocrinopathy, M protein (lambda in 80%), Skin changes / usually occurs in pts with osteosclerotic multiple myeloma who also have hepatomegaly, diabetes, gynecomastia, thickening and hyperpigmentation of the skin and sensorimotor polyneuropathy Lymphoma Hodgkins Disease 2 in 100,0000 / 15-35 yrs (nodular sclerosis) or over 50 yrs (mixed cellularity) Presentation: non-painful swelling of neck lymph node / fever, night sweats, weight loss, pruritis (rare) / contiguous nodal spread / erythema nodosum, icthyosis Diagnosis: biopsy: important to get excisional biopsy rather than FNA in order to see nodal architecture / must see Reed-Sternberg cell (or lacunar cell in nodular variant) on biopsy; unfortunately, RS-like cells have been found in EBV, solid cancers, fungal infections, and other staging: abdominal CT/MRI, gallium scans (sometimes), bone marrow biopsy (sometimes) Complications: suppression of DTH response (T-cell problem) Prognosis: B-symptoms, older age, stage, certain histological type give worse prognosis Treatment: radiation and/or chemotherapy ( HYPERLINK "pharm.doc" \l "mopp" MOPP) nodular sclerosis (1st) excellent prognosis more common in women / often involves lower cervical, supraclavicular and mediastinal nodes / distinct Reed Sternberg (RS) variant known as lacunar cell due to retraction of cytoplasm during fixation collagen bands divide tissue into nodules [ HYPERLINK "pics/hodgkins-nodularsclerosis.jpg" pic] / classic RS cells infrequent [ HYPERLINK "pics/reedsternbergcell.jpg" pic] mixed cellularity (2nd) clinical picture in between lymphocyte predominance and depletion pattern / heterogeneous cellular infiltrate small areas of fibrosis and necrosis / many typical RS cells (binucleate with inclusion-like nucleoli w/ halo) / pts present with disseminated involvement and systemic manifestations / more common in males lymphocyte predominance (3rd) excellent prognosis young males, diffuse, sometimes vaguely nodular infiltrate of mature lymphocytes admixed with a variable number of histiocytes / typical RS cell gives way to popcorn cell lymphocyte depletion (4th) poor prognosis older males / disseminated involvement, systemic manifestations / aggressive diffuse fibrosis - proteinaceous fibrillar material w/ some RS cells and lymphocytes reticular variant - highly anaplastic, large, pleomorphic cells / limited number of typical RS cells Non-Hodgkins Lymphoma over 50 yrs / disseminated (childhood ( intraabdominal, CNS, bone) / B-cell malignancy (80%) / incidence increased dramatically in US in last 50 years / HIV increases risk Presentation: GI complaints, weight loss, neuropathy (usually focal or oligo in distribution; CNS involvement at presentation occurs in 2%), may have hemolytic anemia (warm antibodies/look for spherocytes), thrombocytopenia Pathology: nodal architecture, degree of differentiation, cell origin Diagnosis: imaging studies, testicular ultrasound, cytologic analysis / in CSF, high false negative Treatment: combination vincristine, prednisone, cyclophosphamide, adriamycin, MTX / may lead to  HYPERLINK \l "tumorlysissyndrome" tumor lysis syndrome Prognosis: low grade NHL have high remission rate, but high recurrence rate as well / high grade NHL are frequently cured with aggressive chemotherapy B-cell lymphomas Small lymphocytic lymphoma - incurable low grade / diffuse nodal architecture / involves bone marrow, peripheral blood, spleen / CLL Follicular small cleaved cell lymphoma low grade / cleaved nuclear contour / bone marrow / t (14:18), bcl-2 Diffuse large cell lymphoma (DLBCL) high grade B-cell / increased risk in AIDS patients Prognosis: international prognostic index (IPI) / age, LDH, performance status, Ann Arbor stage, > 1 node involved [cure rate from 20-70% depending on score] Treatment: chemotherapy or BMT (being studied) Primary cutaneous large cell lymphoma (recently described) Cd30+ / negative for 2:5 translocation and ALK expression Differential: lymphomatoid papulosis (small papules that regress spontaneously), primary cut B-cell, SALT lymphomas (recently recognized), low-grade, EORTC Lymphomatoid granulomatosis [ HYPERLINK "http://content.nejm.org/cgi/content/full/356/5/504" NEJM] large B-cell lymphoma / CD-20 positive / EBV association Pulmonary: multiple bilateral nodules (usu. not mediastinal and hilar) Skin: various manifestations (maculopapular, subcutaneous nodules), usu. not confluent [ HYPERLINK "pics/lymphomatoidgranulomatosis.jpg" pic] CNS: mass or isolated cranial neuropathies Ddx: lymphoma, LIP, metastatic cancer, sarcoidosis, Wegeners, cryptogenic organizing pneumonia Treatment: combination chemotherapy (steroids, CTX, rituximab, IFN-alpha) Small non-cleaved cell lymphoma (Burkitts lymphoma) EBV / t(8:14) w/ c-myc / jaw mass (Africa), GI, gonad (US) / large lymphoid cells w/ dark blue cytoplasm (Wright stain) / starry sky appearance are benign macrophages interspersed ALL L3 vacuoles [HYPERLINK "pics/all-l3.jpg"pic][ HYPERLINK "pics/burkittslymphoma-starrysky.jpg" pic] / different form in AIDS patients Marginal zone B-cell lymphoma CD20+, CD5 (-) / extranodal are considered as MALToma MALT lymphoma (MALToma) B- cell / more localized to primary site / stomach (H. pylori) > orbit, adrenal (C. psittaci), intestine (C. jejuni), lung, thyroid, salivary gland, skin (Borrelia), soft tissue, bladder, kidney, CNS) / t(11:12) is worse / treat with chemotherapy / associated with autoimmune disease or chronic inflammation / in case of H. pylori gastric MALToma, may actually regress with eradication of H. pylori T-cell lymphomas Adult T-cell leukemia poor prognosis Presentation: skin lesions, lymphadenopathy, hepatosplenomegaly / often confused for sarcoidosis / may present as pneumonia [HYPERLINK "pics/htlvlungs.jpg"CXR] Epidemiology: caused by HTLV-1 (virus) / lifetime risk in carriers 2.6% in women, 4.5% in men / high incidence in SW Japan, Caribbean, Northern South America Diagnosis: hypercalcemia, elevated WBC, multilobated, atypical lymphocytes [HYPERLINK "pics/htlv1.jpg"pic] Tissue biopsy: must have lab look for chromosomal rearrangement Course: aggressive growth / ~8 month survival Lymphoblastic lymphoma males 2:1 / T-cell ALL / < 20 yrs / 40% of childhood lymphomas / mediastinal mass high cure rate, but frequent CNS relapse from earlier seeding Mycosis fungoides and Sezary syndrome ( HYPERLINK \l "mycosis1" see skin) poor prognosis rare / T-cell lymphoma involving skin / general exfoliative erythroderma / Sezary cells (see picture) [ HYPERLINK "http://dermis.net/dermisroot/en/19924/diagnose.htm" dermis] Presentation: large plaque parapsoriasis evolves into it / demarcation / progression patches, plaques, tumors, viscera / erythroderma, pruritis Course: long (can be years) premalignant phase (only on skin) / multiple biopsies / spontaneous sunlight-induced regressions have occurred Pathology: different from lymphomatoid papulosis / CD30+ / NCI staging system Treatment: total skin electron beam / PUVA / topical nitrogen mustard / biological IFN-a, IL-12, IL-2dab / MTX, bactrim?, retinoids, deoxycoformycin, 2 more Most respond, relapse is the rule Angiocentric nasal T/natural killer (NK) cell lymphoma southern Asia and Latin America Lymphoma in HIV/AIDS patients 6% risk, increases over time (unlike Kaposis) Treatment: low-dose modified chemotherapy under investigation / average survival 2 to 4 months 60% grade III/IV older patients, later stage of AIDS / 90% B-cell / over with EBV DNA / 20% Burkitts lymphoma younger patients, earlier stage of AIDS 20% Primary CNS lymphoma Diagnosis: EBV DNA PCR positive in 90% of cases / stereotactic brain biopsy Presentation: focal neurologic signs, cranial nerve deficits, headaches, seizures / 1 to 3 lesions (3 to 5 cm, often multiple, ring enhancing lesions) / leptomeningeal involvement (40%; 8% as sole manifestation) Treatment: radiation therapy Systemic lymphomas in AIDS GI (25%) Bone marrow (20%) Liver (10%) Lungs (10%) discrete or interstitial CNS (20%) must do LP to stage any systemic lymphoma with AIDS Bone [ HYPERLINK \l "orthopedics" orthopedics]  HYPERLINK \l "bonemalformations" Bone Malformations  HYPERLINK \l "bonecancer" Bone Cancer  HYPERLINK \l "osteoporosis" Osteoporosis General Fluoride concentrations should exceed 1 or 10? ppm in water supply Supplementation for exclusively breast fed infants, certain types of formula Note: increased pressure in bone causes bone pain Orthopedics  HYPERLINK \l "knee" Knee Pain,  HYPERLINK \l "lowbackpain" Low Back Pain,  HYPERLINK \l "fractures" Bone Fractures,  HYPERLINK \l "bonemalformations" Bone Malformations Acute Knee Pain [ HYPERLINK "http://www.annals.org/cgi/content/full/139/7/575" AIM] Causes: see  HYPERLINK \l "inflammatoryjointdisease" acute arthritis Strategy: use Ottawa rules to determine need to r/o fracture with plain film; XR can comment on  HYPERLINK \l "oa" OA (34% will have OA) Ottawa knee rules: injury due to trauma, age > 55, tenderness at head of fibula or patella, inability to bear weight for 4 steps, inability to flex knee to 90 degrees If history suggests ligament or meniscus tear, exam is 80-90% sensitive and specific ( Lachman test better than anterior drawer sign / Pivot test / McMurray test [ HYPERLINK "pics/kneeexam-aim.jpg" diagram of maneuvers] Plain films improves sensitivity but not specificity Bursitis Trochanteric bursitis Lateral hip and thigh pain with tenderness over trochanter / pain with abduction of hips against resistance Bone Fractures types complete, incomplete, comminuted (splintered), compression, transverse, closed, open pathologic (site of pre-existing disease) healing inflammatory - hematoma, inflammatory cells, soft tissue callus at 1 week reparative -osteoblasts deposit woven bone, cartilage envelopes fracture site by week 2-3 remodeling - ossification of cartilage, bony callus bridge, further mineralization Compression Factures (of vertebrae) ?usually do not cause radicular pain Plain Radiography / characteristics of common bone problems  HYPERLINK \l "Osteomyelitis" Osteomyelitis end plate bony erosions which cross disk space (tumors do not usu. cross disk space) Hyperparathyroidism subperiosteal resorption Myeloma osteopenia and lytic lesions RA erosions of bone cortex and cartilage in joint spaces Ankylosing spondylitis squaring of vertebral bodies Bone Malformations Osteopetrosis (Albers-Schonberg Disease) osteoclast dysfunction / thickening of cortex, narrowing of marrow (marble bones) / brittle, fracture easily / autosomal recessive (AR) worst of 4 forms / fractures, anemia, hydrocephaly in utero widened metaphyses and diaphyses Achondroplasia AD or new mutation (80%) / paternal effect / premature ossification of epiphyseal growth plate normal health, intelligence / associated with platybasia, which results in obstructive hydrocephalus and increased ICP / compression of nerve roots Osteogenesis imperfecta OI deficiency in normal type I collagen / thin, brittle bones / blue sclera (choroid), abnormal joints, ligaments, teeth, skin, deafness (ossicles) OI congenita (severe, neonatal disease, fatal) / heterogeneous inheritance OI tarda (compatible w/ life) / AD inheritance Pagets disease (osteogenesis deformans) disorder of bone remodeling / more bone, worse quality / older males / usually polyostotic axial skeleton / viral etiology? Pathology: osteoclasts in Howships lacunae in early lytic lesions, mosaic pattern of new bone Presentation: often asymptomatic / can have repeated fractures / nerve root compression pain (via vertebral body fracture), leonine face, bowed legs, kyphosis / tinnitus, hearing loss if inner ear ossicles involved Diagnosis: plain film shows cortical, trabecular thickening, bone scan shows increased uptake Labs: increased alkaline phosphatase (heat-labile) Complications: increased risk of osteosarcoma / high output cardiac failure (may occur when > 15% of skeleton involved (increased cutaneous metabolism over affected bone) Treatment: calcitonin and/or  HYPERLINK "pharm.doc" \l "bisphosphonates" bisphosphonates (1st) decrease bone turnover / NSAIDs for symptomatic relief Caffeys idiopathic cortical hyperostosis / no good treatment Osteonecrosis (avascular necrosis) Common causes: idiopathic, fracture, steroids Pathology: subchondral infarcts, triangular wedge-shaped necrotic segment, microinfarct (no osteocytes in lacunae), overlying articular cartilage viable (nourished by synovium) Diagnosis: MRI gold standard (detects lesions in ischemic stage), CT 2nd choice, plain films only positive after infarction occurs, bone scan positive after infarction Note: a form of reversible AVN (pre-AVN if you will) can look just like classic AVN on MRI (not sure what difference this will make in management) Legg-Calve-Perths avascular necrosis of femoral head / 2-12 yrs, males > females 4:1 / usually painless limp Treatment: medical management 1st or surgery if discovered late or treatment failure Osgood-Schlatters Inflammation of insertion of patellar tendon / rest and decreased physical activity Fibrous Dysplasia More in females / 20s and 30s / 80% monostotic / ribs, tibia (20%), femur, mandible or maxilla / often with multiple skeletal lesions Treatment prevents progression and/or fracture McCune-Albright syndrome (Albrights hereditary osteodystrophy) Polyostotic fibrous dysplasia, multiple large pigmented nevi (usually on one side of trunk), precocious puberty (more in females), associated with pheochromocytoma Mazabrauds syndrome Osteoporosis [ HYPERLINK "http://www.annals.org/cgi/content/full/137/6/529" annals] reduction in mineralization, bone mass / increased resorption, decreased deposition / primary (age, 14% of white women; 3-5% of white men develop osteoporosis in lifetime) Secondary causes: endocrine (gonadal deficiency, hyperprolactinemia), steroids, hyperthyroid, hyperparathyroid, renal osteodystrophy, vitamin C and D deficiency or malabsorption), drugs (cyclosporine, antiepileptics, heparin, GnRH) Risk Factors: maternal fracture (1.8), hyperthyroidism (1.7), anticonvulsants (2.0), BMD abnormal by 1 SD (1.6), any previous fracture (1.5), caffeine (1.2) Diagnosis: all women > 65 or fracture < 65 yrs should have bone mineral density testing (BMD) / Dexa scans ( Z score compares same age, T score compares to young, adult normal (T scores more useful; osteoporosis = T score < (-) 2.5 SD; every 1 SD below mean doubles fracture risk) / note: alkaline phosphatase mildly elevated in presence of healing fracture Ddx: osteomalacia,  HYPERLINK \l "pagets" Pagets, osteomyelitis, malignancy Treatment: underlying cause and HYPERLINK "pharm.doc" \l "alendronate"PBPs / current thinking is not to use estrogens for prevention of osteoporosis because cardiovascular risks outweigh benefits; only use estrogen for severe, persistent symptoms (see Womens Health Initiative) / can leave on HRT if already on (and no proven CV disease) / postmenopausal women should receive 1500 mg daily calcium (1000 mg if on HRT; most diets only provide 600-700mg) or 400-800 IU vitamin D or a bisphosphonates (decrease incidence of fractures 30-50%) / premenopausal need 100-200 mg/d calcium Hip (see below for more) risk varies more epidemiologically than other / 17% women > 50 yrs / 6% men / happens from falls / initial mortality may be increased up to 10% in 1st yr, then about 50% will not be able to ambulate, then up to 33% become dependent on living Spine 2-3x increase risk > 60 yrs in women / 16% lifetime risk / steroids, lack of estrogen / from normal activities / 66% go undiagnosed / up to 50 yrs, men just as high risk (risk factors include cigarettes, smoking, trauma, Tb, peptic ulcer) Wrist mostly peri/post-menopausal women Osteomalacia and rickets inadequate mineralization / vitamin D deficiency, hypocalcemia and hypophosphatemia / rickets (children): craniotabes (thinning) and frontal bossing, rachitic rosary (costochondral bulging), enlarged wrists and ankles, pigeon breast, lumbar lordosis / osteomalacia (adults): aches and pains / Loosers zones, Milkmans fractures (bilateral, symmetrical, right angles) / abundant osteoid (non-mineralized) on uncalcified cartilage / loss of bone density, cortical thickness Osteomyelitis ( HYPERLINK \l "osteomyelitis" see other) Hip Fractures women > men Average mortality 4% / average 1 year mortality 20% Diagnosis: regular AP lateral X-rays (Johnson and Judet views) / CT scan / MRI Femoral neck fractures graded as Garden I-IV scale Faster operation (if needed) leads to better outcome (operate < 6-12 hrs if possible) / AP view with internal rotation may be helpful for diagnosis Trochanteric fractures if < 1 cm displacement (and no tendency to more displacement), bedrest with early WBAT is an option / if > 1 cm displacement, consider reduction and internal fixation (younger, active) versus conservative management (older, less active) Intertrochanteric fractures more in elderly women high morbidity, mortality (worse if not operated on) / presentation usually leg is shortened, externally rotated initial evaluation ( be sure to assess and consider other concomitant damage to joints (pelvis will be fractured in 10%), nerve damage (can be caused by expanding hematoma; peroneal nerve distribution ( most sensitive and common neurologic finding is weakness in the extensor hallucis longus muscle, signifying a sciatic nerve injury), acute blood loss, vascular damage, AND why the patient may have fallen (cardiac arrhythmia, etc.) prophylactic antibiotics are indicated for all open fractures and for patients being prepared for immediate internal fixation (cefazolin) / if moderate contamination, an associated laceration greater than 1 cm, or if soft tissue injury is extensive, a loading dose of an aminoglycoside should be added to the cephalosporin / a penicillin should be added for clostridial coverage if the injury occurs in an environment that is highly contaminated (proper abx leads to 44% decrease in post-operative infections. complications: avascular necrosis (20% in high-risk subgroups), complications associated with operative delay include recurrent hip dislocations, post-traumatic arthritis, myositis ossificans and aseptic necrosis (8% in anterior fracture dislocations, and 10-20% in posterior fracture dislocations) Other Bone Disorders Scoliosis adolescent females > males / 20% with positive family history Slipped capital femoral epiphyses 20% with referred knee pain (can be misleading) / occurs in pubescent males, happens gradually, can be bilateral / Treatment: surgical with pinning Villonodular synovitis (benign neoplasms) aggregates of polyhedral cells, hemosiderin, foam cells, giant cells, zones of sclerosis Treatment: surgery if possible, usually difficult to excise pigmented villonodular synovitis (PVNS) single or multiple, diffuse involvement, red-brown projections giant cell tumor of tendon sheath (localized tenosynovitis) small, discrete nodule Bone Cancer mets most common form: BLT2KP lung > breast (lytic) > prostate (blastic) > testes, kidney primary malignant: OS, malignant fibrous histiocytoma, adamantinoma, chordoma Osteochondroma most common primary bone lesion / young males / sessile or stalked / cartilage cap / usually stops growing as bones mature Chondroma single or multiple (Oliers Disease, Maffuccis syndrome) / short bones of hands, feet / radiolucent / lobulated, hypercellular, disorganized / focal calcification w/in lesion / self-limited disease Chondrosarcoma (good prognosis) proliferation of malignant cartilage / older males / axial skeleton / surgery only useful option Osteoid osteoma very common / young males / < 2 cm growth / appendicular skeleton / produces pain at night (relieved by aspirin) / radiolucent lesion surround by reactive bone formation / surgical removal 25% relapse due to poor nidus locating by surgeon Osteosarcoma OS (poor prognosis) pre-op and post-op chemotherapy / arm, leg bones (mostly in metaphysis of long bones, usually near knee) produces bone, cartilage, spindle cells / osteoblastic response and large, adjacent soft-tissue mass / cortical destruction with extension in soft tissues (Codmans triangle) Course: usually have mets Parosteal osteosarcoma (POS) (excellent prognosis) young, early middle age, women / long bones / radiolucent string sign along cortex / spindle cells produce well-formed bone Ewings sarcoma (variable prognosis) Pathology: PAS+ cytoplasm / small cell neoplasia / unknown histiogenesis very young, males, lower extremities / flat bones or diaphysis of long bones (not usually in metaphysis) Radiology: moth-eaten intramedullary pattern (permeative appearance), onion skin periosteal reactive bone Treatment: still evolving Fibrous cortical defect very common / young, males, long bones Radiology: metaphysis, sub-cortical, soap bubbles, sclerosis at interface spindle cells, foamy macrophages, hemosiderin, chronic infiltrate / self-limiting at skeletal maturity Fibrous dysplasia very common / single, multiple / young, localization random Radiology: radiopaque, shepherds crook of proximal femur / spindle, cells, woven bone, lack of osteoblastic rimming, Chinese character appearance / no treatment unless symptomatic / excellent prognosis Malignant fibrous histiocytoma (poor prognosis) similar demographics to OS / Radiology: metaphysis, destructive, radiolucent / anaplastic spindle cells, storiform pattern / treatment same and prognosis slightly worse than OS Giant cell tumor of bone benign but aggressive local tumor / young, wide distribution / hemorrhage / surgery when possible / extended curettage (experimental) or resection / prosthesis / 98% monostotic radiation contraindicated (secondary sarcomas) Adamantinoma (good prognosis) primary malignant bone tumor / young males, tibia/fibula / Radiology: may be multifocal (observe carefully) / epithelial or endothelial proliferation / complete surgical extirpation Chordoma malignant bone tumor arising from notochord / 40s to 60s / males / physaliferous cells in acid mucoid background / surgery and post-op radiation survival: sacral 60% (fair) 5 yr, cervical (horrible) 50% 5 yr 0% 8 yr Myositis ossificans athletic adolescents, history of trauma (50%) / central fibroblast proliferation, intermediate zone of osteoid formation, peripheral shell of organized bone Treatment: usually cured by excision Unsorted Bakers cyst can mimic phlebitis 1) swollen calf 2) extrinsic venous compression / diagnose with MRI / usually self-limited (ruptures, causes pain/swelling) then goes away / may recur Pre and Post Op (specific to ortho) Total hip warfarin started pre-operatively, goal INR 2.0-2.5 Dermatology  HYPERLINK \l "skindrugs" Drug Reactions  HYPERLINK \l "eczematous" Eczematous diseases  HYPERLINK \l "atopic" atopic dermatitis,  HYPERLINK \l "seborrheic" seborrheic dermatitis,  HYPERLINK \l "contactdermatitis" contact dermatitis, other eczematous  HYPERLINK \l "skinfungal" Fungal Infections  HYPERLINK \l "papulosquamous" Papulosquamous Disease  HYPERLINK \l "psoriasis" psoriasis,  HYPERLINK \l "lichenplanus" lichen planus,  HYPERLINK \l "lichensimplex" lichen simplex,  HYPERLINK \l "pityriasis" pityriasis rosea  HYPERLINK \l "epidermaltumors" Epidermal Tumors  HYPERLINK \l "epidermalbenign" benign,  HYPERLINK \l "epidermalpremalignant" pre-malignant,  HYPERLINK \l "epidermalmalignant" malignant  HYPERLINK \l "dermaltumors" Dermal Tumors  HYPERLINK \l "dermaltumorsbenign" benign dermal tumors,  HYPERLINK \l "hemangiomas" hemangiomas,  HYPERLINK \l "kaposis" Kaposis sarcoma  HYPERLINK \l "melanocytic" Melanocytic Tumors  HYPERLINK \l "melanocyticbenign" benign,  HYPERLINK \l "melanocyticpremalignant" pre-malignant,  HYPERLINK \l "melanoma" melanoma  HYPERLINK \l "acne" Acne vulgaris  HYPERLINK \l "vesiculobullous" Vesiculobullous  HYPERLINK \l "intraepidermal" Intraepidermal  HYPERLINK \l "subepidermal" Subepidermal I urticaria, atopic dermatitis II  HYPERLINK \l "pemphigus" pemphigus,  HYPERLINK \l "pemphigoid" pemphigoid,  HYPERLINK \l "herpesgestationis" herpes gestationis,  HYPERLINK \l "epidermolysisbullosa" epidermolysis bullosa III  HYPERLINK \l "erythemamultiforme" erythema multiforme (drug eruptions),  HYPERLINK \l "dermatitisherpertiformis" dermatitis herpetiformis  HYPERLINK \l "leukocytoclastic" Leukocytoclastic vasculitis  HYPERLINK \l "skincongenital" Congenital Skin Disorders  HYPERLINK \l "pediatricskin" Pediatric Skin Conditions ETN, PN, salmon patch, milia HYPERLINK "http://dermis.net/dermisroot/en/home/index.htm"Dermis [infinite pics]  HYPERLINK "http://www.dermnet.com" Dermnet ( good site // lots of pics Specific Findings/Manifestations Pruritis Treatment:  HYPERLINK "pharm.doc" \l "atarax" atarax and  HYPERLINK "pharm.doc" \l "doxepin" doxepin are best / sarna is also good / avoid benadryl (because its actually not good for itching), avoid benzocaine (lidocaine is better), avoid topical neomycin (frequently causes irritation) Erythema Nodosum [ HYPERLINK "http://dermis.net/dermisroot/en/30437/diagnose.htm" dermis] so many causes ( HYPERLINK "ddx.doc" \l "en" see Ddx) / usu. painful / originally described by Mozarts father / female > male / 20-30s / usually resolves within 3-6 weeks without scarring Vitiligo areas of depigmentation [HYPERLINK "pics/vitiligo1.jpg"pic][HYPERLINK "http://dermis.net/dermisroot/en/37282/diagnose.htm"dermis] / associated with many systemic conditions like autoimmune diseases (pernicious anemia, hypothyroid,  HYPERLINK \l "sarcoidosis" sarcoidosis) and  HYPERLINK "micro.doc" \l "lepra" tuberculous leprosy Xanthomas hyperlipoproteinemia / extensor surfaces of extremities and buttocks / hyperTG usually eruptive / yellow papules with erythematous halo / marker for CAD Pseudoxanthomatus elasticum [HYPERLINK "pics/pseudoxanthomaelasticum1.gif"pic][HYPERLINK "pics/pseudoxanthomaelasticum2.gif"pic][ HYPERLINK "http://dermis.net/dermisroot/en/42210/diagnose.htm" dermis] this can be a clinical marker for early atherosclerosis / angioid streaks on fundus Foreign body granuloma [HYPERLINK "pics/foreignbodygranuloma.jpg"pic] Pediatric Skin Conditions Erythema toxicum neonatorum benign / days-wks / eosinophils Pustular melanosis more in blacks / weeks-months / hyperpigmented Salmon patch 1st wks / face (fade), nuchal/occipital (persist) Milia face, gingival of neonates / spontaneous resolution Urticaria pigmentosa [ HYPERLINK "http://dermis.net/dermisroot/en/41156/diagnose.htm" dermis] Atopic dermatitis (see other) Seborrheic dermatitis (see other) Linear IgA Dermatosis IM staining in basement membrane Treatment: dapsone, sulfapyridine colchicine is alternative usually remits before puberty flares may not require dosage increase Very small, vesicular lesions surround bullous lesion, perioral predilection, IM shows at dermal, epidermal junction Eczematous diseases [ HYPERLINK "http://www.dermnet.com/moduleIndex.cfm?moduleID=8" dermnet] spongiosis inter-cellular edema / formation of vesicle is exocytosis acanthosis thickened Malphigian layer Acanthosis nigricans [HYPERLINK "pics/acanthosisnigricans1.jpg"pic][HYPERLINK "pics/acanthosis-benign1.jpg"pic][HYPERLINK "pics/acanthosis-benign2.jpg"pic][HYPERLINK "pics/acanthosis-benign3.jpg"pic] Causes: Idiopathic healthy, obese adolescents AD infancy/childhood increases during adolescence / decreases in adulthood Pituitary tumor (Cushings, acromegaly), PCOS, obesity, diabetes drugs (steroids, nicotinic acid, DES) Malignant onset in middle age, progressive (associated with gastric carcinoma, lymphoma, Hodgkins, osteogenic sarcoma) [HYPERLINK "pics/acanthosis-malignant1.jpg"pic] Associations: adenocarcinoma, porphyria cutanea tarda Pathology: symmetrical papillomatous epidermal hyperplasia with hyperpigmentation (really just thicker) Flexural areas most common: axilla, antecubital fossa, neck, skin folds, groin Occasionally: areolae, periumbilical, lips, buccal mucosa / palms, elbows, knees, interphalangeal joints hyperkeratosis thickened stratum corneum lichenified thickened skin from chronic rubbing parakeratosis retained nuclei in stratum corneum Grovers disease transient acantholytic disease / Rx: topical / doesnt respond well to systemic therapy Eczema [HYPERLINK "pics/eczema-fingers.jpg"pic][HYPERLINK "pics/eczema.jpg"pic][ HYPERLINK "http://dermis.net/dermisroot/en/27284/diagnose.htm" dermis] usually presents at early age / positive family history of allergies / pruritic Atopic dermatitis pruritic [HYPERLINK "pics/atopicdermatitis.jpg"pic][HYPERLINK "http://www.dermnet.com/moduleIndex.cfm?moduleID=2"dermnet] allergies / familial / IgE (80%) / childhood / pruritic / 90% will outgrow condition / defective cell-mediated immunity / superinfection (S.aureus) [treat familial Staph carriers] Treatment: moisturizing creams / topical corticosteroids Severe cases: HYPERLINK "pharm.doc" \l "cyclosporine"Cyclosporine A (Neoral) /  HYPERLINK "pharm.doc" \l "tacrolimus" Tacrolimus / Ascomycin, Macrolactam (under investigation) / recombinant IFN-gamma / Zafirkulast / antimicrobial agents / phototherapy Seborrheic dermatitis can be pruritic [HYPERLINK "pics/seborrhoeicdermatitis.jpg"pic][HYPERLINK "pics/seborrhoeicdermatitis1.jpg"pic][HYPERLINK "pics/seborrhoeicdermatitis2.jpg"pic][HYPERLINK "pics/seborrhoeicdermatitis3.jpg"pic][HYPERLINK "pics/seborrhoeicdermatitis4.jpg"pic][HYPERLINK "pics/seborrhoeicdermatitis5.jpg"pic] common, worse with many neurological diseases / common and severe with AIDS / worse in winter / involvement in areas of prominent sebaceous gland activity / infancy and puberty (can present at any age) / causes dandruff / involvement of Pityrosporum ovale Treatment: antiseborrheic shampoos (including ketoconazole) / mild topical corticosteroids Stasis dermatitis [HYPERLINK "http://dermis.net/dermisroot/en/14554/diagnose.htm"dermis] lower legs secondary to venous insufficiency / older patients Contact dermatitis always pruritic [ HYPERLINK "pics/contactdermatitis.jpg" pic] allergic type IV - DTH occurs 2-3 days after exposure Appearance: vesicular, bright red / linear configuration, characteristic of exogenous exposure to antigen or irritant Pathology: spongiosis with intraepidermal vesicle formation Diagnosis: patch test irritation - dry, scaly, less vesicular / scratch test (different) Treatment: baths, wet dressings (Burrows/boric acid) Acrodermatitis enteropathica Zinc deficiency associated with malabsorption / long-term TPN / rarely inherited as AR Nummular eczema coin-shaped lesions [HYPERLINK "http://dermis.net/dermisroot/en/14607/diagnose.htm"dermis] / mistaken for tinea Dishydrotic eczema abnormal sweating, associated with stress Neurodermatitis chronic scratching behavior Asteotic (xerotic) eczema dry skin on extremities / elderly patients with decreased oil on skin Fungi  HYPERLINK "micro.doc" \l "tinea" Tinea sp. microsporum, epidermaphyton, trichophyton / pink by PAS / black by GMS / easily visible on KOH prep  HYPERLINK "micro.doc" \l "candida" Candida overgrowth in moist areas (scrotum, unlike true dermatophytes), eczematous or satellite pustules, produces yeast forms and hyphae  HYPERLINK "micro.doc" \l "malassezia" Malassezia furfur yeast resident makes short hyphae and spores (spaghetti and meatballs) pityriasis versicolor limited to stratum corneum and follicles Mycosis fungoides  HYPERLINK \l "mycosis" T-cell lymphoma (not really a fungus at all) / eczematous eruption [HYPERLINK "http://dermis.net/dermisroot/en/19720/diagnose.htm"dermis] / fungating in later stages / Pautrier microabscesses resemble spongiosis Papulosquamous diseases Psoriasis ( HYPERLINK \l "psoriatic" see psoriatic arthritis) [ HYPERLINK "http://dermis.multimedica.de/dermisroot/en/31346/diagnose.htm" dermis] sharply bordered, often round or plaques with silver scale [ HYPERLINK "pics/psoriasis-back.jpg" pic], (knees [ HYPERLINK "pics/psoriasis-knees.jpg" pic], arms [HYPERLINK "pics/psoriasis.jpg"pic], scalp proliferation of keratinocytes / familial / 1% of population / Koebner phenomenon (areas of trauma) / auspitz sign (blood when you pick at it) / nail problems (onychodystrophy, onycholysis, nail pitting, and subungual keratosis, onychauxis) [ HYPERLINK "pics/psoriasishands.jpg" pic] / arthritis Treatment: topical tar, steroids, anthralin, UV light,  HYPERLINK "pathology.doc" \l "vitamina" retinoids,  HYPERLINK "pharm.doc" \l "mtx" MTX Guttate parapsoriasis (rare) rash lasting more than 2 months / confused with pityriasis rosea Lichen planus pruritic [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/32882/diagnose.htm"dermis] papulosquamous (purple, polygonal, pruritic) / flat-topped plaques covered by Wickhams striae (reticulated scale) [HYPERLINK "pics/lichenplanus.jpg"pic] / wrists, mucous membranes / nail deformities (NOT pitting) / bandlike infiltrate of histiocytes and lymphocytes in upper dermis, hyperkeratosis, acanthosis / Treatment: topical steroids, oral antihistamines / rare in children / usually self-resolving within 1-3 years Lichen variagatus [HYPERLINK "http://dermis.net/dermisroot/en/32551/diagnose.htm"dermis] Lichen simplex chronicus [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/33781/diagnose.htm"dermis] areas that are tempting to rub / hyperkeratosis, acanthosis, histiocytes, lymphocytes Treatment: topical steroids / may have underlying cause that is treatable Pityriasis rosea very pruritic [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/32735/diagnose.htm"dermis] common, viral origin?, young adults / self-limited within 6 wks / trunk (usually), neck, proximal extremities herald patch followed (1-2 wks) by oval lesions (pink papule or plaque with scales) forming Christmas tree pattern (follows tension lines) rare inverse form involves distal extremities and face Ddx: secondary syphilis (serology), tinea corporis (KOH), drug eruptions Treatment: topical steroids, antihistamines Secondary syphilis (HYPERLINK "micro.doc" \l "syphilis"see micro) HA, fever, lymphadenopathy / palms and soles, any form of rash except vesicular / biopsy has variable plasma cells (may not be specific) / RPR, VDRL GI syphilis (HYPERLINK "more/endoscopy\\mi_sy_01.htm"endoscopy) Epidermal Tumors [ HYPERLINK \l "dermaltumors" Dermal Tumors /  HYPERLINK \l "melanocytic" Melanocytic Tumors] Cowden, Muir-Torre ( HYPERLINK \l "tumorsyndromes" see tumor syndromes) Benign Seborrheic keratosis [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/21934/diagnose.htm"dermis] common over 40s / tan to black papules, plaques / areas with numerous sebaceous glands (face, neck, trunk) / a barnacle that looks stuck on / sebaceous adenoma [HYPERLINK "pics/sebaceousadenoma.jpg"pic] Nevus sebaceous [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htm"dermis] yellow linear plaques, elevated, head (hairless area) and neck / sebaceous, apocrine hamartoma / hormone stimulation at puberty causes verrucous growth / surgical excision (can be premalignant lesion for BCC) Keratoacanthoma [HYPERLINK "http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htm"dermis] fast growing (10-20 mm in weeks) volcano-like / slow involuting / exposed (sun-damaged), hairy skin / more in whites / surgical excision because they mimic SCC Epidermoid cyst [ HYPERLINK "pics/epidermoidcyst.jpg" pic][HYPERLINK "http://dermis.multimedica.de/dermisroot/en/36857/diagnose.htm"dermis] epidermis-lined cyst containing hydrated keratin (white pearl) / surgical excision optional Pre-malignant Actinic keratosis 20% change of becoming malignant [ HYPERLINK "pics/actinickeratosis-hands.jpg" pic][HYPERLINK "http://dermis.net/dermisroot/en/35352/diagnose.htm"dermis] atypical keratinocytes / sun-exposure in older patients / reddish base (not tan/brown) papules or plaques, poorly defined, scaly texture / sun damage causes solar elastosis (yellowish skin, blueish collagen change histologically), wrinkles, telangiectasias, comedomes, hyperpigmentation Treatment: cryotherapy (few lesions), topical 5FU (many, ill-defined lesions), excision Premalignant leukoplakia may lead to SCC of mucosa / surgical excision Bowens disease (carcinoma in situ) [HYPERLINK "http://dermis.net/dermisroot/en/23246/diagnose.htm"dermis] non-sun exposed areas / SCC in situ / several cms / Queyrat of penis? / surgical excision Malignant Sebaceous carcinoma [HYPERLINK "pics/sebaceouscarcinoma.jpg"pic][ HYPERLINK "http://dermis.net/dermisroot/en/18406/diagnose.htm" dermis] Basal cell carcinoma (BCC) (good prognosis) [HYPERLINK "pics/bcc.jpg"pic][ HYPERLINK "http://dermis.net/dermisroot/en/18406/diagnose.htm" dermis] most common neoplasm of humans / rolled edge, ulcerated center / small blue nuclei (basal cells) peripheral palisading, stromal retraction / almost never metastasize Noduloulcerative telangiectasia / Treatment: < 1 cm ( cryo, > 1 cm ( excision, high-risk areas ( recur (Mohs microsurgery) Superficial often confused with dermatitis / Treatment: topical 5-FU, cryo Sclerosing deep soft tissue invasion / Treatment: Mohs microsurgery Squamous cell carcinoma (SCC) (good prognosis) [HYPERLINK "http://dermis.net/dermisroot/en/19297/diagnose.htm"dermis] much less common than BCC (still relatively common) but does metastasizes via lymphatics (esp. in non-sun exposed areas such as oral SCC) / scaling, hyperkeratosis (keratin pearls), ulceration / pink (more cytoplasm, keratin) / sun, tobacco, HPV, immunosuppression, Marjolins ulcers [ HYPERLINK "pics/majolinsulcer.jpg" pic] (rare, from burns and osteo and chronic ulcers, long-standing scars) / 35% oral involvement [HYPERLINK "pics/scc-lip.jpg"pic][HYPERLINK "pics/scc-tongue.jpg"pic] / regional lymphadenopathy Treatment: excision (or cryo for small) / non-sun induced means more spread 90% cure rate Cutaneous small cell carcinoma ulcerative, erythematous nodule or superficial erosion, can metastasize / epidermal keratinocytes / sun exposed areas like lower lip Ddx: metastatic small cell carcinoma of the lung, were squamous cell carcinoma, basal cell carcinoma, amelanotic melanoma, carcinoid tumor, Merkel cell carcinoma, neuroendocrine carcinoma, malignant fibrous histiocytoma, atypical fibroxanthoma, and dermatofibrosarcoma protuberans. Dermal Tumors Benign Neurofibroma [HYPERLINK "http://dermis.net/dermisroot/en/23404/diagnose.htm"dermis] tumor of neural tissue (multiple cell types) / soft, skin-colored lesions / single or multiple ( HYPERLINK \l "nf1" neurofibromatosis or von Recklinghausens) / optional excision (may grow back) / increase in size over time Dermatofibroma [ HYPERLINK "pics/dermatofibroma.jpg" pic][HYPERLINK "http://dermis.net/dermisroot/en/22350/diagnose.htm"dermis] hard, brownish nodules / anywhere, any age (common in legs) / optional excision / cheloid or keloid [HYPERLINK "pics/keloid.jpg"pic] is a form that occurs from excessive healing (common in black earlobes) Acrochordon [HYPERLINK "pics/acrochordon.jpg"pic] [ HYPERLINK "http://dermis.net/dermisroot/en/37036/diagnose.htm" dermis] tags of redundant skin in armpits, neck, groin / common in fat people / Treatment: scissors Hemangiomas (mostly benign) [ HYPERLINK "pics/hemangioma.jpg" pic] [HYPERLINK "http://dermis.net/dermisroot/en/22725/diagnose.htm"dermis] Cherry small, red papules on trunks of over 30 yr olds Strawberry congenital, neonatal / may grow to huge size / often regress spontaneously Nevus flammeous macular, red-purple lesion / congenital or neonatal / some regress spontaneously, (port wine stain) persistent ones may be treated with laser therapy [HYPERLINK "http://dermis.net/dermisroot/en/40613/diagnose.htm"dermis] Spider angioma common in females, estrogen therapy, liver disease / can be zapped with laser [HYPERLINK "pics/spiderangioma.jpg"pic][ HYPERLINK "http://dermis.net/dermisroot/en/21601/diagnose.htm" dermis] Pyogenic granuloma granulation tissue / weeping, red, juicy nodules [HYPERLINK "pics/pyogenicgranuloma.jpg"pic] / fingers, mouth / common in pregnancy / grows rapidly / resection [HYPERLINK "http://dermis.net/dermisroot/en/27156/diagnose.htm"dermis] Kaposis sarcoma (malignant) purplish/blue dermal plaques (violaceous plaques) /oval nodules [HYPERLINK "pics/kaposissarcoma-mouth.jpg"pic] / common in AIDS patients (more aggressive) affecting various organs (skin, lungs, GI tract) Pathology: may not be obvious to detect / endothelial cell proliferation (spindle cells), vascularity CXR: peribronchiolar cuffing, patchy infiltrates, effusions Note: do not forget that these can cause internal organ damage with NO skin findings Treatment: radiotherapy or vinblastine in non-AIDS patients Other Dermal Business Sweets Syndrome (Acute Febrile Neutrophilic Dermatosis) [HYPERLINK "pics/sweets.jpg"pic][HYPERLINK "http://dermis.net/dermisroot/en/31053/diagnose.htm"dermis] Neutrophilic inflammatory disease, red/juicy plaques/nodules/bullae on face/extremities Biopsy: neutrophils in dermis (not vasculitis) / neutrophilia, fever Exhibits pathergy not only contiguous, but if you do sterile pin-prick somewhere else on the skin, it should create a similar lesion Associations: AML, AMML, CML, CLL, acute lymphoblastic, hairy cell, myelodysplastic syndrome, multiple myeloma, solid tumor (rarely) Treatment: steroids and work-up for malignancy / also sulfones, SSKI Pyoderma gangrenosum [HYPERLINK "pics/pyodermagangrenosum1.jpg"pic][HYPERLINK "pics/pyodermagangrenosum2.jpg"pic][HYPERLINK "pics/pyodermagangrenosum3.jpg"pic][HYPERLINK "pics/pyodermagangrenosum.jpg"pic][HYPERLINK "http://dermis.net/dermisroot/en/25427/diagnose.htm"dermis] Like an ulcerated version of Sweets syndrome / solitary/multiple, inflammatory purple border, necrotic base Diagnosis: non-specific cultures and biopsy / diagnose by excluding bacterial/mycobacterial infection (must not confuse this with cellulitis) / pathergy ( trauma to lesions begets more lesions (i.e. DO NOT surgically debride lesions) Associations: IBD, arthritis, gammopathy, malignancy, hepatitis, biliary cirrhosis, SLE Treatment: steroids (systemic and intra-lesional), dapsone (or cyclosporin A, FK506), sulfapyridine, azulfidine Dermatofibrosarcoma protuberans (DFSP) [HYPERLINK "http://dermis.net/dermisroot/en/19487/diagnose.htm"dermis] special kind of dermatofibroma / CD34 / requires Mohs surgery Microcystic adenoid carcinoma (MAC) lips, local invasion, neuronal invasion / requires Mohs surgery Sebaceous gland carcinoma (SGC) requires Mohs surgery Melanocytic tumors Benign Melanocytic nevi junctional (brown), intradermal (raised, skin color), compound / may be congenital or acquired / more than 25 moles by age 20 years is marker for increased risk of melanoma (either from nevi in question or future nevi) [ HYPERLINK "pics/acquirednevi.jpg" pic][HYPERLINK "pics/melanocyticnevus.jpg"pic] Ephelis (freckle) normal number of melanocytes, overproducing melanin / darken on exposure Solar lentigo brown macules from sun-exposure Lentigo simplex childhood / diffuse proliferation / NOT due to sun-exposure Cafe-au-lait spot brown macules [HYPERLINK "http://dermis.net/dermisroot/en/37575/diagnose.htm"dermis] / more than 6 big ones correlated with  HYPERLINK \l "neurofibromatosis" neurofibromatosis Nevus spilus flat, tan patch with dark spots [HYPERLINK "http://dermis.net/dermisroot/en/21179/diagnose.htm"dermis] / mistaken for melanoma (excised) Blue nevus so deep it looks blue Mongolian spot black babies bottoms (sacral regions) / resolve by age 3 yrs Spitz nevus pink [HYPERLINK "http://dermis.net/dermisroot/en/20986/diagnose.htm"dermis] / young adults / looks like melanoma / benign course halo nevus children and adults / white halo around residual nevus [HYPERLINK "http://dermis.net/dermisroot/en/37428/diagnose.htm"dermis] / lymphocytic infiltration Pre-malignant Lentigo maligna Hutchinsons freckle / melanoma in situ / sun-damaged skin / elderly, blacks macule with notched border / epidermal atrophy, atypical melanocytes Treatment: excision Dysplastic nevus [HYPERLINK "pics/dysplasticnevus1.jpg"pic][HYPERLINK "pics/dysplasticnevus2.jpg"pic][HYPERLINK "pics/dysplasticnevus3.jpg"pic] / variable color, irregular architecture / surgical excision / watch for others / dysplastic nevus syndrome [HYPERLINK "pics/dysplasticnevussyndrome.jpg"pic] familial condition wherein there are increased number of moles, occur earlier in life, in atypical (and typical) areas / Treatment is sun-avoidance, close follow-up Malignant Melanoma [HYPERLINK "pics/malignantmelanoma.jpg"pic][HYPERLINK "http://dermis.net/dermisroot/en/18195/diagnose.htm"dermis] 5% of skin CA / 3% of all CA / 50% mortality (different depending on stage) S! arise from nevi, T! de novo / incidence increasing (ozone depletion?) Risk Factors: intermittent sun-burns, childhood sun-exposure, large congenital nevus (may transform) [HYPERLINK "pics/melanoma1.jpg"pic][HYPERLINK "pics/melanoma2.jpg"pic], 6-12% as part of familial syndrome / can be transmitted across placenta!!! Diagnosis: DO NOT do shave biopsy / Bx for diagnosis and microstaging / level of invasion (Clarks) I to V (subQ) / nodal, local, satellite, in transit mets / Stage I 90% survival / Stage II 70% survival / consider: ulceration, vertical growth phase / SLN status most important factor Exam: (A)symmetry, irregular (B)order, dark (C)olor, > 6mm (D)iameter, (E)levation Note: may not be pigmented (amelanotic melanoma) [HYPERLINK "pics/amelanoticmelanoma.jpg"pic] Treatment: wide excision [.5 to > 2-3 cm margins, based on size] Chemo/Adjuvant:  HYPERLINK "pharm.doc" \l "ifn" IFN-a2B (Intron A) Aldesleukin (Proleukin) Temozolomide (Temodar) Dacarbazine (DTIC-Dome) Uninvolved nodal basin ( selective lymphadenectomy Get sentinel node blue dye (given right at surgery) and colloid radioactive (given 1 hr pre-surgery) false negative rate of only 5% (80% of which are actually positive using better histological stains and pathologists) SLN technique ( smaller incision, visual confirmation, rescan later, identifies in transit mets PCR has too many false positives but does detect all would be recurrences Prognosis: depth of invasion is the most important factor / women do better than men / truncal location and depigmentation is worse (perhaps due to delayed diagnosis) Prevention: sun-avoidance (sun block not proven to decrease incidence) Lentigo maligna melanoma - best prognosis [HYPERLINK "http://dermis.net/dermisroot/en/18065/diagnose.htm"dermis] most superficial Ddx: basal cell carcinoma, light skin color (especially people who have red hair), history of severe sunburn, porphyria cutanea tarda, Werner syndrome, tyrosine-positive oculocutaneous albinism, xeroderma pigmentosa Superficial spreading malignant melanoma - medium prognosis [HYPERLINK "http://dermis.net/dermisroot/en/17570/diagnose.htm"dermis] most common / non sun-exposed regions Acral lentiginous melanoma - medium prognosis occurs distally (fingers and toes, near nails) / most common malignant melanoma in blacks Nodular melanoma - worst prognosis [HYPERLINK "http://dermis.net/dermisroot/en/18014/diagnose.htm"dermis] solid nodule (no macular component), vertical growth [HYPERLINK "pics/melanoma3.jpg"pic] Acne vulgaris [HYPERLINK "http://dermis.net/dermisroot/en/36249/diagnose.htm"dermis] increased sebum, abnormal keratinization (comedome), bacteria produce FFA (inflammation), hormones (androgens promote, estrogens inhibit androgen production, some have increased androgen sensitivity) comedomes topical retinoids mild inflammatory topical or, if needed, oral antibiotics severe inflammatory oral antibiotics or, if needed, oral isoretinoin oral antibiotics tetracycline, doxycycline, erythromycin, minocycline topical antibiotics clindamycin, erythromycin, sulfur, benzoyl peroxidase (water based less irritating than alcohol based) topical retinoids adapalene, tazarotene (in microsphere delivery system) oral isoretinoin (13-cis-retinoic acid or accutane) for recalcitrant nodulocystic acne / very teratogenic; no pregnancy at least 30 days after stopping / very expensive medication / monitor lab values during therapy other azaleic acid / acne surgery / intralesional triamcinolone (100ul) / chemical peels (glycolic acid, trichloroacetic acid) Avoid: thick, oil based makeups / dial, safeguard 2-3 x day, consider oil-free acne wash or salac if comedomes present / agents that worsen acne: Dilantin, lithium, steroids, kelp (iodides), bromides / recommend normal diet Other forms of acne Rosacea or acne rosacea  HYPERLINK "http://dermis.net/dermisroot/en/30526/diagnose.htm" [dermis] middle-aged, fair-skinned, sun-damaged areas / exacerbation by stress, alcohol, heat Presentation: central facial erythema, may have papules, pustules / clinical diagnosis but can be distinguished from SLE, DM with routine skin biopsy (rosacea will not have interface change) / may get rhinophyma [HYPERLINK "http://dermis.net/dermisroot/en/30730/diagnose.htm"dermis] Treatment: avoid triggers / rapid cooling of oral cavity (e.g. ice) can abort flushing that follows drinking hot beverages / alcohol, caffeine, sun exposure, spicy food have been implicated but may vary on individual basis oral tetracycline,  HYPERLINK "pharm.doc" \l "erythromycin" erythromycin, metronidazole (all effective) topical erythromycin, metronidazole Follicular occlusion triad (acne inversa, acne triad, tetrad)[HYPERLINK "http://dermis.net/dermisroot/en/36097/diagnose.htm"dermis] acne conglobata [HYPERLINK "http://dermis.net/dermisroot/en/36097/diagnose.htm"dermis], cellulitis of scalp, hidradenitis suppurativa Solar acne (Favre-Rachouchout) Neonatal acne Steroid acne Cutting oil acne Pomade acne (petroleum hygiene products) Gram negative folliculitis (see  HYPERLINK "micro.doc" \l "Pseudomonas" Pseudomonas) pustular lesions with line of demarcation, 8-48 hrs after soaking in hot tub or other Vesiculobullous skin diseases Bullous disease in diabetes  HYPERLINK \l "sle" SLE HYPERLINK \l "pemphigoid"Bullous pemphigoid Burn  HYPERLINK \l "cellulitis" Cellulitis Congenital syphilis  HYPERLINK \l "contactdermatitis" Contact dermatitis  HYPERLINK \l "dermatitisherpetiformis" Dermatitis herpetiformis  HYPERLINK \l "eczema" Eczema  HYPERLINK \l "epidermolysisbullosa" Epidermolysis bullosa  HYPERLINK \l "erythemamultiforme" Erythema multiforme Fixed drug eruptions Fungal infections Hand foot mouth disease Herpes gestationis, simplex, zoster  HYPERLINK \l "impetigo" Impetigo Insect bite reaction  HYPERLINK \l "lichenplanus" Lichen planus  HYPERLINK \l "pemphigus" Pemphigus vulgaris/folicaceus  HYPERLINK \l "pct" Porphyria cutanea tarda HYPERLINK "micro.doc" \l "scabies"scabies Staph scalded skin  HYPERLINK \l "ten" Toxic epidermal necrolysis (TEN)  HYPERLINK "micro.doc" \l "vzv" Varicella Vasculitis (SLE, etc) Intraepidermal Blisters ballooning degeneration HSV/VZV acantholysis mainly pemphigus vulgaris spongiosis contact dermatitis (type IV) miliaria (heat rash) miliaria rubra, very pruritic [HYPERLINK "http://dermis.net/dermisroot/en/36070/diagnose.htm"dermis] eczema some infants/children grow out of it [HYPERLINK "http://dermis.net/dermisroot/en/36070/diagnose.htm"dermis] adults: eczema herpeticatum (disseminated HSV) [HYPERLINK "http://dermis.net/dermisroot/en/11499/diagnose.htm"dermis] impetigo mild: Bactriban and antibacterial soap moderate: 1st generation cephalosporin rarer form: impetigo herpetiformis [HYPERLINK "http://dermis.net/dermisroot/en/29476/diagnose.htm"dermis] tinea ( HYPERLINK "micro.doc" \l "capitis" see micro) scalded skin ( HYPERLINK "micro.doc" \l "scaldedskin" see micro) cellulitis ( HYPERLINK \l "cellulitis" see other) Subepidermal Blisters Type I (anaphylaxis) ( HYPERLINK \l "typeone" see immuno) Urticaria (insects, drugs, cold, sun induced IgE response) Atopic dermatitis (IgE allergies) pruritic / more common than erythema multiforme / consider outpatient skin testing / systemic steroids hardly ever used for this now Type II (cytotoxic, cytolytic) ( HYPERLINK \l "typetwo" see immuno) Pemphigus (Pemphigus vulgaris) serious, rare [HYPERLINK "http://dermis.net/dermisroot/en/29511/diagnose.htm"dermis] Pathology: IgG or IgM, complement in epidermis intercellularly / eosinophils Presentation: can be difficult to diagnose with oral lesions preceding cutaneous lesions by weeks/months pemphigus vulgaris (oral lesions / intact blisters are common) [HYPERLINK "pics/pemphigus.jpg"pic] pemphigus foliaceus (superficial, oral lesions / intact blisters are rare) Findings: skin sloughs away (Nikolskys sign) / intraepidermal blisters should be able to be advanced with application of external pressure (theres probably a name for this) Complications: loss of electrolytes, super-infections, associated with malignancies (e.g. lymphoma) Ddx: paraneoplastic pemphigus Treatment: high-dose systemic HYPERLINK "pharm.doc" \l "corticosteroids"steroids (120-150 qd then prednisone 60-80 mg and steroid-sparing agent (e.g. Immuran 50 mg bid or plasma exchange, Cytoxan, Cellcept) then prednisone 50 mg qod (gradual steroid taper may take up to a year) rituximab (newly used; alone and in combination) Paraneoplastic Pemphigus Syndrome - poor prognosis painful mucosal ulcerations [HYPERLINK "pics/pps1oral.jpg"pic][ HYPERLINK "pics/paraneoplasticpemphigus.jpg" pic], polymorphic skin lesions (scalded skin [HYPERLINK "pics/pps2scaldedskin.jpg"pic], conjunctivitis [HYPERLINK "pics/conjunctivitis.jpg"pic], EM [HYPERLINK "pics/pps4em.jpg"pic] lymphoreticular malignancies Pathology: vacuolization of basal cells, keratinocyte necrosis, acantholysis / pemphigus/pemphigoid-like Ig / special IF on rat bladder shows intracellular Abs / HLA-Cw14 and HLA-DRB103 Treatment: treat underlying malignancy / prednisone or cyclosporin or plasmapheresis Senear-Usher syndrome [HYPERLINK "http://dermis.net/dermisroot/en/29664/diagnose.htm"dermis] overlap syndrome with features of lupus erythematosus (LE) and pemphigus foliaceus Bullous pemphigoid not-life threatening [HYPERLINK "pics/pemphigoid.jpg"pic][ HYPERLINK "pics/bullouspemphigoid.jpg" pic][HYPERLINK "http://dermis.net/dermisroot/en/29935/diagnose.htm"dermis] Mainly in elderly Presentation: urticaria-like and pruritic, erythematous lesions gradually give way to tense, sub-epidermal bullae on erythematous or normal-appearing skin / groin, axilla, and flexural areas / no acantholysis, minimal or no mucosal lesions / lesions may come and go without treatment / can verify blisters are subepidermal by pressing on the intact blister edge (if it extends its likely some other blistering process) Pathology: linear band of IgG, C3 at basement membrane / eosinophils Treatment: 1st line  HYPERLINK "pharm.doc" \l "tetracycline" tetracycline and niacinamide / 2nd line prednisone +/- azathioprine Herpes gestationis [HYPERLINK "http://dermis.net/dermisroot/en/26713/diagnose.htm"dermis] similar to pemphigoid / 2nd trimester Epidermolysis bullosa can be fatal [HYPERLINK "http://dermis.net/dermisroot/en/40853/diagnose.htm"dermis] group of diseases (mostly congenital) / lesions mostly in area of friction and trauma / no immunofluorescence / come and go indefinitely / variable severity, can be fatal / often results in severe anemia (give  HYPERLINK "pharm.doc" \l "erythropoetin" Epogen and IV iron) Dermatitis herpetiformis (Duhring-Brocq Disease) very pruritic [HYPERLINK "http://dermis.net/dermisroot/en/29366/diagnose.htm"dermis] uncommon, HLA B8, DR3 / associated with celiac disease (20% with lab-evidence of malabsorption, 4% symptomatic celiac-sprue) Presentation: clustered small red papules and vesicles symmetrically located on extensor surfaces, particularly elbows, knees, and buttocks / very pruritic Pathology: vesicles are subepidermal, with neutrophilic infiltrate in upper dermis / direct IF shows IgA along the basement membrane in dermal papillae / some say IgG also present (activates alternative complement) Linear IgA bullous dermatosis [HYPERLINK "http://dermis.net/dermisroot/en/30140/diagnose.htm"dermis] Lesions non-pruritic / can be drug-induced Type III (immune complex) ( HYPERLINK \l "typethree" see immuno) [HYPERLINK "http://dermis.net/dermisroot/en/43431/diagnose.htm"dermis] Erythema Multiforme (minor/major) pathogenesis is similar to GVHD of skin / lymphocytes may have non-specific immune complex, complement deposition / common reactio+,789:ݸ̧wjcYA.jhwh|CxB* CJ OJQJUaJ phh|CxB* CJph hhhih|Cx0J6>*h!jhih|Cx6Uhhih|Cx6hjhih|Cx6Uh h|Cx6h h].h5B*CJaJph̙'hhi0J5>*B*CJ aJ ph̙ hhi5B*CJ aJ ph̙)jhhi5B*CJ UaJ ph̙h5B*CJ aJ ph̙9:   O P t u ^gdff^`gdgd $7$8$@&H$a$gdi$7$8$@&H$^a$gdVRk#k#      ; < = A B C D ^ ѹ쇹lQ4jhwh|CxB* CJ OJQJUaJ ph4j]hwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph4jwhwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph^ _ ` b c e f } ~  ͶͣͣͶͣͣmͶͣͣRͶͣͣ4jhwh|CxB* CJ OJQJUaJ ph4j)hwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph4jEhwh|CxB* CJ OJQJUaJ ph    ' ( ) . / 0 1 G H I M N Q R i ͶͣͣͶͣͣmͶͣͣRͶͣͣ4jRhwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ ph4jjhwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ phi j k p q t u ͶͣͣͶͣp]Bp4jhwhwB* CJ OJQJUaJ ph%hwhwB* CJ OJQJaJ ph.jhwhwB* CJ OJQJUaJ ph4j*hwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ ph   ѮрhMh6hh,hwh|Cx0J>*B* CJ OJQJaJ ph4jwhwh|CxB* CJ OJQJUaJ ph.jhwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph4jhwhwB* CJ OJQJUaJ ph%hwhwB* CJ OJQJaJ phhwB* CJ OJQJaJ ph.jhwhwB* CJ OJQJUaJ ph,hwhw0J>*B* CJ OJQJaJ ph   ) * + , I J K O P Q R S l ͶͣͣͶueM:%hwhwB*CJ OJQJaJ ph.jhwhwB*CJ OJQJUaJ phhwB* CJ OJQJaJ ph%hwhwB* CJ OJQJaJ ph4j_hwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph4jhwh|CxB* CJ OJQJUaJ phl m n u v y z ͻͫeN34j hwhwB* CJ OJQJUaJ ph,hwhw0J>*B* CJ OJQJaJ ph4jI hwhwB* CJ OJQJUaJ ph%hwhwB* CJ OJQJaJ ph.jhwhwB* CJ OJQJUaJ phhwB*CJ OJQJaJ ph#hwhw0J>*CJ OJQJaJ .jhwhwB*CJ OJQJUaJ ph4jhwhwB*CJ OJQJUaJ ph    # $ % ' ( E պՈueM:%hwh4DeB* CJ OJQJaJ ph.jhwh4DeB* CJ OJQJUaJ phh4DeB* CJ OJQJaJ ph%hwh|CxB* CJ OJQJaJ ph4j hwhwB* CJ OJQJUaJ ph,hwhw0J>*B* CJ OJQJaJ ph4j5 hwhwB* CJ OJQJUaJ ph%hwhwB* CJ OJQJaJ ph.jhwhwB* CJ OJQJUaJ phE F G L M N P Q n o p { | } ~ Ͷͣx]xFxx+4j hwh|CxB* CJ OJQJUaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph4j hwh|CxB* CJ OJQJUaJ ph.jhwh|CxB* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph%hwh4DeB* CJ OJQJaJ ph,hwh4De0J>*B* CJ OJQJaJ ph.jhwh4DeB* CJ OJQJUaJ ph4j% hwh4DeB* CJ OJQJUaJ ph 辮hQA).jhMphMpB* CJ OJQJUaJ phhwB* CJ OJQJaJ ph,hwhx0J>*B* CJ OJQJaJ ph4j hwhxB* CJ OJQJUaJ ph%hwhxB* CJ OJQJaJ ph.jhwhxB* CJ OJQJUaJ phh4DeB* CJ OJQJaJ ph%hwh|CxB* CJ OJQJaJ ph,hwh|Cx0J>*B* CJ OJQJaJ ph.jhwh|CxB* CJ OJQJUaJ ph         - . / ѹ|cN2c7j hwh5B* CJ OJQJUaJ ph(hwh|Cx5B* CJ OJQJaJ ph1jhwh|Cx5B* CJ OJQJUaJ ph%hwh|CxB* CJ OJQJaJ ph%hwhwB* CJ OJQJaJ ph,hMph4De0J>*B* CJ OJQJaJ ph.jhMphMpB* CJ OJQJUaJ ph4j hMphKJB* CJ OJQJUaJ ph%hMphMpB* CJ OJQJaJ ph / 4 5 6 7 N O P U V W X m n o r s t u v w λΦλΦnλ`R<*jhsFhsFB* CJOJQJUphhsFB* CJOJQJphh|CxB* CJOJQJph7jhwh5B* CJ OJQJUaJ ph7j3hwh5B* CJ OJQJUaJ ph(hwh|Cx5B* CJ OJQJaJ ph%hwh|CxB* CJ OJQJaJ ph1jhwh|Cx5B* CJ OJQJUaJ ph/hwh|Cx0J5>*B* CJ OJQJaJ phw !տ{eVLLL{hW1B* CJphh|Cx0J5>*B*CJph+j6hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|CxB* CJphh|CxB* CJOJQJphhsFhsF0J>*CJOJQJ*jhsFhsFB* CJOJQJUph0jhsFhqB* CJOJQJUph!hsFhsFB* CJOJQJph!"#&'7Buzo`N`E``h|Cx0J>*CJ"jh|CxB* CJUphjh|CxB* CJUphh|Cx0J5>*CJ%jPh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph h|Cx5CJ8 h|CxCJ8h-B* CJphh|CxB* CJphh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jhZ )h5B*CJUph stuZh?WFG~9:^gdg ^`gd <@^gd <@^gdff CDEWXZ[\tuv}~̼́oZoIoo hOhO0J>*B* CJph(jFhOh6B* CJUph"jhOhOB* CJUphhOhOB* CJphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx0J>*CJjh|CxB* CJUph"jHh|CxB* CJUph 567?@BC\مp[(jkhOh6B* CJUph(jhOh6B* CJUph hOhO0J>*B* CJph(jhOh6B* CJUph(j(hOh6B* CJUphhOhOB* CJphhOhO0J>*CJ"jhOhOB* CJUph(jhOh6B* CJUph#\]^fghi}~&ٚٚp[(jhOh6B* CJUph(j!hOh6B* CJUph(jhOhOB* CJUph hOhO0J>*B* CJph(jMhOh6B* CJUphhOhOB* CJphhOhO0J>*CJ"jhOhOB* CJUph(jhOh6B* CJUph#&'(=>?@\]^hijkٚp[(jhOh6B* CJUph(jhOh6B* CJUph(j hOh6B* CJUph hOhO0J>*B* CJph(jhOh6B* CJUphhOhOB* CJphhOhO0J>*CJ"jhOhOB* CJUph(j hOh6B* CJUph# 89:UVWXlmnpqstxiWiNii<"jh|CxB* CJUphh|Cx0J>*CJ"j\h|CxB* CJUphjh|CxB* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphhOhOB* CJphhOhO0J>*CJ"jhOhOB* CJUph(jfhOh6B* CJUph   789DEGHf٧ٕكsgh|Cx5B* CJphjh|Cx5B* CJUph"jh|CxB* CJUph"jh|CxB* CJUph"jh|CxB* CJUphh\ 0J>*B* CJph"j,h|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"fgh|}~  vhVh"jsh|CxB* CJUphhn8[0J>*B* CJph"jh|CxB* CJUphh|Cx0J>*B* CJph"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUph  !$%'(BCDKLMNPQklmtuvwyzǵѧǕѧǃyohb h|CxCJ h|Cx5CJh <@B* CJphh|CxB* CJph"j7!h|CxB* CJUph"j h|CxB* CJUphhn8[0J>*B* CJph"jQ h|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"jh|CxB* CJUph!-./678IKLnopwxGJux &GH񾸱񾱾񾃱|sh@XhffCJ h|Cx>*CJh|Cx(j"hZ )hB*CJUph(jI"hZ )hB*CJUph h|Cx5CJ h <@CJ h|CxCJh|Cx0J>*B*CJph(j!hZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph+:zGu%&GHaxE h^`hgd{V2h^hgd{V2h^hgdg & F 88^8gd Hh^hgdffgd@X^gdg^gdgH`xDEFPQstuʺӮwqk[j$h <@h|CxCJU h <@CJ h{V2CJh|Cx0J>*CJj$h|CxCJUjh|CxCJU hs CJh{V2h|Cx5CJ h{V25CJh <@h|Cx0J>*CJj#h <@h|CxCJUh <@h|CxCJjh <@h|CxCJUh <@h <@CJ h|Cx5CJ h|CxCJh|Cx h|Cxh#E#zwMNS !8^8gd)8^8gd{V2h^hgdg8^8gdg h^h`gdg h^h`gd{V2 #$?@AJKghӎuicZQh^]h|CxCJhhCJ hCJhreqh|Cx0J>*CJjw%hreqhb*CJUhreqhreqCJjhreqhreqCJUh^]h0J>*CJj%h^]hCJUh^]hCJjh^]hCJU hn8[CJ h|CxCJ h|Cx5CJ h <@CJjh <@h|CxCJUh <@h|Cx0J>*CJ#$%78:;abcxyz4Ǘzmzdzh|Cx0J>*CJj'h|CxCJUjh|CxCJU h <@CJ h <@5CJ h|CxCJ h|Cx5CJj'h^]h7SCJUj}&h^]h7SCJUh^]h^]CJh^]h|CxCJh^]h|Cx0J>*CJj%h^]h7SCJU h^]CJjh^]h^]CJU#45TUVdew MNSidzǭǧǡǛǎuicc h)CJh'f)h|Cx0J>*CJj(h'f)h7SCJUh'f)h'f)CJjh'f)h'f)CJU h\ CJ hnp CJ h{V2CJ hn8[CJ hQoCJ h{V25CJ h|Cx5CJ h|CxCJhh|Cx0J>*CJj (hh6GnCJUhhCJjhhCJU%!"$%()/04︲~mgagZNZNZBZh+5B*CJ$phh+5B*CJ$ph h+5CJ$ hCJ hCJ hghn0J>*B*CJph̙(j)hghnB*CJUph̙hghnB*CJph̙"jhghnB*CJUph̙ hnCJ h|CxCJh|Cx0J5>*B*CJph+j(hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph!"56\]  k!l!!!!!^gd & F^gdg^gdg^gdg`gd%gd%gd+^gd+^gd+`gdgd456]dfg       ʻʩʻʉʻwʻe#j,h+h|CxCJUaJ#j+h+h|CxCJUaJ#j+h+h|CxCJUaJh+h|Cx0J>*CJaJ#jb*h+hCJUaJjh+h|CxCJUaJh+h|CxCJaJh+h|Cx5CJaJh+hoTCJaJh@Xh5CJaJ h5CJ$$ # , > ? Y Z p q r v w y z N!T!l!!!ťť|nc\V\VRVh|Cx h|CxCJ h|Cx5CJh@Xh%CJaJhoTh|Cx5>*CJaJhoTh|Cx>*CJaJh+hCJaJ#j,h+h6CJUaJh+h|Cx0J>*CJaJ#jj,h+h6CJUaJjh+hLCJUaJh+ho7CJaJh+hoTCJaJh+h|CxCJaJh+hLCJaJ!!!!!!!!!-"."Z"f"r"s"""""""""##/#0###Ǽwng^WKW *hLh5oX5CJ h5oX5CJh@Xh|CxCJ h|Cx>*CJhthh|CxCJhthh|Cx0J>*CJj>-hthhwCJUhthhthCJjhthhthCJU hn8[CJ h|CxCJ h|Cx5CJh@XhNzCJaJhNz5>*CJaJhNzh|Cx5>*CJaJhNzh|Cx>*hNzh|Cx>*CJaJ hCJ hNzCJ!!!Z""##/###A$Y%%X&&&&'''((((([)^gdggd@X^gdg`gdNzgdNz####A$M$O$X$b$c$u$w$~$$$$$$$$$$$$$%%%.%/%Y%b%%%%%%ĻĻުުޠޓު}td}j*.hZ )hCJUh}h}CJjh}h}CJUh|Cx0J>*CJj-h|CxCJUjh|CxCJU h|Cx5CJh}dah}da5CJh}dah|CxCJh}dah}daCJ h}da5CJh}dah|Cx5CJ h|CxCJ h5oX5CJ h5oXCJ h}daCJhLh5oXCJ$%%%%%%X&Y&b&r&x&{&&&&&&&&')'/'2'P'Q't'u'v'''''''V(ཱིì|l`ìh}h|Cx0J>*CJj.h}h}CJUh}h}CJjh}h}CJUhG+DB* CJphh|CxB* CJph h-CJ hn8[5CJh}dah}da>*CJ h}daCJ h|Cx5CJ h5oXCJh5oXh5oXCJ h5oX5CJ h|CxCJjh}h}CJUh}h|Cx0J>*CJ"V(W(r(s(t(((((((((( )A)Y)[)g)u)|)))))))))))))))b*l*üǖǜǜǜǍǃǜǖzsjǜd h]CJhhCJ h5CJ *h|Cx5CJhh|Cx5CJhh|CxCJ hCJ h|Cx5CJh@Xh|CxCJaJhoTh|Cx5>*CJaJ h|Cx>*CJh|Cx h|CxCJh-{h|Cx0J>*CJjx/h-{h CJUh-{h-{CJjh-{h-{CJU$[)))****T+[+\++R,S,,,----]....^gd(*^gd@Xgd@X ^`gdg^gdg^gdg^gdl*v*w***********)+2+D+E+\++++ , ,,$,%,2,Q,S,h,i,j,оڰ鐇wke^W h>Gh|Cx h|Cx>*CJ h\ CJhgh|Cx0J>*CJj`0hghgCJUhghgCJjhghgCJU h8z^CJ h-CJ h|Cx5CJh-{h|Cx0J5>*CJ"j/h-{h 5CJUh-{h-{5CJjh-{h-{5CJU h|CxCJ h]CJh]h]5CJj,k,,,,,,,,,,---.............C/i//÷åsg^Oh@Xh|CxB* CJaJphhL7h|CxCJhL7h|Cx0J>*CJj2hL7hBCJUhL7hL7CJjhL7hL7CJU h\ CJ h|CxCJ h|Cx5CJh@Xh|CxCJaJh@Xh|Cx5CJaJh|Cx h|Cx>*CJ h>Gh|Cxh>Gh|Cx0J>*j31h>GhU h>Gh>Gjh>Gh>GU.C/0N000001I2J2v2L3 4 404444555^gdCgdC^gdR^gdg^gdg^gdg^gd@X^gd@X/////00!0*00000011q1|1I2J2v2L3333333 4 404𺮺zsmfmsmsm[OhRh|Cx5CJaJhRh|CxCJaJ h|Cx>*CJ h|CxCJ h|Cx5CJhRh|CxaJhCh|Cx5CJaJh@Xh|CxB* CJaJphh@Xh|Cx5CJaJh|Cxh@Xh|Cx>*CJaJh@Xh|CxCJaJh(*h|Cx0J>*CJaJ#j2h(*hpdkCJUaJh(*h(*CJaJjh(*h(*CJUaJ0444444444555*646777778s8w889 9!9<9=9>9G9H9j9k9ocVjh9h9CJUh}h|Cx0J>*CJj2h}hnCJUh}h}CJjh}h}CJUh|CxB* CJph h|CxCJH*hRh|Cx5CJaJhRh|CxB* CJaJphhRh|CxCJaJhCh|Cx5CJaJh|Cx hn8[5CJ h|Cx5CJ h-CJhQohQoCJH* h|CxCJ 5W7777[8889::;;;<<<<==J>K>r>*?^gdg^gdg^gdg^gdg^gdR^gdRk9999999999::::::::::;F;I;J;O;;;<<====J>K>r>*?+?0?1?;?=?>?V?ȻȲȻȻȻȻȻȻȮȻȮȢpjhRh|CxCJUaJhRh|CxCJaJhRhn8[5CJaJhRh|Cx5CJaJ hRh|Cx h|Cx5h|CxhghgCJ h|Cx5CJ hgCJ h|CxCJh9h|Cx0J>*CJjh9h9CJUjc3h9hLsCJUh9h9CJ+*?+?k?????|@}@@@AACAqArAAAAp7$8$H$^p` 7$8$H$^ 7$8$H$^ & F7$8$H$^gd{V2 7$8$H$^gd{V2^gd{V2 ^`gdR^gdRV?W?X?h?i??????????????8@B@a@b@|@}@@@žvkv]vYRM h|Cx>* h|Cx6>*h|Cx jh{V2h|CxCJaJh{V2h-CJaJh{V2h|CxCJaJ h{V2CJh|Cx0J>*CJjM4hZ )hCJUjh|CxCJU h|CxCJ h|Cx5CJ h|Cx>*CJ hRh|CxhRh|CxCJaJhRh|Cx0J>*CJaJjhRh|CxCJUaJ#j3hRh|CxCJUaJ@@@@@@@@@@@A%AqA}AA BB[CpCqCCCCCCD E ElEnEpEFF(G*G,G¼zp^z"j9h|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJ h|Cx5CJ h|CxCJH*h-h}dah|Cx h|Cx5CJ h\ CJ h-CJ h|CxCJ h|Cx>*h|Cx0J>*B*ph'j5hZ )h>*B*Uphh|Cx>*B*phjh|Cx>*B*Uph$AA B BB B9BRBSBYBBBnMkd5$$Ifl04- .'4 layt{V2 $7$8$H$If 7$8$H$^gd{V2 7$8$H$`gd{V27$8$H$ p^p` @ 7$8$H$^@ BBB C C C"CECFCXMkd6$$Ifl04- .'4 layt{V2 $7$8$H$IfMkd 6$$Ifl04- .'4 layt{V2FCGCYC[CCCCCCJMkd^7$$Ifl04- .'4 layt{V2 $7$8$H$If $7$8$H$IfMkd6$$Ifl04- .'4 layt{V2CCCC"D$DHDDXMkd28$$Ifl04- .'4 layt{V2Mkd7$$Ifl04- .'4 layt{V2 $7$8$H$IfDDD E E8E:EnE $7$8$H$If 7$8$H$^gd{V2 7$8$H$^gd{V2 7$8$H$^gd{V2Mkd8$$Ifl04- .'4 layt{V2nEpEE0FxFFFPG|GGG||||||||| $7$8$H$Ifwkd9$$Ifl0-2%e t04 la4yt{V2 ,GLGNGPGGGGGHHHPHRH~HHHHHHHHHHHIIIIIIIIJ J!J"J#J$Jٴ٢ӕ|plf hCJh|CxhRGh|Cx0J>*CJjF<hRGhRGCJUhRGhRGCJjhRGhRGCJU"j;h|CxB* CJUph"jr;h|CxB* CJUph h|Cx5CJ h|CxCJ h|CxCJh|CxB* CJphjh|CxB* CJUphh|Cx0J>*B* CJph%GGGHH||| $7$8$H$Ifwkd,:$$Ifl0-2%e t04 la4yt{V2HHPHHHI.IDIbII J!J|||||||||| $7$8$H$Ifwkd:$$Ifl0-2%e t04 la4yt{V2 !J"J#J$JBJJJJJJJztkbbk`[[gdw^gd^gd7$8$H$ 7$8$H$^gd{V2wkd<$$Ifl0-2%e t04 la4yt{V2 $JBJJJJJJJJ KLLL|MMMMMMM+O,OLOMONOĸxpxaYGa#jd=h5hCJUaJh5CJaJjh5h5CJUaJhDECJaJhwCJaJhwhw5CJaJh[fCJaJhwhDECJaJ jhwh[fCJaJhwh[fCJaJhwh[f5CJaJhwh|CxCJaJhwh|CxCJ4aJ4 hCJhCJaJhhCJaJhh5CJaJJKNLLMzOOOOOPGPPPPP*QmQQ%S&SSSSS & Fgdn^gdn^gdg^gdgNOUOVOzOOOOOOPP P PGPoPPPPPPPCQJQlQmQQQQQQQQQQQRƻzkzjhwh[fCJUaJhwh[fCJaJhwh[f5CJaJhnhn5CJaJhnhnCJaJhnCJaJhnh'CJaJhnh[fCJaJhnhwCJaJhnhw5CJaJhwCJaJjh5h5CJUaJh50J>*CJaJ#RRRRR1R2RGRHRIRLRMRORPReRfRgRjRkRRRRSSSSS$S%S&Sųšřm_WLhwh7 CJaJh[fCJaJhDhw0J>*CJaJ#j|?hDhI<CJUaJhDhDCJaJjhDhDCJUaJhwCJaJ#j?hwh6GnCJUaJ#j>hwh6GnCJUaJhwh[fCJaJhwh[f0J>*CJaJjhwh[fCJUaJ#j#>hwh6GnCJUaJ&S.S/S?SSSSSSSTTbTgTTTTTTTT'U1U>U?UrU|U~UUUUU^VbVVVVVVWWWWWϿسﯫwoh2fCJaJhDECJaJhh5CJaJhCJaJ hCJ h5CJhwhCJaJh3hhXh7 0J>*CJj?hXh3CJUhXhXCJjhXhXCJUh7 h7 >*CJ h7 CJh7 h7 5CJ+S&U'U?UrUU^VVVVWoWWWWXjXXXXZZ$ZZ^gdg ^`gdg^gdg^gdg & Fp^pgdgWWWWWWWXX XXXXXXX`YmYYYZZ$Z%ZZZ[[[μٮ覛󐂐zzzvpj`ZTJh,h,>*CJ h,CJ hpCJhphp5CJ h|CxCJ h2fCJh|CxhpCJaJ jhwh[fCJaJhwh[fCJaJhwh}daCJaJh}daCJaJh55h|Cx0J>*CJaJ#jP@h55h?rCJUaJh55h55CJaJjh55h55CJUaJhwh|CxCJaJhwh|Cx5CJaJZZZ[[[[[\ \\\\^~^^V___^gdLk ^`gdLk p`^p``gdLk & F^gdLk^gd{V2 ^^gd,^gdp^gdg[5[M[f[g[[[[[[[\ \\\%\&\'\+\,\-\.\ǸzfWKh{V25B* CJphhh|Cx5B* CJph'h yh|Cx0J5>*B* CJaJph/j@h yh|Cx5B* CJUaJph h yh|Cx5B* CJaJph)jh yh|Cx5B* CJUaJphhh|CxB* OJQJphhh|CxCJ8OJQJ h|CxCJh2fh|Cx5CJh2fh2f5CJ h2fCJ hpCJ h,CJ.\/\R\S\T\a\b\c\d\e\\\\\\\\\\\\\\\\\\\\ٟهoaI/jBhh|Cx5B* CJUaJphh y5B* CJaJph/j4Bhh|Cx5B* CJUaJph/jAhh|Cx5B* CJUaJphh{V25B* CJaJph'hh|Cx0J5>*B* CJaJph/j:Ahh|Cx5B* CJUaJph hh|Cx5B* CJaJph)jhh|Cx5B* CJUaJph\\\\\ ] ] ]]]]]'](])]=]>]@]ι|kZB.Z'hh|Cx0J5>*B* CJaJph/jChh|Cx5B* CJUaJph hh|Cx5B* CJaJph hh|Cx5B* CJ aJ ph'h yh|Cx0J5>*B* CJaJph/j(Ch yh|Cx5B* CJUaJph h yh|Cx5B* CJaJph)jh yh|Cx5B* CJUaJphhh|CxB* CJphhh|CxB* CJaJph)jhh|Cx5B* CJUaJph@]A]V]W]X][]\]^]_]|]}]~]]]]]]]]]]]]]]]]ٕo[C/jQEhh|Cx5B* CJUaJph'hh\ 0J5>*B* CJaJph/jDh2qhWb5B* CJUaJphh2q5B* CJaJph/jeDhh|Cx5B* CJUaJph'hh|Cx0J5>*B* CJaJph/jChh|Cx5B* CJUaJph hh|Cx5B* CJaJph)jhh|Cx5B* CJUaJph]]]]]]]^^^^^^^^(^.^/^1^2^H^ijćxij`LLijij'hLkhW)0J5>*B* CJaJph/j3FhLkh|Cx5B* CJUaJphhLkh|CxB* CJaJph'hLkh|Cx0J5>*B* CJaJph/jEhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph)jhLkh|Cx5B* CJUaJph hh|Cx5B* CJaJph)jhh|Cx5B* CJUaJphH^I^J^N^O^Q^R^n^o^p^z^{^~^^^^^^^^^^^ҾҭҭҾҭoWCoҭ'hLkhW)0J5>*B* CJaJph/j|GhLkhW)5B* CJUaJph hLkhW)5B* CJaJph)jhLkhW)5B* CJUaJph/jGhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph'hLkh|Cx0J5>*B* CJaJph)jhLkh|Cx5B* CJUaJph/jFhLkh|Cx5B* CJUaJph^^^^^^^_______8_9_:_@_A_B_C_V_X_Y_ҾҭҭҾҭҭ}Ҿiҭ\I%jhLkh>5B* CJUphhLkh>B* CJph'hLkhn8[0J5>*B* CJaJph/jHhLkh|Cx5B* CJUaJph/j|HhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph'hLkh|Cx0J5>*B* CJaJph)jhLkh|Cx5B* CJUaJph/jHhLkh|Cx5B* CJUaJphY_w_x_y________________ȶȩveMv9veve'hLkh|Cx0J5>*B* CJaJph/jIhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph)jhLkh|Cx5B* CJUaJph h yh|Cx5B* CJaJphhLkh>B* CJphhLkh|CxB* CJph#hLkh>0J5>*B* CJph%jhLkh>5B* CJUph+jbIhLkhOw5B* CJUphhLkh>5B* CJph_______ ` ` `````*`+`,`1`2`4`5`\`]`^`t`u`w`x````ҾҭҭҾҭҭ}ҾҭҭeҾҭҭM/j*B* CJaJph)jhLkh|Cx5B* CJUaJph/jXJhLkh|Cx5B* CJUaJph````````````aaaaaaa1aŭ֠~hVGhLkh|Cx5B* CJph#hLkh|Cx0J5>*B* CJph+jdMhLkh|Cx5B* CJUphhLkh|Cx5B* CJph%jhLkh|Cx5B* CJUphhLkh|CxB* CJph/jLhLkh5B* CJUaJph hLkh|Cx5B* CJaJph)jhLkh|Cx5B* CJUaJph'hLkh|Cx0J5>*B* CJaJph_``(b)bbb/c0cPcQcYcZccccc1dwddddd^e^^`^gd2f^gdLk p`^p``gdLk1a2a3a6a7a9a:aUaVaWa_a`aaabadaeaaaaaaaaaaaaaaaaaҾҭҭҾҭҭiҾҭҭQҾҭ/j>OhLkh|Cx5B* CJUaJph/jNhLkh|Cx5B* CJUaJph'hLkhn8[0J5>*B* CJaJph/jTNhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph'hLkh|Cx0J5>*B* CJaJph)jhLkh|Cx5B* CJUaJph/jMhLkh|Cx5B* CJUaJphaaaaaaaaaaaaaaabbbbb®®q\qD\/jPhLkhLk5B* CJUaJph)jhLkhLk5B* CJUaJph hLkhLk5B* CJaJph/jPhLkh|Cx5B* CJUaJph'hLkhn8[0J5>*B* CJaJph'hLkh|Cx0J5>*B* CJaJph)jhLkh|Cx5B* CJUaJph/jOhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJphb&b'b(b)b*bGbHbIbNbObPbQbnbobpbǺ|hSB*S/jsQhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph)jhLkh|Cx5B* CJUaJph'hLkh|Cx0J5>*B* CJ aJ ph/jPhLkh|Cx5B* CJ UaJ ph hLkh|Cx5B* CJ aJ ph)jhLkh|Cx5B* CJ UaJ phhLkh|CxB* CJphhLkh|CxB* CJaJph)jhLkhLk5B* CJUaJph'hLkhLk0J5>*B* CJaJphpb}b~bbbbbbbbbbbbbbbbbbbŭ֜o[ND5Djh|CxB* CJUphh|CxB* CJphhLkh|CxB* CJph'hLkh>0J5>*B* CJaJph/jWRhLkhOw5B* CJUaJph)jhLkh>5B* CJUaJph hLkh>5B* CJaJph/jQhLkh|Cx5B* CJUaJph hLkh|Cx5B* CJaJph)jhLkh|Cx5B* CJUaJph'hLkh|Cx0J5>*B* CJaJphbbbbbbbccc,c-c/c0c6cPcQcXcYccccccccccwddddiejeeeǵǩpd[ jh|CxCJhI=h|Cx0J>*CJjShI=hCJUhI=hI=CJjhI=hI=CJU h|Cx>* h|CxCJh|Cxh2fh|Cx5B*CJph"j1Sh|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"jRh|CxB* CJUph#^eeeeeeeefffff"g=g>gFgPggggggg-h` ^` ^`^^^eeeeeeDfEfZf[f\fgfhfiffffffffffffgggghh.h8h;hHhܷܮxic]W] h\ CJ h|CxCJ hn8[CJh|Cx0J5>*B*CJph+jThZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphhn8[h?<h|CxCJh?<h|Cx0J>*CJjTh?<hSCJUh?<h?<CJjh?<h?<CJU h|Cx5CJh|Cx htiCJ h|CxCJ"-h.hHhIh]hhnioiiii&jsjtjjkk/klkkkkkkk ^gd ^gd ^gd HhIh]hghhhhhhhhhhhhh i.i/iEiFiGiKiLiMieiminioiiiiiiiiߺ|sieh|Cxh!9h|Cx>*CJh)h|CxCJh)h|Cx0J>*CJjUh)h ,CJUh)h)CJjh)h)CJU h-CJ hn8[CJhjh|Cx0J>*CJjUhjhn8[CJUhjhjCJjhjhjCJU h|Cx5CJ h|Cx>*CJ h|CxCJ#iijjj"j#j$j%j&j+jtjjjjjjjjjjjkkk/kkkkkllxllllllﵬ|sc|jVh#hRfCJUh#h#CJjh#h#CJU h|Cx6CJhh|Cx0J>*CJjvVhh_CJUhhCJjhhCJU h|Cx>*CJ h|Cx5CJhn8[0J>*CJh|Cx0J>*CJjVh|CxCJU h|CxCJjh|CxCJU$kklllylmm$m%m1mpmmn$n?nnnnnn o)oo & Fgd0 & Fgd0^gd`gd0^ & F^gd ^gd p^pgd llllm$m%m/m0m1m=mImJmpmzmmmmmn#n$n/n7n8nRnSnqnrnsnnnnnnnnnnnnſװתװכqggh0h05CJhjT*h|Cx0J5>*CJ"jlWhjT*hOw5CJUhjT*hjT*5CJjhjT*hjT*5CJU hCCJ hn8[CJh0h0CJ h0CJ h05CJ h|Cx5CJh|Cx h|CxCJh#h|CxCJjh#h#CJUh#h|Cx0J>*CJ(nnno o(o)o=oooppphpypzppp/q0qEqqqqlrxrrrrsssss/s0s9sdses*CJ"jWhh5CJUhh5CJjhh5CJUh1]h1]5CJ h|CxCJ h|Cx5CJ h1]5CJ h1]CJ hCCJh0h0CJ h05CJ h0CJ*ophp0qqlrrr0swDwEwwwwwww!x"xxxxxxxxxyy>y?yټټټټ߬٣ٕ jh|CxCJmHnHu jh|CxCJ h 5CJ h|CxH*hN*CJ h0CJ hN*CJj[h/h/FCJUh/h/CJjh/h/CJU jh|CxCJmHnHu h[CJ hN{?{N{P{Q{g{h{i{m{n{p{q{{Ǿ笣vk^j;]h|CxCJUhN*CJh|Cx0J5>*CJj\h|Cx5CJU h|Cx5CJjh|Cx5CJUh!9h!9CJh|Cx56CJh|Cx5>*CJhN*CJh|Cx0J>*CJj5\h|CxCJUjh|CxCJU h|CxCJ h|Cx5CJ(h|Cx5B*CJph#{{{{{{{{{{{{{{{{{{{{|4|5|I|J|K|Y|Z|\|]|q|r|s|u|v|{|||||||||||ٿٸ٬٬tj_h|Cx5CJUjn_h|Cx5CJUh|Cx0J5>*CJj_h|Cx5CJUjh|Cx5CJU h|Cx5CJj^h|CxCJUj^h|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUj]h|CxCJU,||||||||||| } } } })}*}+}A}B}D}E}^}_}`}f}g}h}i}}}}}}}}}}}}}}}}}N~X~m~ԶíԠíԓíԄwíj&bh|CxCJU hn8[CJhn8[0J>*CJjah|CxCJUj>ah|CxCJUh|Cx0J>*CJj`h|CxCJUjh|CxCJU h|Cx5CJ h|CxCJh|Cx0J5>*CJjh|Cx5CJUj>`h|Cx5CJU.}}N~>xzʀ%<bЁBCRP & F^` & F & F^ & F` & F^` & F^^m~n~~~~~~~~~~    '();<>NPQxyzúÞОÕúÞ~njchZ )hCJU h|Cx5CJj{ch/whs>LCJUh/wh|CxCJh/wh|Cx0J>*CJj ch/whs>LCJUh/wh/wCJjh/wh/wCJUhn8[0J>*CJh|Cx0J>*CJjbh|CxCJU h|CxCJjh|CxCJU$!"#,-PQqrsvɤ֗~re\Le@h7h|Cx0J>*CJjfhZ )hCJUh7h7CJjh7h7CJUhah|Cx0J>*CJjfhZ )hCJUhahaCJjhahaCJUh"h|Cx0J>*CJjreh"hNCJUh"h"CJjh"h"CJU h|CxCJh|Cx0J>*CJjh|CxCJUjdhZ )hCJUvwz#$%{| DQUZkoϿست엎~rkeXjh78h78CJU hN*CJhnh|Cx0J>*CJjhhnhCJUhnhnCJjhnhnCJU hn8[CJhjT*h|CxCJhjT*h|Cx0J>*CJjghjT*hOwCJUhjT*hjT*CJjhjT*hjT*CJU h|Cx5CJ h|CxCJjh7h7CJUĂł/;PU"#$()*LMtuvȻȻȻȮsjZsNsȻh$hh|Cx0J>*CJjih$hh%&CJUh$hh$hCJjh$hh$hCJUhG{h|CxCJhG{h|Cx0J>*CJj ihG{h.CJUhG{hG{CJjhG{hG{CJU h|Cx5CJ hN*CJjh78h78CJUjhh78hCJUh78h78CJׄ؄34Cۅ}mAB[^gdt & Fp^pgdt & F^gdt & F^`gdt & F^`gdt & F` & F & F^`p^p؄4Iiuۅ܅ %&}҆ӆmvAB߈BYzkh|Cx0J5>*B*CJph%jjh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph jh|CxCJmHnHu jh|CxCJh|Cx0J>*CJj|jh|CxCJUjh|CxCJU hN*CJ hn8[CJ h|CxCJ*.3@ABEF]`bouvΊϊЊ܊݊ !;A(0$'{;;;;ͱ;ͅ~tn hn8[CJhW)h|Cx6CJ hW)5CJ h|Cx5CJh/,ht0J>*CJjkh/,htCJUh/,htCJjh/,htCJU h/,CJ jhtCJ htCJh"(h/,CJ ht>*CJ h/,>*CJh/,ht>*CJ h|CxCJ hN*B*CJphj9lh0 hjCJUh0 h0 CJjh0 h0 CJUh0 h|CxCJ hn8[CJ hn8[5CJhW)hZ5CJ hZCJ hW)CJ hmCJhZhZCJ hZ5CJ h|CxCJ h|Cx5CJ֎؎ގߎFSeq־yjccYcSLS hZ5CJ hZCJhpahpa5CJ h|Cx5CJh|Cx0J5>*B*CJph+jGmh!9h5B*CJUphh!95B*CJphjh|Cx5B*CJUph h|CxCJH* h|CxCJ hpaCJ hmCJ#hmhm0J5>*B*CJph%jhmhm5B*CJUph+jlh0 hj5B*CJUphӏԏߏ #$-.jqryΑϑ2;<= 23RSTbcnopqz|ɹҭߚߚ~ҭxnxhZhZCJH* hZCJjInhW)h{CJU h\ CJ hn8[CJ hn8[5CJhW)hn8[0J>*CJhW)h|Cx0J>*CJjmhW)h{CJUhW)hW)CJjhW)hW)CJU h|Cx5CJhZh|CxCJ h|CxCJhpah|Cx5CJ+|ϓГݓ )PQ-`hӕԕՕﴮ}e/jnhU"hb*5B*CJUaJphhU"5B*CJaJph)jhU"hU"5B*CJUaJphhU"CJaJ hU"CJ hpaCJhpahpa5CJ h|Cx5CJ hRh|Cx hW)CJ h|Cx6CJhmhm5CJ hmCJ hn8[CJ h|CxCJhmh|Cx5CJ%q-`tҗ'-ǘߘR  & F pp^pgd & F pp^pgd H & FgdLk^gdLk & F^gdLkgdR & F^gdLkՕٕؕڕܕ )*+./02AYZ[}ȾtbȸO@hpahpa5B*CJph%jhpahpa5B*CJUph#hpahn8[0J5>*B*CJph+j[ohZ )h5B*CJUphhn8[5B*CJph%jhpahn8[5B*CJUphhpahn8[CJ hn8[CJ h|CxCJhpah|Cx5CJ hpaCJhU"CJaJ)jhU"hU"5B*CJUaJph'hU"hU"0J5>*B*CJaJph}~txҗܗ',-.ֻֻ֬}si}sb[bNjhhCJU hj5CJ h2q5CJhjh2q5CJh2qh2q5CJ h2qCJ h|CxCJ h|Cx5CJ hpaCJ+jphZ )h5B*CJUphhpahpa5B*CJphhpahpaCJ#hpahpa0J5>*B*CJph%jhpahpa5B*CJUph+johZ )h5B*CJUph.RSTijlƘǘݘޘ RXuvw|}~ȼȧȼul\ujthh$&%CJUhhCJjhhCJU h|Cx0J>*jqh|CxUjh|CxUh|Cx h|Cx5CJ jhjh2qCJh2qh2qCJ h|CxCJ h3}CJ h2qCJhh|Cx0J>*CJjhhCJUj(qhhI<CJUhhCJ˚̚ /01=>AB_`almn›ƛǛ˛̛ћӛ{uu{nehjhjCJ hj5CJ hjCJ h|CxCJH*hN rh|CxCJjthN rh-CJUhN rh|Cx0J>*CJj}thN rh-CJUhN rhN rCJjhN rhN rCJU h|Cx5CJ ho7CJ hn8[CJ h|CxCJjhhCJUhh|Cx0J>*CJ& Ii 7QΠ ;ci & F pp^pgd H & Fp^pgdLk & F^`gdLk & F^gdLk,-.GHIRiq7;FHgh}~uoh^XRX hZOeCJ h CJh h 5CJ hy5CJ hyCJhn8[h|Cx0J5>*CJ"jvhn8[h|Cx5CJUhn8[h|Cx5CJjhn8[h|Cx5CJUh h|Cx5CJ h|CxCJ h|Cx5CJhJxhj0J>*CJjquhJxh$CJUhJxhJxCJjhJxhJxCJUhJxhjCJ )0QWrtzΠנ /019:;<\]^abcd./Ǯ򤞎uǮobjh Jh JCJU hjBCJjwhZ )hCJUh J0J>*CJj0wh Jhz CJU h JCJjh JCJUh|Cx0J>*CJjivhZ )hCJUjh|CxCJU hFCJ hCJhyhyCJ hyCJ ho7CJ h|CxCJ h|Cx5CJ&/UVW`abghqrϣУѣգ֣أ٣¼vȏfv`Y h|Cx5CJ h/CJj{h Jhz CJUh J0J>*CJjBzh Jhz CJUjh JCJUho70J>*CJj}yhZ )hCJUjh|CxCJU h|CxCJ hjBCJ h JCJh Jh J0J>*CJjh Jh JCJUjxh Jhz CJUh Jh JCJ!֤פWXiԥy+,Mɧʧ & F^gdLk^gdLkp^pgdLk & F^`gdLk ^`gdLk & Fp^pgdLk & F^`gdLkgdR & F^gdLk & F pp^pgd HĤŤ֤פWX]^tvƥ*+,Mʧҧuiuhn8[5B* CJphh|Cx5B* CJphho75B* CJph hn8[CJ ho7CJh\Gh|Cx0J>*CJj{h\GhCJUh\Gh\GCJjh\Gh\GCJU hn8[5CJ h|Cx5CJ hCJ h CJh|Cxho7 hRh|Cx h|CxCJ heCJ)a {$mnīVv & Fp^pgdLk^gdLk^gdLkgdR & F & F^gdLk & F^gdLkknqǨɨԨ֨!)*1 Pbg$)*elnë̫>h; qh5CJjh; qh|Cx5CJUh|Cx h|Cx>*CJ ho7CJ hn8[CJh|Cx0J>*CJjG|hZ )hCJUjh|CxCJU hn8[5CJ h|Cx5CJ h|CxCJ:>?@IJPRa89:BCFHZ[ghǾǸtk[tOthdh|Cx0J>*CJj~hdh}_CJUhdhdCJjhdhdCJU hn8[CJ h|CxCJH*h|Cx0J>*CJj}hZ )hCJUjh|CxCJU h|Cx5CJ h|CxCJh; qh|CxCJh; qh|Cx5CJh; qh|Cx0J5>*CJjh; qh|Cx5CJU"j }hZ )h5CJUV^v~Įʮ Xgjޯ° fl±ʱ Zmͺ| h|CxCJH*#hNkXhNkX0J5>*B*CJph+j\hNkXh5B*CJUphhNkXhNkX5B*CJph%jhNkXhNkX5B*CJUph hNkXCJ hu>*CJhuhu>*CJ huCJ h|Cx5CJ h|CxCJhdh|CxCJ0vĮ !! >n± h^`hgdNkX h^h` & F 88^8h^h ^`gdLk^gdLk^gdLk & Fp^pgdLkDnP>? & F^gdLk & F^`gdLk & F^gdLk  & F^gdLk^gdLk & F^^gdu & F 88^8^PYĴŴ!=?NOPuvw489:,-׸細׸~ jh|CxCJmHnHu h3CJ h35CJjhZ )hCJU hn8[5CJhn8[h|Cxh|Cx0J>*CJj)hZ )hCJU hCJjh|CxCJU h|CxCJ h|Cx5CJ huCJ ho7CJ h5/%CJ134:xV0";[v^gdLk & F^`gdLk ^ gdLk ^`gdLk & F pp^pgdQ^gdLk & F^gdLk & F^gdLk-@Ax./09:V{۸ܸݸ-.>ELP\_ù˹zs h35CJjhh_CJUhh|Cx0J>*CJj hh_CJUhhCJjhhCJUhh|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ jh|CxCJmHnHu h|CxCJ,"vȺҺԺ0Mu 9:;>?STDzǹǥwǹǹq hhNCJhn8[0J>*CJhZ9h|Cx0J>*CJj0hZ9h^-CJUhZ9hZ9CJjhZ9hZ9CJU *h|CxCJ h|Cx5CJ h35CJ h|CxCJh|h|CJh3h3QfCJH* h3QfCJH* h|CJ h3QfCJ h3Qf5CJ h3CJ)v0M .aqP ^gdLk p^p`gdLk & F^gdLk ^`gdLk^gdLkp^pgdLk½-.4KS`ai%&LVqrukY"jWhZ )h5CJUh,g+h,g+>*CJhQyh|Cx0J5>*CJ"jhZ )h5CJUhQyhQy5CJjhQyhQy5CJU h|Cx5CJ hhNCJ h,g+CJ h|CxCJh,g+h|Cx0J5>*CJ"jhZ )h5CJUh,g+h|Cx5CJjh,g+h|Cx5CJU ˿׿-:<NP\ '(QRĽulf hn8[CJh|Cx0J>*CJj$h|CxCJUjh|CxCJU *h|CxCJ ho7CJ h)CJ h|CxCJ h36CJh3h36CJ h35CJ h|Cx5CJ h3CJhQyhQy>*CJ hQyCJhQyhQyCJjhQyhQy5CJUhQyhQy0J5>*CJ( Zinf?^gdLk ^`gdLk^gdLk ^`gdLkp^pgdLk^gdLkfm ?34$;\]V46T\ľ} h8XCJ h>CJhjT*hjT*5CJ hjT*CJ hLkCJh|Cx h|CxCJH* h|Cx>*CJ ho7CJ h|Cx5CJ h|CxCJhh|CxCJhh|Cx0J>*CJjhh#,CJUhhCJjhhCJU13#$;]T45N,-JK` & F^gd ^gd  ^`gdLk^gdLk^gdLk45N,K`aja$-.:;D*+,ﷳzqazj݇h3h.CJUh3h3CJjh3h3CJUh|Cx5>*CJ h|Cx5CJh|Cx56CJ hpCJ h 5CJ h CJh  h|CxCJhjT*hjT*0J>*CJj hZ )hCJUhjT*hjT*CJjhjT*hjT*CJU hjT*CJhjT*hjT*5CJ&`ak`a"#L & F^gd/ & F^gdLk & F^gdLk & F^`gdLk & F^gdLk,0145MNOUVab~HU_`Դ殧|n|d|hehe0J>*j6hehb*UjheheU hehe heCJ hn8[CJ hEuCJ h|Cx6CJ h|Cx5CJ h|CxCJjh3h.CJUjLh3h.CJUh3h3CJh3h|CxCJjh3h3CJUh3h|Cx0J>*CJ')^gd'i^gdR & F^gdEu & F^gd'i^gd'i & F^gd'ij~mn)uvMNYZqr 67ABCMvxth|Cx6B* CJphh|CxB* CJphhn8[5B* CJphh|Cx5B* CJph hn8[CJ hRCJ h'iCJ ho7CJ h|Cx5CJ h|Cx6CJ h|CxCJ hehe>yzvwDEOJK`$%@AgdLk^gd!9^gd'i^gd'ituIPu{z CFOP_wEM %-8JK^`t#ǾǢhEuh|Cx0J>*CJj׉hEuh HCJUhEuhEuCJjhEuhEuCJU h!9CJ h|Cx6CJ ho7CJ hn8[CJ h|Cx5CJ h|CxCJ h'iCJ>#$%@AUWXlmnvw} BCDIJKTվ˵ժxfXLhRh#R%5CJaJhRh|Cx0J>*CJaJ#jhRhigCJUaJhRhCJaJjhRhCJUaJhRh4T=>*CJaJhRh|Cx5CJaJhRh|CxCJaJh|Cx0J>*CJjPh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJhLkhLk5CJ(aJ( hLkCJh|Cx5B*CJphA|}K&Kn(K[  & F[gdR & FZgdRp^pgdR ^`gdR^gdR^gdLkT#&-KO[@Abcdlmns!'(=KY[gȹȆȆȆwjhRh|CxCJUaJhRCJaJh)Mh)M0J>*CJaJ#j`h)MhGpTCJUaJh)Mh)MCJaJjh)Mh)MCJUaJhRh|CxCJaJhRh|Cx5CJaJhRho7CJaJhRh4T=CJaJhRh#R%CJaJ-?@ŹŮŹţţţŹʼnŮ~o~]o#jhRhwCJUaJjhRhwCJUaJhRhwCJaJ jhRh|CxCJaJhRhQCJH*aJhRhQCJaJhRhn8[CJaJhRh|Cx5CJaJhRh|CxCJaJhRh|Cx0J>*CJaJjhRh|CxCJUaJ#j!hRh|CxCJUaJ" ha-y%krs^gdR@ ^@ gdRp^pgdR & F\gdR,.acd<?Ir̶̾ק|peZepeNeehRhQ>*CJaJhRh4T=CJaJhRhQCJaJhRh|Cx5CJaJhq:hw0J>*CJaJ#j hq:hQCJUaJhq:hq:CJaJjhq:hq:CJUaJh|CxCJaJ jhRh|CxCJaJhRh|CxCJaJhRhwCJaJjhRhwCJUaJhRhw0J>*CJaJUxy~ȳvk`QjhRh@'FCJUaJhRhS{CJaJhRh.6CJaJ'hRhv(0J5>*B*CJaJph/jhRh5B*CJUaJph hRhv(5B*CJaJph)jhRhv(5B*CJUaJphhRhv(CJaJhRhQCJaJhRho7CJaJhRh|Cx5CJaJhRh|CxCJaJ  #$%457Զ|pppdYJYjhRh4T=CJUaJhRh4T=CJaJhRh4T=5CJaJhRh|Cx5CJaJh?h|Cx0J>*CJaJ#jh?hQCJUaJh?h?CJaJjh?h?CJUaJhRh|CxCJaJ$hRh|Cx0J>*B*CJaJphjhRh@'FCJUaJ#j-hRhb*CJUaJhRh@'FCJaJrs !@^mnŹŮ~~~~sŮŮhŮh`hh\CJaJhRh\CJaJhRhn8[CJaJ jhRh|CxCJaJhRh|Cx>*CJaJh"(hRCJaJhRhRCJaJhRh|CxCJaJhRh|Cx5CJaJhRh4T=CJaJhRh4T=0J>*CJaJjhRh4T=CJUaJ#jhRh9CJUaJ%1_>O%& ^`gdLk ^`gdR@ ^@ gdR ^`gdRp^pgdR^gdR=?MNOPbch'(*@VZ[\ꨣ}s}md^X^d hLCJ h_CJh_h_CJ h.6CJh_h_6CJ h_5CJh|CxB* CJOJQJph h|Cx5CJh|Cx h|CxCJ h|Cx5hRhaJh|CxCJaJhRCJaJh\CJaJhRh\CJaJhRh4T=CJaJhRhn8[CJaJhRh|CxCJaJhRhtCJaJ"c()@A[ =>@^gdLkp^pgdLk ^`gdLk@ ^@ gdLk^gdLk & F^gdLk @ ^@ `gdLk & F@ ^@ gdLk p^p`gdLk u=>GHnop789=>@A^f/0FGHLͿ͕Ϳ͎{n{eh2q0J>*CJjh2qCJUjh2qCJUh2qh2qCJ h2q5CJ hntCJ h2qCJ h|Cx0J>*jˏh|CxUjh|CxUh|Cx h|Cx5CJ ho75CJ h|CxCJ hCJ h5CJhhh>* h5h_h_CJ h_CJ'@^/Nw()FGR-pq ^` & F\^^`gdLk & F~gd2q^gd2q^gdLkLM')FGRbcqr 5AYaﶰ h|Cx6CJ jh|CxCJ hn8[CJh|CxhLkh|Cx56CJaJ hntCJ h|CxCJ h|Cx5CJhh2q0J>*CJjhh2qCJUhh2qCJjhh2qCJU h2qCJjh2qCJU0q45BYm] & F1 pp^pgdCjR ^`gdLk^gdLk^gdLk ^`gdLk ^`^ & F\#'(HIJXYmv+G\]fU` K/8Ĵͨ ho7CJ jh|CxCJhl~hl~>*CJ hn8[CJhg@h|Cx0J>*CJjhg@h|CxCJUhg@hg@CJjhg@hg@CJUhg@h|CxCJhl~h|Cx5CJ h|Cx5CJ h|CxCJ hl~CJ5U`r/x?  ^`gdLk^gdLkgdN & F2 pp^pgdCjR & F9 pp^pgdCjR^gdLk & F1 pp^pgdCjR# ~︬︬k︬+jhZ )h5B*CJUph hn8[CJh|Cx0J5>*B*CJph+jnhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hl~CJ h|Cx5CJh|Cxh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU!-./5679?@ABIx} ?I )ľyrkrrrrrrrrd`rh|Cx h|Cx>*CJ hn8[5CJ h|Cx5CJ hShS0J>*B*CJph̙(jUhShfgB*CJUph̙hShSB*CJph̙"jhShSB*CJUph̙ hSCJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jhZ )h5B*CJUph%&rsD c   S   ( ) n ^gdLk@ ^@ gdLk & F2 pp^pgdCjR^gdLk^gdLk ^`gdLk ^`gdLkgdN&0ABjkloprs򡚡~hYSM hSCJ h2FCJh(90J5>*B*CJph+jזhZ )h5B*CJUphh(95B*CJphjh(95B*CJUph h(95CJ h(9CJ h.u CJh|Cxh|Cx0J5>*B*CJph+j,hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJ/ 0 1 7 8 C c h    % S [ ] h l        ( ) - n t              - R l  jh(9CJ h(9CJ h(95CJ h2FCJ hn8[CJ h2F5CJ h|Cx5CJ h|CxCJ hSCJ hShS0J>*B*CJph̙(jxhShfgB*CJUph̙hShSB*CJph̙"jhShSB*CJUph̙.n    - > O 6    A!-p^pgdj & F pp^pgdQ ^`gdLk^gdLk^gdLk^gdLk & F2 pp^pgdCjRl m       6 ? e f     AM_mx{}ľxrlblbl[ h|Cx>*CJh:h:5CJ h:CJ ho7CJh:h|Cx5CJaJh:h:CJaJh/*CJaJh:h|CxaJh|Cx h(95CJ hn8[CJ h|CxCJ h|Cx5CJ h(9CJhgh(9CJhgh(90J>*CJjOhghgCJUhghgCJjhghgCJU# !%&H.JKlmn~Dzԡ{neUnj4hShjCJUhShjCJjhShjCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU ha[CJ hBhB0J>*B*CJph̙(jܘhBhfgB*CJUph̙hBhBB*CJph̙"jhBhBB*CJUph̙ hBCJ hjCJ h|CxCJ h|Cx5CJ69M,-\fgྲྀڞċrf]ѽڽhShjCJhShS0J>*CJjhSh%CJUhShSCJjhShSCJU hmCJ h/*CJhmh|CxCJhmhmCJ hm5CJ h|Cx5CJ hSCJ hj5CJhjhjCJ h|CxCJ hjCJjhShjCJUhShj0J>*CJ$D(6T|.4! & F5 8pp^pgdCjR & F6 8pp^pgdCjR & Fx pp^pgd H & Fogdj & F pp^pgdQ^gdLkDGH,-F}~(1sĽz hjCJh!9hm0J>*B*ph$jh!9hmB*Uphh!9hmB*phjh!9hmB*Uph h!9hm hmCJ h[CJ ho7CJ hn8[5CJhShSCJ hS5CJ hSCJ h|Cx5CJ h|CxCJ/ 5.245ABEHQrst!'N^_񝭔񀭔jh|CxCJU hn8[5CJh|Cx0J>*CJjÛhZ )hCJUjh|CxCJUh|CxB* CJph h|CxCJH*hjhjCJ hj5CJ hDCJ hjCJ h:CJ h|Cx5CJ h|CxCJhjh|CxCJ2!NYZr*U ^``^`gdFgdLkp^pgdLk^gdLk^gdLk ^`gdLkYZrsʽuh_hn8[0J>*CJjh|CxCJUhkh|Cx0J>*CJjphkhb*CJUhkhkCJjhkhkCJUh|Cx0J>*CJjh|CxCJU h|Cx5>* h_CJ h|Cx5 h|Cx>*CJ hFhFhLkh|Cx5CJ aJ hLkCJ h|CxCJjh|CxCJU"()UVklmpq򻱻ykdZT h|CxCJjh|CxCJU h|Cx>*CJhLkh|Cx56CJaJhLkhLk56CJaJ h|Cx5CJjDh|CxCJUh|Cx0J>*CJj۞h|CxCJUjh|CxCJU h|CxCJh hn8[0J>*CJh h|Cx0J>*CJjhh hCJUh h CJjh h CJUU*ABn 34: # $  ^`^`gdLk^ ^`()BHop  %ټٯ٢ߙٌߙj֡h|CxCJUjih|CxCJUhn8[0J>*CJjh|CxCJUjh|CxCJU h|Cx>*CJho70J>*CJjh|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU1%&'./1249MNcdehiklмЯ~qhXqLhLh|Cx0J>*CJjhLhSCJUhLhLCJjhLhLCJUh_h_0J>*CJh_h|Cx0J>*CJj%h_hi@!CJUh_h_CJjh_h_CJUjh|CxCJU h|Cx>*CJ h|CxCJhn8[0J>*CJh|Cx0J>*CJjh|CxCJUjIh|CxCJU$ , h v              e!f!r!t!!!!!!ɤɛ㖊yylcSljhZ )hCJUhhCJjhhCJU h|Cx6CJh|Cx h|CxCJhLkh|Cx56CJ h|Cx5hh|CxCJhh|Cx0J>*CJj'hhLCJUhhCJjhhCJU h_CJ h|Cx>*CJ h|CxCJhLh|CxCJjhLhLCJU$ @ F h v       !(!5!A!e!t!!!!!!:"""^p^p ^` ^`gd_ ^`^!!!!!!!"""2"3"4"8"9":"@""""""""""""""׽א{tm{aVNhFCJaJh Qh|CxCJaJh Qh|Cx5CJaJ h|Cx5CJ h|Cx5CJh|Cx ho7CJhr0Yhr0YCJaJhr0YCJaJhr0Yh|Cx0J>*CJjhr0Yhb*CJUhr0Yhr0YCJjhr0Yhr0YCJU hr0YCJ h|Cx6CJ h|CxCJhh|CxCJjhhCJUhh|Cx0J>*CJ""""""""N#r#}####$$X$Y$%%&&^gdff^gdLk ^` ^`gd Q^gdN^"-#.#D#E#F#J#K#L#M#N#y#z##############$$$$X$b$o$r$y$$$氨pd]]] h|Cx5CJhffhff0J>*CJjhffhwTCJUhffhffCJjhffhffCJU hFCJ hn8[CJ h|CxCJh QCJaJhFh QCJaJhFh Q0J>*CJaJ#jvhFh}CJUaJhFhFCJaJjhFhFCJUaJh Qh QCJaJ$$$%%%%6%7%8%;%<%>%?%n%o%p%s%t%v%w%%%%%%%%%%%%%%%%̷֩̔֩֩j֩c h|Cx5CJ(jhZ )h QB*CJUph(jԨhZ )h QB*CJUph(jhZ )h QB*CJUphh Q0J>*B*CJph(jjhZ )h QB*CJUphh QB*CJphjh QB*CJUph h QCJ h QCJ h|CxCJ jh|CxCJ"%&o&p&&&&&&&&&''''''''(( (((#(:(D(](g(ͻحآ琄vkvkvkckZvkvkhff5CJaJhffCJaJhUhffCJaJhUhff6CJ]aJhUhff5CJaJhffhffhff6CJ]aJh'hffCJaJh'hff0J>*CJaJ#j>h'h%szCJUaJh'h'CJaJjh'h'CJUaJhffhffCJaJhffhff5CJ\aJ&&8&J&V&&&&&&&"'*'M'Z'd'r's'''' $IfgdwT^gdR0`gdff^gdff ^gdff ^`gdffp^pgdff^gdff''''( (#(D(g((((((()*)<)=)R)`)v)w)x)))))) $IfgdwTg(r(~(((((())=)R)u)w)x)))))))))))*"*#*%*-*R+V++++,,ٶ|nchk5CJ\aJhkhk5CJ\aJhkCJaJhffCJaJhffhff5CJ\aJ hffhff5B* CJaJphhffhffCJaJhffhff6CJ]aJhffCJaJhUhff5CJaJhUhffCJaJhUhff6CJ]aJhUhmf6CJ]aJ$))))))**!*"*#*$*%*+|s^gdffgdff^gdR0kkd$$Ifl*F4'   t6    44 laytR0 $IfgdwT +Q+R+++,L,n,r,,,,,,]-.//`01c2o2^gdLk^gdLkgdff^gdk^gdk^gdff,%,&,R,S,v,w,,,,,,,,,,,,,,,,--]-i------.m.n.........t////ʽʶĥęʊsh|Cx5B*CJphh|Cx0J5>*CJjƫh|Cx5CJUjh|Cx5CJU h|Cx6CJh h|Cx5CJ h 5CJ hn 5CJ h|CxCJ h|Cx5CJhffhffCJaJhffhkCJaJ jhkhkCJaJhkhkCJaJ-///80D0R0U0`0i0r0012!2%2c2l2n2o2y24444_5a55555555555C6P6666666666666777777h-Dh-D5CJ ho7CJ h-DCJh-Dh|CxCJ hn8[5CJh-Dh|Cx5CJ hCJhn hn CJ hn 5CJhn h|Cx5CJ hn CJ *h|Cx5CJ h|Cx>*CJ h|Cx5CJ h|CxCJ7o24455567i7}7~7778899,9d9999: p^p`gdLk ^`gdLk^gdLk^gdLk & F pp^pgdQ7~77777777777888k8v888888888:<:=:Y:]::::::::::;%;@;H;J;P;;;;;<ɣhshsCJjhshsCJU hG"CJh|Cx0J>*CJj/h|CxCJUjh|CxCJU h|Cx6CJh|Cx ho75CJ h|Cx5CJhn8[5B* CJphh|Cx5B* CJph h|CxCJ1::<:=:Y::;@;;;;;;;-<Mkd$$Ifl0,J 4 la ytLk$If^gdLk^gdLk & F^gdLk & F^gdLk<<<+<,<-<e<f<====='>(>I>J>K>Q>R>|>>>>>>.?N??????@ @!@F@ǺǭǣǓdzǃdzdzdzdzdztj *hJv1hJv1CJj *hJv1hJv1CJU h|CxCJH*h|Cx0J>*CJjͰhZ )hCJUjh|CxCJU hG"CJ h|Cx5CJ h|Cx6CJ hsCJ h|CxCJhsh|CxCJhsh|Cx0J>*CJjhshsCJUjhshfgCJU$-<.</<?<d<e<x<<]Mkd$$Ifl0,J 4 la ytLkMkd}$$Ifl0,J 4 la ytLk$If<<<<<<<<=9=]Mkd$$Ifl0,J 4 la ytLk$IfMkdQ$$Ifl0,J 4 la ytLk 9=:=G=R=S=g==]Mkd$$Ifl0,J 4 la ytLk$IfMkd%$$Ifl0,J 4 la ytLk======|>>>]TTTK^gdLk^gdLkMkdc$$Ifl0,J 4 la ytLk$IfMkd$$Ifl0,J 4 la ytLk>>>?.?/?N???@@AABBBdBCCDDD0EFF & Fgdm^gdN^gdLk^gdLk ^`gdLkF@G@H@R@S@V@^@h@@@@ADAEA]A^A_AdAeAfAgAiAjA~AAAAAAAAAB BBBBB:B;BUBľzs hn8[5CJjh|CxCJUhn8[0J>*CJh|Cx0J>*CJjPh|CxCJUjh|CxCJU h|Cx5CJ h|Cx>*CJ h|CxCJhJv1h|CxCJ# *hJv1h|Cx0J>*B*CJphj *hJv1hJv1CJU"j *hZ )hCJU(UBVBWB^B_BdBpBBBBBBBBBBCC*C^CCCCCCCCCCCCCCCCCҽwqk^jhnp hnp CJU hG"CJ hmCJh|CxB*CJph& *hJv1h|Cx0J5>*B*CJph.j *hZ )h5B*CJUph *hJv1h|Cx5B*CJph(j *hJv1h|Cx5B*CJUph h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUj&h|CxCJU#CCCCDDDD%D&D'D+D,D0D;DmDpDDDDDDDDDD/E0EEEEEEEFFFFF6F˴ˤ˝˖ːˤˊˊːːːˊshhh|CxB*phjhh|CxB*Uph hh|Cx hmCJ hn8[CJ hG"5CJ h|Cx>*CJ h|Cx5CJh|Cx0J>*CJjӴh|CxCJUjh|CxCJU h|CxCJhnp h|Cx0J>*CJjhnp hnp CJUj^hnp hs!CJU hnp CJ'6F7F8F:F;F>F?FgFhFiFkFlFoFpFFFFFFFFFFFFFFGGGgGpGGGGGGGGݼݼǎ{q{jjccc h|CxCJH* h|Cx5CJhmh|Cx5CJ hmCJ h|Cx>*CJ h|CxCJhh|Cx5$jhhB*Uph$jhhB*Uphhh|CxB*ph hh|Cxhh0J>*B*phjhh|CxB*Uph$j>hhB*Uph&FGgGG4H5HXHHHHJ5JJJJJLRLLCMM8N ^gdLk p^pgdLk`^``gdLk^gdLk^gdLk & FgdmGGGGGGG,H/H6HXH]HHHHHHHHHHHIIIIIJ5JAJUJWJkJrJsJtJJJJJJKKK Lǹǭǭǹǹǂǹǭxǹh-Dh|Cx6CJ hGycCJ h|Cx0J>*jh|CxUjh|CxUh|Cx hn8[5CJ hn8[CJ hG"CJ h|Cx5CJ h|Cx>*CJ h|CxCJhxh|Cx0J>*CJj3hxh'CJUhxhxCJjhxhxCJU, L L LLLLLRLXLLLMM)M*M+MAMBMCMNMMM8N*CJjh|CxCJUjh|CxCJU h\ 5CJhh|Cx0J>*j\hUhjhhU h|Cx5 h|CxCJ h|Cx5CJh|Cx h|Cx0J>*jh|CxUjh|CxU+8NNO(O)OCOZO[OOOOP+QQQ RRROS-TwTTp^pgdLk^gdLk^gdbOC ^`gdLk^gdLkgdN ^gdLkOOOOOPPPPPPPQ Q+Q1QQQQQQQQQQQQQQQQQQQRRR R Rƺyƺƺcy+jFh!9h555B*CJUphh550J5>*B*CJph+jh55h?r5B*CJUphh555B*CJphjh555B*CJUph h55CJ hG"CJ h|CxCJ h78CJ h|Cx0J>*jRh|CxUjh|CxUh|Cx h|Cx5CJh55h55CJ& R R RRRR6R7R8RARBRDRZR[RuRvRwR|RRRRRRRRRRS>SNSOS[SSξײש䜓wkdd^Th\h|Cx5CJ h\CJ h|CxCJH*h55h550J>*CJh55h|Cx0J>*CJjNh55h?rCJUh55h55CJjh55h55CJUhbOCh|CxCJhbOCh|Cx0J>*CJjhbOChbOCCJUhbOChbOCCJjhbOChbOCCJU h|CxCJ h|Cx5CJh55h|CxCJ h55CJ ST,T-T8TwTTTT U#UV@VDVVVVVVVVVWWAWJWWWXXXXXXXXXXXXYɈ h|Cxhh|Cx0J>*B*CJph(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUphh|Cx hG"CJ hn8[CJ h|CxCJH* h|CxCJH* h|Cx5CJ h|CxCJ h?<CJ h\CJ5T UU5V@VVAWWXXXXXXYY $$7$8$H$Ifa$ $7$8$H$IfgdNp^pgdLk^gdLkYYY.Y0Y $$7$8$H$Ifa$ $7$8$H$If`kdV$$IflF4 $,~     4 laytLkYY1Y5YMYPYYYYYYYYYYYYYYYYY Z ZgZoZsZtZZZZZZZZ[ܷܮzo`ojh QhFCJUaJh QhFCJaJhFhFCJaJhFCJaJhF5CJaJhFhF5CJaJ hFCJ hG"CJh>lh|CxCJh>lh|Cx0J>*CJjVh>lh7CJUh>lh>lCJjh>lh>lCJU h|Cx5CJh|Cx h|CxCJ hn8[CJ#0Y1Y5YJYLYz $$7$8$H$Ifa$ $7$8$H$If $7$8$H$If`kd$$IflF4 $,~     4 laytLkLYMYQYkYYYYY $$7$8$H$Ifa$ $7$8$H$If`kdV$$IflF4 $,~     4 laytLkYYYYYYYzz $$7$8$H$Ifa$ $7$8$H$If $7$8$H$If`kd$$IflF4 $,~     4 laytLkYYYZ Z%Z(Z+Z.Z $$7$8$H$Ifa$ $7$8$H$If`kd$$IflF4 $,~     4 laytLk.Z/Z3ZFZIZ $$7$8$H$Ifa$ $7$8$H$If`kd=$$IflF4 $,~     4 laytLkIZJZMZ_ZaZ $$7$8$H$Ifa$ $7$8$H$If`kd$$IflF4 $,~     4 laytLkaZbZgZpZqZ $$7$8$H$Ifa$ $7$8$H$If`kd=$$IflF4 $,~     4 laytLkqZrZsZtZ [k[[j\\\f]g]s]|zuup & F, & F^gdLk & F^gdLk 7$8$H$^gdLk`kd$$IflF4 $,~     4 laytLk [[[[[[ [![k[[[[[[[[[[[[[j\s\Ž~gTLC9hFhF5CJhF5CJaJhCJaJ$hFhF0J>*B*CJaJph,jhv h%&B*CJUaJphhv B*CJaJph&jhFhFB*CJUaJphhFhF5CJaJhFhFCJaJhFCJaJhFCJaJh QhFCJaJh QhF0J>*CJaJjh QhFCJUaJ#j=h QhFCJUaJs\\\\\\\\\\]]]] ]!]"]+],].]/]H]I]J]P]Q]R]S]e]f]g]]]]] ^ ^!^ȶҨȖҨȄҨvlf hCJhh5CJhhn8[0J5>*CJ"jhh|Cx5CJU"jhh|Cx5CJUhh|Cx0J5>*CJ"jhh|Cx5CJUhh|Cx5CJjhh|Cx5CJU h|Cx5CJhFh|Cx5CJ aJ h|CxCJ hFCJ%s]]]]]] ^ ^@^^&_``=aaZbzbbbL5CJUh% h% 5CJjh% h% 5CJUh% h|Cx5CJ *hG"5CJ *h\BCJ *h\Bh\B5CJ *h|CxCJh% h% 0J>*CJjh% hs>LCJUh% h% CJjh% h% CJU h% CJ h|CxCJ h|Cx5CJ h\B5CJ```````````aaa;aIaaaa"bObZb`bybzbbbbbbbbb$c*CJ+ccdddeeMeseffggggtiuiii]jj^gdLkgdN & F pp^pgdQ & F pp^pgd H & F^gdLk & F^gdLk^gdLkdddddd'd(dadgdnd}dddddse{eeeeeeeeee3f4fWfXfYf\f]fff漰ib hpa5CJ+jhZ )h5B*CJUphh|Cx5B*CJphh|Cx0J5>*B*CJph+j=h!9h5B*CJUphh!95B*CJphjh|Cx5B*CJUph h|Cx>*CJ hG"CJ hjCJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ#ffffggggggggghhhh hyhhhhhhhhhhhhhhhhiiii%iȫ䊚qjhZ )hCJUh|Cx0J>*CJjThZ )hCJUjh|CxCJU h|CxCJH*h|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJUhn hn 5CJ hn CJ h|CxCJ h|Cx5CJ hpaCJhpahpaCJ&%i&i'i+i,i.i/i^i_i`irisitiui{i|iiiiiiiiijjjjjj]jbjjjjjjjjj,k?kBkCkLkZkkkkll0lLlll»ֻֻֻֻֻֻֻֻֻֻֻ֪֤֚֐֤֊֊ hcCJh'oh|Cx5CJh'ohG"5CJ h'oCJh'oh'o5CJ hn8[5CJ h|Cx5CJh|CxjhZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU6jjkk,kBklNlll!mvmnno}oppppq^gdLk^gdLk & F pp^pgdQ & F pp^pgdQ & F^gdLklll!m%m&m'mvmmmmmnnHnInnnnnnnnno%o}oopp4p6ppptquqqqqqqqrrrrssttGtHtItTtUtth>h|Cx0J>*CJj|hZ )hCJUh>h>CJjh>h>CJUh>h|Cx5CJ h|CxCJH* hG"CJ hn8[CJhch|Cx5CJ hG"5CJ h|Cx5CJ hcCJ h|CxCJ7qqqqrPrrrrr6ssstttttttt=u>u ^`^^gdLk^gdLk & F^gdLk & F^gdLktttttttguvvv=v>v?vMvNvvvwwwwww)w*wJwKwLwTwUwwwxĴͨĘͨ͏yi]V h|Cx6CJh^lh|Cx0J>*CJjUh^lh;~%CJUh^lh^lCJjh^lh^lCJUhMWh|CxCJjhMWh}fCJUhMWh|Cx0J>*CJjIhMWh}fCJUhMWhMWCJjhMWhMWCJU h|Cx5h|Cx h|CxCJ hLkh|Cx5B* CJ4aJ4ph3 hLkCJ!>uguvvavvvwwwwwwwVxWxcxxxxxxxyyy ^`^^gd"(^xxxxx&y(y)yByCyDyKyLyNyOyhyiyjyqyrysyyyh|p|w|}}6}<}C}M}~~~~~~۶񩠐{wpwppehNh|CxCJaJ h|Cx5CJhG"h h|CxCJh h|Cx0J>*CJjEh hDCJUh h CJjh h CJUhmBh|Cx0J>*CJjhmBhf1CJUhmBhmBCJjhmBhmBCJUhmBh|CxCJ h|CxCJ h|Cx5h|Cx%yyyyyKzYzizxzzzz.{/{7{g|h||}5}6}M}}~~^gd5^p^p^ ^`~~~ -.[.olmY̓   ^`gdd^gdd ^`p^p ^`^^gdN^~  .67.osՁށmYb̓  ehozrxyzŹдۖx h5h5 h5CJ hCJh|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJU h|Cx5hdh|Cx5CJaJhdh|CxCJaJh|Cx hN5CJ h|Cx5CJ h|CxCJhNh|CxCJaJhNh|Cx5CJaJ/ emn{ lmyz$ABNɈˈ܈^`gd5gd5`^BNȈ܈&./0:$&'?@AGHIߋe~ȌɌόی|qjffh|Cx hn8[5CJhdh|CxCJaJhdh|Cx0J>*CJaJ#jhdhGpTCJUaJhdhdCJaJjhdhdCJUaJhdhG"CJaJhdh|CxCJaJhdh|Cx5CJaJhdCJaJ hG"CJh|Cx5B*CJph h|CxCJ h|Cx5CJ(܈/0;cxދߋef~$If^gdLk ^`gdd^gdd^gdd^ ^`ȌɌό8. $Ifkd$$Iflֈd  &w, 0*4 laytLk$Ifό֌׌،ٌڌی8kd$$Iflֈd  &w, 0*4 laytLk$Ifی  !$If$If $If01ABef{|}~ÍōÏƏǏȏɏ؏LNP^_`ɤɛ{hdB*CJphh|CxB*CJ8ph *h|CxB*CJ8phh h|CxCJh h|Cx0J>*CJjh h&CJUh h CJjh h CJU hG"CJ hn8[CJ h|CxCJ h|Cx5CJ h|Cx5CJh|Cx h|CxCJ/>88888$Ifkd$$Iflֈd  &w, 0*4 laytLk8. $Ifkd$$Iflֈd  &w, 0*4 laytLk$If&8kd$$Iflֈd  &w, 0*4 laytLk$If&'(/0188kds$$Iflֈd  &w, 0*4 laytLk$If8=>?@AB8kdZ$$Iflֈd  &w, 0*4 laytLk$IfBJabcde$Ifefnyz{>8888$IfkdA$$Iflֈd  &w, 0*4 laytLk{|}~.kd($$Iflֈd  &w, 0*4 laytLk$If $If8kd$$Iflֈd  &w, 0*4 laytLk$If8kd$$Iflֈd  &w, 0*4 laytLk$If$IfÍčōƍ>555/$If^gdLkkd$$Iflֈd  &w, 0*4 laytLkƍӍۍskd$$Ifl\d  (F4 laytLk$If    $IfskdZ$$Ifl\d  (F4 laytLk  $Ifskd$$Ifl\d  (F4 laytLk#$%&$Ifskd$$Ifl\d  (F4 laytLk&'3456$Ifskd$$Ifl\d  (F4 laytLk67BCDE$Ifskd$$Ifl\d  (F4 laytLkEFRSTU{{{$If $IfskdH$$Ifl\d  (F4 laytLkUVbcde$Ifskd$$Ifl\d  (F4 laytLkefrstu$Ifskdt$$Ifl\d  (F4 laytLkuv$Ifskd $$Ifl\d  (F4 laytLk$If$Ifskd$$Ifl\d  (F4 laytLk$Ifskd6$$Ifl\d  (F4 laytLk$Ifskd$$Ifl\d  (F4 laytLkŽ$Ifskdb$$Ifl\d  (F4 laytLkŽÎǎȎɎʎ$Ifskd$$Ifl\d  (F4 laytLkʎˎΎώЎю$Ifskd$$Ifl\d  (F4 laytLkюҎ$Ifskd$$$Ifl\d  (F4 laytLk$Ifskd$$Ifl\d  (F4 laytLk$IfskdP$$Ifl\d  (F4 laytLk$Ifskd$$Ifl\d  (F4 laytLk  $Ifskd|$$Ifl\d  (F4 laytLk  $Ifskd$$Ifl\d  (F4 laytLk#$%&$If$Ifskd$$Ifl\d  (F4 laytLk&'2345$Ifskd>$$Ifl\d  (F4 laytLk56=>?@$Ifskd$$Ifl\d  (F4 laytLk@AOPQR$Ifskdj$$Ifl\d  (F4 laytLkRSabcd$Ifskd$$Ifl\d  (F4 laytLkdemnop$Ifskd$$Ifl\d  (F4 laytLkpqxyz{$Ifskd,$$Ifl\d  (F4 laytLk{|$Ifskd$$Ifl\d  (F4 laytLk{ $If$IfskdX$$Ifl\d  (F4 laytLk$IfskdW$$Ifl\d  (F4 laytLk$Ifskd$$Ifl\d  (F4 laytLk89:;$Ifskd$$Ifl\d  (F4 laytLk;<HIJK$Ifskd$$Ifl\d  (F4 laytLkKLMNOP_mgZ ^`gdio$ & F^`a$gd"(^gdLkskd$$Ifl\d  (F4 laytLk `a~Ȑɐː̐羴vjXK6X(j~hdhc B*CJUphhdhdB*CJph"jhdhdB*CJUphhio5B*CJphh|Cx0J5>*B*CJph%jh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|CxB*CJph hdCJhd0J>*B*CJph(jEhZ )hdB*CJUphhdB*CJphjhdB*CJUph   ()*4578LMNPQSTiӾiQ/jhTh|Cx5B*CJUaJph/jThTh|Cx5B*CJUaJph'hTh|Cx0J5>*B*CJaJph/jhTh|Cx5B*CJUaJph hTh|Cx5B*CJaJph)jhTh|Cx5B*CJUaJphhdB*CJph"jhdhdB*CJUph hdhd0J>*B*CJphijknoqrБҾҭҭҾҭoWCoҭ'hZ7h|Cx0J5>*B*CJaJph/jhZ7h|Cx5B*CJUaJph hZ7h|Cx5B*CJaJph)jhZ7h|Cx5B*CJUaJph/jhTh|Cx5B*CJUaJph hTh|Cx5B*CJaJph'hTh|Cx0J5>*B*CJaJph)jhTh|Cx5B*CJUaJph/j2hTh|Cx5B*CJUaJphБёґߑ%&()JKL[\^_tҾҲҁiҾҁҁQҾҁҁ/jkhTh|Cx5B*CJUaJph/jhTh|Cx5B*CJUaJph hTh|Cx5B*CJaJphhdB*CJphh|CxB*CJphh|Cx5B*CJphh|Cx5B*CJph'hTh|Cx0J5>*B*CJaJph)jhTh|Cx5B*CJUaJph/jqhTh|Cx5B*CJUaJphtuvyz{|}~ҾҭxeVLB-)jhZ7h|Cx5B*CJUaJphhZ7B*CJphh|CxB*CJphh|Cx0J5>*B*CJph%jUh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|CxB*CJphhTh|CxB*CJaJph hTh|Cx5B*CJaJph'hTh|Cx0J5>*B*CJaJph)jhTh|Cx5B*CJUaJph/jhTh|Cx5B*CJUaJph}G9{|;< qrklm & F & F^gdd & F^gdio & F@ ^@ gdio & Fgdio @ ^@ `gd=1?^gdio^gd"( ^`gdiogdioĒŒǒȒܒݒޒ345®®~®o`VD`"jh|CxB*CJUphh|CxB*CJphjh|CxB*CJUphhTh|CxB*CJaJph/jhZ7h|Cx5B*CJUaJph/j-hZ7h|Cx5B*CJUaJph'hZ7h|Cx0J5>*B*CJaJph)jhZ7h|Cx5B*CJUaJph/jhZ7h|Cx5B*CJUaJph hZ7h|Cx5B*CJaJph5EFGHQR}~ʓ˓̓דؓړۓ¯™¯qgUg"jzh|CxB*CJUphh|CxB*CJph+jhTh|Cx5B*CJUph#hTh|Cx0J5>*B*CJph+jzhTh|Cx5B*CJUph%jhTh|Cx5B*CJUphhTh|Cx5B*CJphhdB*phh|CxB*phjh|CxB*CJUphh|Cx0J5>*B*CJph %&'2356LMNabdeֵֵֵֵֵֵsֵֵ]+jhTh|Cx5B*CJUph+jNhTh|Cx5B*CJUph+jhTh|Cx5B*CJUph+jlhTh|Cx5B*CJUphhTh|Cx5B*CJph#hTh|Cx0J5>*B*CJph%jhTh|Cx5B*CJUph+jhTh|Cx5B*CJUph ʔ˔̔ϔДҔӔ012EFGHҼҔ~h^Njh|Cx5B*CJUphh|CxB*CJph+jkhTh|Cx5B*CJUph+jhTh|Cx5B*CJUph+jhTh|Cx5B*CJUph#hTh|Cx0J5>*B*CJph+j4hTh|Cx5B*CJUphhTh|Cx5B*CJph%jhTh|Cx5B*CJUphh"(5B*CJphHbcdlmopƕǕȕʕ˕͕ΕѸweS"jh|CxB*CJUph"j7h|CxB*CJUph"jh|CxB*CJUphh|Cx0J>*B*CJph"jQh|CxB*CJUphjh|CxB*CJUphh|CxB*CJphh|Cx0J5>*B*CJphjh|Cx5B*CJUph%jh|Cx5B*CJUphh|Cx5B*CJph &'(789:abcyz{|紥}nX}I?hioB*CJphh1 h|Cx5B*CJph+jh1 h|Cx5B*CJUphh1 hd5B*CJph#h1 h|Cx0J5>*B*CJph+jlh1 h|Cx5B*CJUphh1 h|Cx5B*CJph%jh1 h|Cx5B*CJUphh|Cx0J>*B*CJph"jh|CxB*CJUphh|CxB*CJphjh|CxB*CJUph|}ɖʖ˖ܖݖߖ  ,-.9:;<=[\]qrstta%jhTh|Cx5B*CJUph"jXh|CxB*CJUph"jh|CxB*CJUph"jdh|CxB*CJUph"jh|CxB*CJUphhTB*CJphh|Cx0J5>*B*CJph"jxh|CxB*CJUphh|CxB*CJphjh|CxB*CJUph&tחؗٗڗ0134OPQYȹȹ{l`Jȧ+jp hTh|Cx5B*CJUphhT5B*CJphhT0J5>*B*CJph+j hTh|Cx5B*CJUph+j\ hTh|Cx5B*CJUph#hTh|Cx0J5>*B*CJphhZ70J5>*B*CJph%jhTh|Cx5B*CJUph+jhTh|Cx5B*CJUphhTh|Cx5B*CJphYZ[\^_ҘӘ՘֘   ȹȹȔȹȹrȹȹ\ȹPhT5B*CJph+j hTh|Cx5B*CJUph+jl hTh|Cx5B*CJUphhZ75B*CJphhZ70J5>*B*CJph+j hTh|Cx5B*CJUphhTh|Cx5B*CJph%jhTh|Cx5B*CJUph#hTh|Cx0J5>*B*CJph#hThn8[0J5>*B*CJph,-.<=?@XYZoprstəʙ˙ݙޙ戀zgzTz%j h|Cx5B*CJUph%jp h|Cx5B*CJUphh|CxB*CJphh|Cx5B*CJph+j h"Ph%sz5B*CJUphh"P5B*CJphhT5B*CJphh|Cx0J5>*B*CJph+j hS{h95B*CJUphhS{5B*CJphjh|Cx5B*CJUph012=>@ABZ[\hilmܷÚ~k\VRVCjh|CxB*CJUphh|Cx h|CxCJh|Cx0J5>*B*CJph%jZh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|CxB*CJph%jh|Cx5B*CJUphh|Cx5B*CJphh|CxB*CJphh|Cx0J5>*B*CJphjh|Cx5B*CJUph%jph|Cx5B*CJUphɚ UV%&<=͜Μ:;<CNO$If^ & F 7$8$H$^gd\ & F( ^gd\gd=^gd\ƚǚ89:RSUVWǛ&<OPtѽѽwqkd h|Cx5CJ hG"CJ hn8[CJjdh|CxCJUh|Cxh|Cx0J>*CJjh|CxCJUjh|CxCJU(jfh/h$#B*CJUph h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(jh/h$#B*CJUphh/B*CJph#tuvʜ˜():;UWY[hjln6:Z`ŸƟʟܾțțțțȔȔȔȔȔȔȔ h|CxH*h|Cx h|Cx5CJ jh|CxCJmHnHu(jh/h$#B*CJUphh/B*CJph h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(jGh/h$#B*CJUph4OPTbcgmEkd$$Ifl0dT^ 4 la$IfEkd$$Ifl0dT^ 4 la֝mEkd$$Ifl0dT^ 4 la$IfEkdW$$Ifl0dT^ 4 la֝םڝ۝ܝߝmEkd$$Ifl0dT^ 4 la$IfEkd$$Ifl0dT^ 4 lamb  !$IfEkdK$$Ifl0dT^ 4 la$IfEkd$$Ifl0dT^ 4 la&mEkd$$Ifl0dT^ 4 la$IfEkd$$Ifl0dT^ 4 la&(.028:mEkd$$Ifl0dT^ 4 la$IfEkdw$$Ifl0dT^ 4 la:<DmEkd$$Ifl0dT^ 4 la$IfEkd?$$Ifl0dT^ 4 la6ZTUo^`~^ & F ^`^Ekd$$Ifl0dT^ 4 la()TUWcdRShijmn^`z|維{rejhqh|CxCJUh|Cx5CJH* hMCJ hG"CJ jh|Cx5CJhrh|Cx0J>*CJjkhrhQCJUhrhrCJjhrhrCJUhMh|Cx5CJH*hMh|Cx5CJ h|CxCJH* h|Cx5CJ h|CxCJhn8[ h|Cx>*h|Cx h|Cx5&dfh~ƤȤ>H./>?IJKMxy»ȬȬȬȻȜȖȖȻȜȉpdȻhrh|Cx0J>*CJjhrhQCJUhrhrCJjhrhrCJU hqCJ hn8[CJh2h2CJH* h2CJh|Cx5CJH* h|Cx5CJ hMCJ h|CxCJhqh|Cx0J>*CJjhqh|CxCJUjhqh|CxCJUhqh|CxCJ&ƤȤ.Kdŧ٧D] & F^`gd;, & F^gd;,^h^h & F^p^pʦ˦̦GHIbcvwçħԧէ{o򭡭hb[ hM5CJ h|CxCJ h|Cx5CJhnhk1w0J>*CJjhnh$.CJUhnhnCJjhnhnCJU jhk1whk1wCJhk1whk1wCJhk1w0J>*B*CJph(jnhbqhk1wB*CJUphhk1wB*CJphjhk1wB*CJUph hk1wCJ hk1w5CJ# ./8ȩ^bIVr./0RST[\^}ห}vov hn8[5CJ h|Cx5CJh!3h|CxCJh!3h|Cx0J>*CJjhZ )hCJUh!3h!3CJjh!3h!3CJU h!3CJ ho-CJh|Vh|VCJ h|VCJ h|Cx5CJ hMCJ h|CxCJh;,h|Cx5CJ hM5CJhMhMCJ%/ȩs+qrث+{|}Ϭ7$8$H$ & F^` & F^ & F & F pp^pgd^` & Fp^pgdM & F^`gdM̬ͬ   !"=>YZ[efijĭ񾸾񾏾yly_yj]h|CxCJUjh|CxCJUh|Cx0J>*CJjoh|CxCJUjh|CxCJU(jhZ )hB*CJUphh|CxB*CJph ho-CJ h|CxCJh|Cx0J>*B*CJph(jKhqhB*CJUphhqB*CJphjh|CxB*CJUph%ϬЬ$%%&jkZ|#$/0PQp^pgdNL^gdNL^gdNL^gdq^gdq^gd;, & F" 88^8gd;,ĭŭ#$56STUhiȮɮ̮ͮ SY[]u{$/ h|Cx>*CJ h|CxCJH* h|Cx5CJj!hPhHwCJU hPCJjA!h|CxCJU ho-CJj h|CxCJUjO h|CxCJUh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU2/PQ^_hqs~-NO_k56PQRefgsuvǾDZvj"hZ )hCJU hea5CJh|Cx0J>*CJjK"h|CxCJUjh|CxCJUh|Cx hbq5CJ hbqCJhbq5CJ\ h|Cx5CJ ho-CJ h|Cx>*CJ h=CJh|CxCJmHnHu jh|CxCJmHnHu h|CxCJ.Q^_~߱ghrsٲ-.>NOp^pgdbq ^`gdbq ^`gdbq^gdNLp^pgdNL ^`gdNL^gdNLO^_gjȷ^gdNLgd= & F ^gd H p^p`gdbq ^`gdbq & Fp^pgdbq & F^`gdbq^gdNL`gdbq ^`gdbqʹδϴҴӴ۴9ŵǵҵ24׸Ѥ~q~aqj%heahKuCJUjheaheaCJUheaheaCJ hea5CJ h;%CJhnhn5CJ heaCJhnhea5CJhnh|Cx5CJhn8[0J>*CJjH$hZ )hCJU hnCJh|Cx0J>*CJjh|CxCJUj#hZ )hCJU h|CxCJ% :<NRjlƷ06lprsŸMɲɲɮɧɘykɧɲe hNLCJh|Cx0J>*B*CJph(j%hqhB*CJUphhqB*CJphjh|CxB*CJUph h|Cx>*CJh|Cx jh|CxCJmHnHuheah|CxCJ h|CxCJ hea5CJ h|Cx5CJheaheaCJjheaheaCJUheahea0J>*CJ'ȷ/klŸS 5_bxy*+ ^gdNL^gdNL & F 8^gd H ^`gdNLp^pgdNL^gdNL ^`gdNLMNZ]befgxy|}~+78;RSXYlmrsfмҼ FHRT`b뺴亴 hNLCJH* hNLCJhNL5CJ\ h|Cx>*CJ h!]_CJh|Cx jh|CxCJ h|CxCJH* h|Cx5CJ h|CxCJ jh|CxCJmHnHuD+78=˻fhB8^8gdNLp^pgdNL ^`gdNLgdNL^gdNL & FgdNL & F 88^8gdNLh^hgdNL&'GHlm ^`  @AMNOP|}~Ľy(jM&h.hJB*CJUphh.h&KB*CJph"jh.h|CxB*CJUphh.h|CxCJ h|Cx5CJ h|Cx>*CJ h&KCJh|Cxh|Cx5CJH* h|CxCJH* h|CxCJ h|Cx5CJ hNL5CJ hNLCJ hNLCJH*/5[׿(@A & F 88^8gd&Kgd.h^hgd&K h^`hgdNLgd=8^8gdNL & F 88^8gdNLh^hgdNLp^pgdNL~dfjfh01]^abhi[iklDzԫ{ h!]_CJ ho->*CJ h|Cx>*CJ hn8[CJ h|Cx5 h|CxCJH* h|CxCJh|Cx h|Cx5CJ(j'h.hJB*CJUphh.h&KB*CJphh.h|CxCJ"jh.h|CxB*CJUph h.h|Cx0J>*B*CJph0hjh!kVab h^`hgd&K & F 88^8gd&Kgd= & F ^gd&Kh`hgd&K^gd&K8^8gd&Kat{&(*0prtGHungna hn8[CJ hn8[6CJ h|Cx6CJh|Cx0J>*B*CJph(j(hZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph h|CxCJH* h|Cx5CJhrh|CxCJhrh|Cx0J>*CJj'hrhQCJUhrhrCJjhrhrCJU h|CxCJ&buz{vq & FgdJ^gd&K & F 88^8gd&K & F ^gd&K & F p88^8gd&K h^`hgd&K^gd&K 8h^8`hgd&KHijkno@^  ѽљѽ~l_J(j)hN rh-B*CJUphhN rhN rB*CJph"jhN rhN rB*CJUph hN rCJ(jX)hZ )hB*CJUphh|CxB*CJph h|Cx5CJ hB CJ hJCJ h|CxCJH* h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(j(hqhB*CJUphhqB*CJphMln @ & F p  ^ gd H & F p  ^ gd H 8^8`gd&K ^ gdN r ^`gd&K h^`hgd&K & FygdN r^gdN r & F 88^8gd&Kh^hgd&K   (MYln,.46<=@Aabcnopqͳͳͭͭͭ͞th|Cx0J>*B* CJph"j*h|CxB* CJUphh|CxB* CJphjh|CxB* CJUph hn8[CJ h|CxCJH* hn8[6CJ h|Cx6CJ h|Cxh h|CxCJ h|Cx5CJ hN rCJhN r0J>*B*CJph"jhN rhN rB*CJUph'@p9vz h^`hgd&K ^`gd&K ^`gd&K` & F ^gd&K & F 88^8gd&Kh^hgd&K & F p  ^ gd H!"#./12TUȷȧܔxeV@+j*-h5QhA-5B*CJUphh5Qh5Q5B*CJph%jh5Qh5Q5B*CJUphh5QB* CJph"j,h|CxB* CJUphh|CxB* CJphh|Cx0J>*CJj+hZ )hCJUjh|CxCJU h|Cx5CJ h|CxCJh|Cx0J>*B* CJphjh|CxB* CJUph(j#+hZ )hB* CJUphUVYZ["#$78췡췋Ѕ{n{e{YR h|Cx5CJh&Kh|Cx>*CJaJh|Cx0J>*CJj /h|CxCJUjh|CxCJU h|CxCJ+jx.h5QhA-5B*CJUph+j-h5QhA-5B*CJUphh5Qh5Q5B*CJphhdQB* CJphh5QB* CJph#h5Qh5Q0J5>*B*CJph%jh5Qh5Q5B*CJUph ThTd VXZhj|򨞉{rhrhr^rh.h|CxCJH*h.h|Cx5CJh.h|CxCJh|Cx0J>*B* CJph(j/hZ )hB* CJUphh|CxB* CJphjh|CxB* CJUphhOh|CxCJhOh|Cx0J>*CJj/hOh CJUhOhOCJjhOhOCJU h|CxCJ h|Cx5CJ$z|n  }=tI^ & FDh`h` & F & F ^`h^hgd&K & FB pp^pgdCjR^gd&K8^8  89:FG,-abs   %&;ƴЦ昍xqqgjh|CxCJU h|CxCJH*h*h|CxCJh&Kh|Cx>*CJaJh|CxCJmHnHu jh|CxCJmHnHuhKh|Cx0J5>*CJ"j0hKh|Cx5CJUhKhK5CJjhKhK5CJU h|Cx5CJ h|CxCJh.h|CxCJh.h|CxCJH*%;<=FGJKNO  2P "MN*̾ٷٷٷٷٷ٢ٙٷو~uh*h|CxCJh|CxCJOJQJ jh|CxCJOJQJh|Cx jh|CxCJ hn8[CJ ho-CJh|Cx5CJH* h|Cx5CJ jhMCJmHnHu hMCJ h|CxCJH* h|CxCJh|Cx0J>*CJjh|CxCJUj71h|CxCJU-IiJ,-8D ^` ^`gd= & FK^ & FC & FC` & FD^gd*^*+,;<=>BCbc!  <=䱪䉪h&Kh|Cx5CJ(aJ( hn8[CJh|CxhQ!=h|CxCJaJ h|Cx5CJ hdCJ jh|CxCJ jh|CxCJ h|CxCJH* jh|CxCJOJQJ h|CxCJH* h|CxCJh|CxCJOJQJ jh*h|CxCJ4 W & FgdQ!= ^`gdM^gdM^gdM ^` ^`^ 2*WxkOP\ ^`gd\^gd\^gd\^gdM^gdM()*+HIJUVWXoŶ{o[{K{@hWhWCJaJhWhW0J5>*CJaJ&j2hWh=)i5CJUaJhWhW5CJaJ jhWhW5CJUaJh$ah+0J5>*CJ"j 2h$ah5CJUh$ah$a5CJjh$ah$a5CJU h+5CJ hW5CJh|Cx0J5>*CJj1h|Cx5CJU h|Cx5CJjh|Cx5CJUopqvwxyӵ|r`|R|K h+5CJhdh|Cx0J5>*CJ"j>4hdh|Cx5CJUhdh|Cx5CJjhdh|Cx5CJUhdh|Cx0J5>*CJ"j3hdhc 5CJUhdhd5CJjhdhd5CJUjl3h|Cx5CJU h|Cx5CJh|Cx0J5>*CJjh|Cx5CJUj2h|Cx5CJU1jkrAMOP[\^pqrsz{|}ʶummbmmmmhW1hWCJaJh CJaJh*hWCJaJhWCJaJhWhW15CJaJhW1hW1CJaJh/Z}hW1CJ$aJ$h/Z}hW15CJ aJ hW1h|CxCJaJho- h|Cx5h|Cx h|Cxh h|Cx5hh/Z}h/Z}CJ$aJ$h|Cx5CJ$aJ$h/Z}h|Cx5CJ aJ h|CxCJ&\]rsJ @ `^@ ``gd/Z} @ ^@ `gd/Z}@ ^@ gd/Z}^gd/Z}@ ^@ gd\ ^`gd\ @ ^@ `gd\p^pgd\^gd\JluNRpxY !5=]c;ȺȳȭȳȺȳȳȦȜȏxmxjh>Gh|CxU h>Gh|Cx h|Cx5CJh|Cx0J>*CJj4h|CxCJUjh|CxCJU h|CxCJH* hCJ h|Cx5CJ hn8[CJho-h|Cx h|CxCJhW1h|CxCJaJh/Z}h|Cx5CJ$aJ$hW1hW1CJaJhWCJaJh CJaJ)5p5]DE.^gdg@^gdg@^ & FK`gd* p^p`gd/Z}^gd/Z}@ ^@ gd/Z};<=ABCDEYij?BȿȳΤȿȓȌȅsk[sjn6hg@h|Cx5Uhg@hg@5jhg@hg@5U hg@5 hg@hg@ h|Cx6CJ hg@CJh|Cx0J5>*CJj5h|Cx5CJUjh|Cx5CJU jh|CxCJ h|CxCJ h|Cx5CJ h>Gh|Cxh>Gh|Cx0J>*jh>Gh|CxUj"5h>Gh|CxU-./EFZN|rcYGc"j6hdQh$.5CJUhdQhk1w5CJjhdQhk1w5CJUhdQh|Cx5CJhdQhdQ5CJh|CxhThT5hg@hTCJaJhg@hT>*CJaJhk1whT hTCJhThT>*CJh*hTCJh'Xh|Cx5CJaJ hg@hg@ h|Cx5 hg@5jhg@hg@5Uhg@hg@0J5>*./EFZNHZ hh^h`hgd*^gd/Z}^gd/Z}gd= & F^gd/Z} & F^gd/Z} & F^`gd/Z} & F^gd/Z}gd'Xgdg@ms+,-ɼɬٚvpfpYS h/ CJjh/ h/ CJUh$hIw5CJ hIwCJhIwhdQ5CJhdQhdQ5CJhdQh$5CJ hdQCJ h|CxCJh$h$0J>*CJj>7h$h$CJUjh$h$CJUh$h$CJ h$5CJhdQh|Cx5CJjhdQhk1w5CJUhdQh|Cx0J5>*CJQt,->BFT & FgdIw & FgdIwh^hgd/Z} h^hgdIw p^p`gd* & FF 8 ^ `gdCjR p^p`gd* & FC 8 ^ `gdCjRTeq RSs2+,3W & FCgd & FCgd`gd8^8gd/Z}h^hgd/Z} & FgdIw & FgdIw9:;>?Sqvwx 7:RSvǷа{ohh[RhhCJjhhCJU h|Cx6CJhTh|Cx0J>*CJj8hThCJUhThTCJjhThTCJUhTh|CxCJ h|CxCJ h|Cx5CJj<8h/ h1CJUh/ h/ CJ hIwCJh/ hIw0J>*CJjh/ h/ CJUj7h/ h1CJUvwx+,03no(1|vw ľıĦĊı}td}X}ıhh|Cx0J>*CJj :hh9%CJUhhCJjhhCJU ho-CJhho-CJaJhhn8[CJaJhh|CxCJaJ h|Cx5CJ haRCJ h_CJ h|CxCJhho-0J>*CJhh|Cx0J>*CJjhhCJUj9hhA-CJU {| >OPc8^8gd/Z} & F$ 8pp^pgd/Z} 8^8`gd/Z} h^h`gd/Z}h^hgd/Z} & FC 8^gdCjR^gd^gd/Z}gd & F gdA-)*Ocdekl}>@"&#<Ka3459:DEF򿶦~ h|Cx>*CJhq h|CxCJhq hn8[0J>*CJhq h|Cx0J>*CJjs:hq hCJUhq hq CJjhq hq CJUh|Cx h|CxCJH* ho-CJ jh|CxCJmHnHu h|Cx5CJ h|CxCJ h|Cx6CJ1c""#<OBt & F% 8^gd/Z} ^`gd/Z} h^h`gd/Z} 8^8`gd/Z}h^hgd/Z} ^ gd/Z}^gd/Z} & F# pp^pgd/Z} & F# p^pgd/Z}GH^hkmFĽĶĶΪxjh'Xh'XCJUaJh'Xh'X5CJaJh'Xh'X5CJaJh'Xh'XCJaJh'Xhd5CJaJ h|CxCJH* h|Cx5CJ h|CxCJh/Z}h'Xh|Cx5CJaJh|Cx jh|CxCJmHnHu h|CxCJH* h|Cx5CJ h|CxCJ(Y.R`gd'Xgd= & F% 0`0gd`^gd/Z}gd'X & F& 8pp^pgd/Z} & F% pp^pgd/Z} 8^8`gd/Z}FGHOPR      [ \       0 1 2 ; < A M m x        ZŽŹzsmgmg hdCJ h-CJ h|Cx>*CJ h|Cx5CJh|Cx0J>*CJj;h|CxCJUjh|CxCJU h|CxCJH* h|Cx5CJ h|CxCJh|Cxhdh'XCJaJh'Xh'XCJaJh'Xh'X0J>*CJaJjh'Xh'XCJUaJ#j:h'Xh8ECJUaJ$RS     * |      ? @ A k l y z    ^gdd^ & FC & Fgdd^gd'Xgd'X  YZl& %&NOlEo` p^p` ^`^gdd ^`^ @ ^@ `Zl}$%&')ɹҭ坒{rb{VJh-h|Cx0J>*CJh-hd0J>*CJj<h-hc CJUh-h-CJjh-h-CJUhdhd5CJh|CxCJmHnHuhdh|Cx5CJmHnHuh) hd0J>*CJj6<h) hc CJUh) h) CJjh) h) CJU hdCJ h|CxCJhdh|Cx5CJhdh|Cx>*CJ)+-5689bcdyz|}%²ѦѝѦѝtѦѝdѦ^ hdCJj>h-hc CJUj*>h-hc CJUhn8[0J>*CJj=h-hc CJUh-h-CJh-hd0J>*CJj"=h-hc CJU h-CJh-hdCJjh-h-CJUh-h|Cx0J>*CJh-0J>*CJh-h-0J>*CJ$%&-124cp "@K`a$:;XYlmwxǤ h|Cx5CJ jh|CxCJ h|Cx>*CJh?h%{5CJ h%{CJ hq 5CJhq hq 5CJ hq CJ h?CJ ho-CJ h) CJhdhd5CJ hqCJ hq5CJhqhq5CJ hdCJ h|CxCJ1opc"#9:JKj2Hjp^^gd= ^``^gd-^,P\bcdm#79:JKO{{{ *h|CxCJh=h|Cx>*CJaJh*h|CxCJaJh-h|Cx5CJh-h-5CJ h-CJ h|Cx5CJ h-5CJ h|CxCJh/h|Cx0J5>*CJ"j$?h/h/F5CJUh/h/5CJjh/h/5CJU-jtvx24HJ.4$%HIgh)*GHITUڱ񞕅yhMWh|Cx0J>*CJj?hMWh}fCJUhMWhMWCJjhMWhMWCJU h%{CJ ho-5CJh) h) CJ h) 5CJ jh) h) CJ h) CJ h|Cx5CJh|Cx5>*CJ *h|CxCJ h|CxCJ jh|CxCJ/pe.$%gh]&v89] ^`gd\^gd\^gd\^UV]jv~&/v9]^Wp!!G!I!!!"#######e$s$$ % % %F%P%Q%R%T%k%%%%%%jGh|CxCJUjh|CxCJU hn8[5CJh=h|Cx5CJaJh|CxOJQJ h|Cx5 h|CxCJH* h|Cxhh|Cx h|Cx>*CJ ho-CJ h|Cx5CJ h|CxCJhMWh|CxCJ;]^{|Vlkd@$$Ifl0<' x04 la<$Ifgd= VWp$If$Iflkd@$$Ifl0<' x04 la< G $Iflkd4A$$Ifl0<' x04 la<G H c }  $IflkdA$$Ifl0<' x04 la<     $IflkdbB$$Ifl0<' x04 la< !!F!q!$IflkdB$$Ifl0<' x04 la<q!r!!!!$IflkdC$$Ifl0<' x04 la<!!!X""$Iflkd'D$$Ifl0<' x04 la<"""##  $If$IflkdD$$Ifl0<' x04 la<##$$$$IflkdUE$$Ifl0<' x04 la<$$$^$$$IflkdE$$Ifl0<' x04 la<$$$$$$IflkdF$$Ifl0<' x04 la<$$$ % % %!%E%%%%&M&u&v& & Fgd=lkdG$$Ifl0<' x04 la<%%%:&L&u&&&&&&?'E'`'a'u'v'w'y'z'''''(((((((((((((((()))*).)/)0)1)ߞ~thMhM0J>*jIhMhGGUjhMhMU hMhM hM5CJjHh|CxCJUhq hq CJ hq CJ hq 5CJ hn8[CJj2Hh|CxCJUh|Cx h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ-v&&&&?''((((1))**+k+++,<---.. & F| ^` & FzgdGyc^^gd`^ & F1)=)))I********** + +++++++*+k+u++++++,,,,ͻ~xrrrhaXhhCJ h5CJh-Dh-D5CJ h4iCJ hwNCJhwNhwN5CJ hMhM0J>*B*CJph(jIhMhGGB*CJUphhMhMB*CJph"jhMhMB*CJUph hMCJhGychGycCJ hICJ h|CxCJ hGyc5CJ hGycCJhGychGyc5CJ!,,7,8,9,>,?,@,A,B,C,c,d,e,n,v,w,y,z,,,,,,,,,}qeUejKh-Dhc CJUh-Dh-D0J>*CJh-DhG"0J>*CJj Kh-Dhc CJUh-Dh-DCJjh-Dh-DCJU h-DCJhh-DCJhhCJ hh0J>*B*CJph(jxJhhGGB*CJUphhhB*CJph"jhhB*CJUph,,,,,,,-;-<-E-u-v-w------. .!.".$.'.+.,./.G.R.Ǻ}k]O]Ohxh|Cx0J5>*CJhxhx0J5>*CJ"jLhZ )h5CJUhxhx5CJjhxhx5CJU hGycCJ hxCJ jhwNhwNCJ hwNCJ h|CxCJ h|Cx5CJ hCJ h-DCJhn8[0J>*CJh-Dh-D0J>*CJjh-Dh-DCJUjLh-Dhc CJUR.S.`.............//////00?0@0i0j0k0p0q0r0s0t00000ߩvokd h-D5CJh|Cx h|Cx5CJ h4ih4i0J>*B*CJph(jYMh4ihGGB*CJUphh4ih4iB*CJph"jh4ih4iB*CJUph h-DCJ h CJ jh4ih4iCJ hG"CJ h\ CJ h4iCJ hGycCJ h|CxCJ jh|CxCJmHnHu$.///s0t00001L11111233m33 & F`^^gd= & Fp^pgd-Dp^p^ & F{gdGyc^gd-D ^ gd  & F|01 1'1K1L1U111/202C2D2c2d2e2h2i2z2{22222222333)3*3m3x3y333¼¯¯zssnfn]] jh|CxCJ jh|Cxh h|Cxh h|Cx5CJjNhth7qCJUhth|Cx0J>*CJjNhth7qCJUhthtCJjhthtCJU h=CJ h|CxCJh|Cxh,4h-D5CJhdh-DCJ hdCJh-Dh-D6CJ h-DCJh-Dh-D5CJ$3 4\4^444B5C5[5\5k555555555 6$6%696H6I66`^  & F^ & F` & F344m4n4444444A5C5\5l5t55555%686I6Q6R6[6\6]6q6r6s6w666666666xr h|CxCJ h|Cx5CJ$hB0J>*CJh|Cx0J>*CJj;Ph|CxCJUjh|CxCJU h|Cx5CJ hG"CJh|Cx hmCJhmh|Cx0J>*CJjvOhZ )hCJUhmhmCJjhmhmCJU jh|CxCJ h|CxCJ'66666G7H7n7777888A8F8\8a8888888899#9W9  ^``66666677777 7!7'7(7+7,7@7A7B7D7E7F7G7777777778ǹ񳈂{ri_jh|CxCJU jh|CxCJ *h|Cx5CJ h|Cx5CJ h|CxCJ h|Cx5CJ "jQh|CxB*CJUph"jQh|CxB*CJUph h|CxCJhG"0J>*B*CJphh|Cx0J>*B*CJph"jPh|CxB*CJUphh|CxB*CJphjh|CxB*CJUph 888888)888D899!9#9%9&999999999::&:O:P:Q:_::::ٷ{tga hk+CJjhk+hk+CJU h=h|Cx jh|CxCJmHnHuh|Cx0J5>*CJ%jRh|Cx5B* CJUphjh|Cx5B* CJUphh|Cx5B* CJph hn8[CJ h|Cx5h|Cx h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjQh|CxCJU W9999&:M:P:_:::::;;j;;V<<k==== & F` !`^gd=  & F & F ^`:::; ;;;7;9;:;^;_;`;d;g;h;j;q;r;s;t;;;;;;;;;;;<ſХŇxm`Whq4hq4CJjhq4hq4CJUh|Cx0J5>*CJjiTh|Cx5CJUjh|Cx5CJUhG"0J>*CJh|Cx0J>*CJjShZ )hCJUjh|CxCJU hq4CJ h|Cx5CJh|Cx h|CxCJhk+h|Cx0J>*CJjhk+hk+CJUj1Shk+hfgCJU<<<"<#<V<X<y<z<<<<<<<<<<<<<<<<<<<<<=k=p=======пвпМЏvjfh|Cxh#$h|Cx0J>*CJj)Vh#$hCJUh#$h#$CJjh#$h#$CJUjUh|CxCJUh|Cx0J>*CJjSUh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJhq4h|Cx0J>*CJjhq4hq4CJUjThq4h CJU%====>2>I>[>l>}>>>>>??T@w@@@@ ! & F^gdO & F^ & F^gd5(' & F` & F & F^` & F^`====>>>>>>>??)?+?2?>?~??????w@}@@@@@@@AA AA)A*A+A6A9A:A=A>A\A]A^AdAeAhAiAA􂮘jWh|CxCJUhG"0J>*CJh|Cx0J>*CJjVh|CxCJUjh|CxCJU h|Cx5CJh|CxhOhO5>*CJhOhO5CJ hO5CJ h5('5CJ hOCJ h|Cx5CJ h|CxCJ hG"CJ2AAAAAAAAAAAAAAAAAAAAA B B BBBB"B#B6BBBBBC CCCCCCCCC,D9DDDDDDDDDEE`EdEEEEEEٿٲ٫٫٤٤٫٫٫٫٫٫٫٫٫٫ٞ٫٫٫ hG"CJ h|CxCJH* h|Cx5CJjYh|CxCJUjXh|CxCJUjXh|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjWh|CxCJU>@BB*BCDCCCCCC,D}DDD`E ^ gd\ & F @ ^gd\ & F p@ @ ^@ gd\ ^`gd\^gd\^gd\ p ^gd\ p ^gd\`EEEEE/FgF G GGG{HHH.I/I & F^gd\ & F^`gd\ ^`gd\^gd\^gd\@ ^@ gd\  h^ `hgd\  h^ `hgd\ & F p@ @ ^@ gd\ @ h^@ `hgd\EFFF GGHHHH/I6I7I9I:IDIEIMINIcIIIIIII;J*CJh;-`h|CxCJh;-`h;-`>*CJ h;-`CJh;-`h;-`5CJh;-`hn8[5CJh;-`h|Cx5CJh;-`h;-`CJ h;-`5CJ hG"CJ h|CxCJ h|Cx5CJ6/INI*jAZh/*hI<U h/*h/*jh/*h/*Uh|Cxhrvhh|Cx0J>*jxYhU hrvhhrvhjhrvhhrvhU#}OOOPP^PPPPCQQQRyRzRRRSSSTTT^^gd,`^gd5gd= & Fgd\^gd\RRRRRRRRRRRRRRR S SSSSSSSGSHSJSKSgShSiSrSsSvSwSSѼѼѼѼpѼ%j\h|Cx5B*CJUph%j\h|Cx5B*CJUph%j[h|Cx5B*CJUph%j[h|Cx5B*CJUph h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph%jZh|Cx5B*CJUphh|Cx5B*CJph$SSSSSSSSSTTTT#T$T+T,TKTTTTTTTTUU%U&UWUXUUUVV7V8VgVhViVVVVVV#W/W1W@WBWNWfWWǵǵǯǦǝǗǐǦǦǦǦǦǦǼlj *h|CxCJ h|Cx5>* h,CJ *h|Cx5CJ jh|CxCJ hn8[CJ h|CxCJH*h|Cx h|Cx5CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph%j]h|Cx5B*CJUph3TTTUEUUU)VhViVVVVVfWWWW"XXXXXXXgd=`^gd\ ^`gd\^gd\^`WWWWWWWWWpXsXtXvXwXxXXXXXXYYYYY.Y/Y0YxmaWGWj]hZ )hCJUjh|CxCJUhB h|Cx5CJaJhB hB CJaJhB CJaJhB 5CJaJhB hB 5CJaJh|Cx5CJaJh=h|Cx5CJaJh$h$CJH* h$CJ h|Cx5CJ h|CxCJ *hBh|Cx0J>*CJ"j] *hBh|CxCJU *hBhBCJj *hBhBCJUXXYY8YYYYYZ[:[;[Mkd^$$Ifl0dN ,+ (4 layt\  $If & F$If^gd\gd= 0Y4Y5YQYSYxYYYYYYYYYYYYYYYBZoZZZI[[[[[[[[ \\\\\]6^7^N^\^]^^^_^i^)_B_C_I_N_P_f_s_u_|_}___ܠܴ hCJ h5CJ h|Cx5>* h>xCJ h|Cx5CJ hn8[CJ h|Cx6CJj!_hZ )hCJUhn8[h|Cx hHoCJ h|CxCJjh|CxCJUh|Cx0J>*CJ:;[<[I[[[[[[\KMkdG`$$Ifl0dN ,+ (4 layt\  & F$If & F$IfMkd_$$Ifl0dN ,+ (4 layt\\\\\\\\]] & F$Ifgd>xMkd`$$Ifl0dN ,+ (4 layt\ & F$If] ]]]]]]'^(^YMkda$$Ifl0dN ,+ (4 layt\ & F$IfMkda$$Ifl0dN ,+ (4 layt\(^)^7^]^^^_^k^^YMMA & F^gd\ & F^gd\MkdYb$$Ifl0dN ,+ (4 layt\ & F$IfMkda$$Ifl0dN ,+ (4 layt\^^^(_)_B_C_s_t__````aaa b7b8bAbkblb|b ^`^^` & F & F & F^gd\__`````aaaaaabbb*b6b7b@bkblbmb|bbbbbbbbccccccccccddddddeCeEeQe_e`eaeeƼ̦̟ hKCJjh|CxCJU h|Cx>*CJ h CJh0ch0c5CJ hn8[CJhxhx5CJ hxCJ h0cCJ hG"CJ h|Cx5CJ h|Cx5 hCJhh5CJ h|CxCJ h.JCJ6|bbbbcccccc6dddDeEeQeRee & F* h88^8gdh^h hh^h`h & F^gd0c & F & F^ & F^`^gd^gd0ceeeeeef=fEfKffggg g ggg+gZgggZh|h~hhhhiii,j-j/j5jIjQjjj!k'k.k/kkkJlTlmͻͩͻͻ͖͖͆͢͢͢͜͢}} jh|CxCJ h\ CJh$ah$a5CJ h$aCJ hCJ h|Cx5CJ hn8[CJ jhBhBCJ hBCJ hG"CJ hKCJ h|CxCJh$a0J>*CJh|Cx0J>*CJjh|CxCJUjbhZ )hCJU/e>fvff[ggYhZh}h~hii-j/j k!k)kkk ^`^ h^h` & F^gd$a & F+ 88^8gd^ & F8^8 h^`h8^88^8gdKkkkflglmm9mFmxmymmm-n\nnnnnUoVoeooo & F+ ^gd ^`^ ^8^8^mmm9mBmCmPmQmmmmmmmmm\nfnnn>o@oUobouovo|o}oooooooooooppppp!p"p2p3pXpYpwpxpppppppppqqqqTqq߼ﵯ hBCJ h|CxCJ h|Cx5CJ h5CJ hG"5CJ h|CxCJH* h;-`CJ jh|CxCJ h|Cx5CJ jh|CxCJ h|CxCJ jh|Cxh|Cx@o2p3pXpwpppppppVqqqEr]rrrr ^` 8h^8`hgd2rh8^8 & F+ p^p` & F & F^gd5 & F^gd5^ & F+ ^gdqqqqq?r@rEr`rbrrrrr;s=ssstt3t4tIt u uu$u4u5uPuQuRuZu[u\u]uuuuuľ~rjh|Cx5CJUhn8[0J>*CJh|Cx0J>*CJjch|CxCJUjh|CxCJUh=h|Cx5CJaJh=h|CxCJaJ h|CxCJ h|Cx>*CJh|Cx h|Cx5CJ h|CxCJH* jh2rhh2rhCJ h2rhCJ h|CxCJhBh|Cx5CJ'rr s.s}sstt3t4tktltttt u uuuuuvSv & F+gd= & F+ p`^p``^ ^`8^8 ^`uuuuuuuuuvvvvvv v vvvv>v?v@vQvRvSvTvyvzv{vʂӲpb[Ljveh|Cx5CJU h|Cx5CJh|h|Cx0J5>*CJ"jdh|h<5CJU h|CJh|h|0J5>*CJ"jdh|h<5CJUh|h|5CJjh|h|5CJUh|h|CxCJh|h|CJ h|5CJh|Cx0J5>*CJjh|Cx5CJUjdh|Cx5CJU{vvvvvvvvvvvv w wwww9w:wwwwxxx)x+x9xDxkxlxxxxxxxxx$y%yyyyyƼƯƟƋƅƀ̀̀|̀̀̀̀|up h|Cx>* h|Cx5>*h{ h|Cx5 h5CJ h{ CJ h{ 5CJ h,5CJ h|Cx5CJh|Cx0J>*CJjeh|CxCJUjh|CxCJU h|CxCJh|Cx h|CJh|h|CJh|h|5CJjh|Cx5CJUh|Cx0J5>*CJ,Svvvvwwww:wwwxxx h^hgd{ & Fh^hgd{ h^h`gd{ h^`hgd{  & F 88^8gd H  ^ `gd{  & Fh^h`gd{  & Fh^hgd{  & F+gd| xlxxx%yyyyyzzzz|||||}}} & F^` & F^ & F^ & F8^8gd{ h`hgd{  & F 8^`gd Hyyyzzzz+{,{L{M{N{\{]{^{||3|4|5|E|F|P|||||@AԁՁRUVyz{voavjVghMphKJU hMphMpjhMphMpU hMph|Cxhn8[ h>h|Cxh>h|Cx0J>*jfh>hjU h>h>jh>h>U h ] h|Cxh ] h|Cx0J>*jpfh ] h HU h ] h ] jh ] h ] Uh|Cx h|CxCJ h|Cx>*CJ$}%~&~^~JKeՁ΂ς()^gd0* & F`gd{  & F & F^` & F^ & F^{͂ς߂ !%&'HKƒփ$%EF\]Ҋӊ27VWFMyzƴৣhM h0*H* jh0* h0*6] h0*5\h0* h0*CJ h|Cx>*CJ h|Cx0J>*jgh|CxUjh|CxU h 6gCJh0*h|Cx>*CJ aJ h|CxCJh|CxjhMphMpUhMph|Cx0J>*4ƒ׃؃ك(Nnkdh$$Iflrd7X \(U! 64 layt0* $IfgdJ 12<*Xnkd_i$$Iflrd7X \(U! 64 layt0* $IfgdJXYbcщwnnnnnnn $IfgdJkdj$$Iflrd7X \(U! 64 layt0*^2Xwnnnnnnn $IfgdJkdj$$Iflrd7X \(U! 64 layt0*XY]emu}wnnnnn $IfgdJkdlk$$Iflrd7X \(U! 64 layt0*}~2Fzwnnnnnnn $IfgdJkdl$$Iflrd7X \(U! 64 layt0*zPQRYvw-.3efgox@JRTpܔ4FƕȕDƺ h0*CJh!!h!!CJaJhKCJaJhb"LCJaJh!!CJaJh!!hKCJaJh!!hK5CJaJh!!5CJaJ h!!h0* h0*CJ h0*H*jymh0*Ujh0*UhMh0* h0*6]3$Rwnnnnnn $IfgdJkdl$$Iflrd7X \(U! 64 layt0*x;wnnnnn $IfgdJkdn$$Iflrd7X \(U! 64 layt0*;<N"wnnnnnn $IfgdJkdo$$Iflrd7X \(U! 64 layt0*Pɒ.dwnnnnnn $IfgdJkdKp$$Iflrd7X \(U! 64 layt0*defgyT4wgbYH7 & F 88^8gdA- & F 88^8gdA-h^hgd!!gd!![$\$^gd0*kdp$$Iflrd7X \(U! 64 layt0*4ȕFЖ s'oٙٚDG & F^ & F` & F^ & F^gd H & Fhh^h`h  & F & F 88^8gdA-̖djs|ؘ֘٘'8:nouٙڙϹ鳩鳩锊xjh!3h|Cx0J5>*CJ"j2rhZ )h5CJUh!3h!35CJjh!3h!35CJU h8z^CJh1 h1 CJH* h1 CJh|Cx0J>*CJjqh|CxCJUjh|CxCJUh%h%6CJ h%CJ h|CxCJ h|Cx5CJh|Cx h!!CJ)ٚD\Û89GVsuӝܝޝ*yv֢nh8+h|Cx0J>*CJjrh8+hCJUh8+h8+CJjh8+h8+CJU hpCJhaQh|Cx5CJaJ hG"5CJ h-CJ hn8[CJ hG"CJ h|Cx>*CJ h|Cx5CJ h|CxCJ8Gsӝޝ+yӟ>uvޠ֢gdaQ & F^` & F` & F & Fp^p & F^ & F^֢nBʥ 3aݦn:֨bCb & F^gdV & F^ & F` & FgdaQ & F & F^ˤ̤ͤդ֤פBLoȥʥݥamݦn񫢛iZh|Cx0J5>*B*CJph+jshL' hU# 5B*CJUphhL' 5B*CJphjh|Cx5B*CJUph h|Cx5CJhaQhaQCJ haQCJhL' h|CxCJ hL' h|Cx0J>*B*CJphjbshL' hU# CJUhL' hL' CJjhL' hL' CJU h|CxCJh8+h|CxCJ#n~֨٨3MbrBCLMNVWabk34GHYЫkѬլ#$%/ú򖣍h|Cx0J>*CJjtth|CxCJUjh|CxCJUh|Cx56CJh|CxhaQhaQCJ haQ5CJ haQCJh1 h1 6CJH*h1 h1 6CJ h1 CJ hVCJ h|CxCJ h|Cx5CJ7b1kԬլ2\v"5B8^8` & F & F`  & F & F^ & F`gdaQ/02\v"5X[]uƮǮϮ,BD"|XeDzȲfoڴ۴12Gh|Cx0J>*CJjth|CxCJUh|Cx hn8[CJ hKCJ hG"CJh|Cx56CJ h|Cx5CJ h|CxCJjh|CxCJUA&Zl|1eòϲ  $=Nfq & F & F^ & F & F & F` & F^<j1d|P`Ƿ co & F & F & F^ & F^ & F`  & F & FGHIbcP^`fL clo12345uvw{|}ٿٹٳٳ٭ى hKCJ h|0J>*juh<Ujh|Uh| h|CJ h?CJ hG"CJ h|Cx6CJ hKCJ h|Cx5CJ hn8[CJ h|CxCJh|Cx0J>*CJjh|CxCJUjpuh|CxCJU6θ~OǻȻ̼uʽ3|0 & F>  8^`gdD & Fh^hgd{ & F8^8gd{ 8^8gdK & F ^gd H^gd{ & F^gd{ & F^ & FOXǻȻVtzʼ  tuʽֽ3@ϾѾ/03¿ÿֿƹ~~~qjhDhDCJU hKCJ h\ CJ hDCJ hn8[CJ hnp CJhnp hnp 5CJ hG"CJ h3CJ h|Cx6CJ hDCJ hn8[5CJhDh|CxCJ h|Cx5CJhDh|Cx5CJhKhK>*CJ hKCJhKhK5CJ h|CxCJ)0x0jk$IW h^h`gd{ & F`gd[T  & Fh^hgd{  & Fh^h`gd{ & Fh^hgd{ 8^8gdD & F8^8gd{ ÿ 0;k}$%13;]ſseh|Cx0J>*B*CJph(jEwhbqh$#B*CJUphhbqB*CJphjh|CxB*CJUph hKCJ h|Cxh h3CJ hG"CJ h|Cx5CJ h|CxCJhDh|CxCJhDh|Cx0J>*CJjhDhDCJUjvhDhxCJUhDhDCJ' bkKQ{ 3KKSy!#68LM[޾޾޵޾ h|Cx5 *h|CxCJ jhjCJ hG"CJhjhj5CJ hn8[5CJ *h|Cx5CJ hjCJ hj5CJ h|CxCJH* h|CxCJ h|Cx5CJBb4{3KyM & Fh^h`gd{  & F p  ^ gdQ & F ^gdQ h^h`gd{ & F8^8gd{ [y~$;>Q *68`sKL\]d 徵뾢圑yhDh|CxCJ aJ hD5CJ hDCJhDhDCJ aJ hDCJhT h|Cx5CJhT hT CJhT h|CxCJhT hT 5CJ h|CxCJH*hDh|Cx5CJ hDCJ hG"CJ h|CxCJ hT CJ h|Cx5CJhG"h|Cx-M `uKL\]^gdDgdD 8^8`gd{ & F^gdT  & F8^8`gd{ & F^gd{  & Fh^h`gd{ & F8^8gd{ 8^8gd{  trP|"D^ ^` & F^`  & F^ & F & Fgd@ & F^gdDgdD  !st} +,[\qr}ʩqht^hn8[0J5>*CJht^h@0J5>*CJ"jwht^h$5CJUht^ht^5CJjht^ht^5CJUh@h|CxCJ jh|CxCJh@h@CJ h@5CJh@h@5CJ hG"CJ h|CxCJh@h|Cx5CJ h@CJ(#$PQfghtuvTUtuvyz|"%DFGLѿ۫ycTh|Cx0J5>*B*CJph+jxh[Thk5B*CJUphh[T5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJh|Cx h|Cx5 h@CJht^h@0J5>*CJ"jAxht^h$5CJUht^ht^5CJht^h@CJjht^ht^5CJUht^h@0J>*CJ hj$  ,;<=Wvw  !7>CFUVaf -.Az򸬸h@h|Cx56CJh@56CJ jhBhBCJ hBCJ h@CJ jh|CxCJh'Qh|Cx5CJ h|Cx>*CJ h'QCJ jh|CxCJmHnHu h|CxCJ h|Cx5CJ8n,w Wgh  -{ & F^`gd{ & F^gd{ & F^gd'Q & F^gd'Q & F & F` & F gd@^z{3PYeiqxOSl24JKLM꽶𽮪~ hbq0J>*jzh$#UjhbqU h|Cx0J>*jCyh$#Uhbqjh|CxU h|Cx5CJh|Cx h@CJ h|Cx6CJh_h_CJ h_5CJ h_CJ h 6gCJ h|CxCJ h|Cx5CJh@h|CxCJ124Yd7\ 7$8$H$^gdIG7$8$H$^`gdIG & F^`gdIG & F^gdIG & F^ & F^gd~8 & Fgd= & F^gd{ & F^gd{ XYbdm   7<OPyz{ֿֿ֯֠֐փzj^hRGh|Cx0J>*CJj}|hRGhRGCJUhRGhRGCJjhRGhRGCJUj{hZ )hCJU hn8[CJh|Cx0J>*CJjzhZ )hCJUjh|CxCJU hIGCJ hIG5CJ h|CxCJ jh~8h~8CJ h~8CJ h|Cx5CJ hbqh|Cxhbq$ "#KLMZ[\d &()RSTcdzs h0Ru5CJ h0RuCJj~hZ )hCJU hIG5CJj~hZ )hCJUhIGh|Cx5CJhIGhIG5CJ h|Cx5CJ hIGCJhIGhIG0J>*CJjL}hZ )hCJUhIGhIGCJjhIGhIGCJU h|CxCJ) / n_/ & FgdtD ^`gdtD & FgdtD^^ 7$8$H$^ & F^`gdIG & F^gd0Ru7$8$H$^`gdIG/;'IKLnopstvлݪ~oY~G~#h+h+0J5>*B*CJph+jth+hA-5B*CJUphh+h+5B*CJph%jh+h+5B*CJUph h+CJ hG"CJ h|CxCJ h|Cx5CJ h0Ruh0Ru0J>*B*CJph(jh0Ruh+B*CJUphh0Ruh0RuB*CJph"jh0Ruh0RuB*CJUph h0RuCJh0Ruh0Ru5CJvw1첖m[UNGNU hn8[5CJ h|Cx5CJ h|CxCJ#h+h$0J5>*B*CJph+jIh$hA-5B*CJUph%jh+h$5B*CJUph h$CJ+jh$hA-5B*CJUph h+CJ#h+h+0J5>*B*CJph+jh$hA-5B*CJUphh$5B*CJph%jh+h+5B*CJUph1234abcfgh   g 8BҼᡛxqe[h|CxB* CJphh|Cx5B* CJph h|Cx>*CJ+jh+hA-5B*CJUph h|CxCJ h|Cx5CJ hjCJh+h+CJ#h+h+0J5>*B*CJph+jh+h+5B*CJUphh+h+5B*CJph%jh+h+5B*CJUph h+CJ h$CJBDGLQXmnwz{  _cduv˹}tnhhn^hhdhd6CJ htDCJ hn8[CJh0Ruh|CxCJh0Ruh0RuCJ h0Ruh0Ru0J>*B*CJph(jHh0Ruh+B*CJUphh0Ruh0RuB*CJph"jh0Ruh0RuB*CJUph h0RuCJ h|Cx5CJ h|CxCJh|Cx5B* CJphh|CxB* CJphh|CxB* CJH*ph!-*.IK`bfFfoq 8N'+#&'146?Qb궬ꙒꙒ hIG>*CJ h|Cx>*CJ hG"CJ htDCJhtDhtD5CJ htD5CJ hRGCJhtDhtD6CJhtDh|Cx6CJ h0RuCJ hIGCJ h|CxCJH* h|CxCJ h|Cx5CJhtDhtDCJ9/*bf8' & F^gdtD & F^`gdtD & F^ 7$8$H$^ 7$8$H$^gd0Ru 7$8$H$^7$8$H$^` & F+ 7$8$H$^gd'56@O\fz~uskd$$Ifl\d <0*t$ @  '4 layt{ & F$If & F^gd{  $2OPskd}$$Ifl\d <0*t$ @  '4 layt{ & F$If PQmn & F$Ifskd$$Ifl\d <0*t$ @  '4 layt{ *.FG & F$Ifskd$$Ifl\d <0*t$ @  '4 layt{ HMNO^j9:;<HILz-8:GI[qr˻ˮ˥˞˓˓ˇ~wp˓ghsw7hDCJ hD6CJ hD5CJhD56CJh^lBhD56CJ hKCJ hDh hD5hhD0J>*CJjhDCJUjhDCJU hDCJ hDCJh=h|CxCJaJ hIGCJ jh|CxCJ hn8[5CJ h|CxCJ h|Cx5CJ(GHP[\] & F$Ifskd?$$Ifl\d <0*t$ @  '4 layt{ ]^ktuv & F$IfskdՇ$$Ifl\d <0*t$ @  '4 layt{ vwxKLsne``WO & FgdD`gdDgdDh^hgdDgd= & F`gdIG & F^gd{ skdk$$Ifl\d <0*t$ @  '4 layt{ 3i +,P-.6 & FgdD^gdD h^h`gdD & FgdD`gdD8^8gdDgdD & FgdD,NP[cx{  .6DEGRV`lv"59CNYyг򠕎 h|CxCJ h|Cx5CJh=h|CxCJaJh=h|Cx>*CJaJ hD6CJhD0J5>*CJ"jhZ )hD5CJUjhD5CJU jhDCJ hD>*CJ hKCJ hDCJ hD5CJ56\]atu4ab  & F^ & F^` & F^gd=gdD & FgdDNZ]_u2abcqr_`  PQ}~򶭝ujhywhywCJU hn8[CJhRh|CxCJhRhR0J>*CJjohRh CJUhRhRCJjhRhRCJUh|Cx5>*CJ h|Cx6CJh|Cx56CJ h|Cx>*CJ h=h|CxCJaJh|Cx h|CxCJ h|Cx5CJ+bc'C\,-InoUVv & F^gd ( & F^gd ( & Fgd=~-9:HIoz{67VvYz@AUVžwjj{h|CxCJUjh|CxCJUh+h|Cx5CJhb"Lh!!h|Cx h|Cx5 hG"CJ hn8[CJ h|Cx6CJh|Cx56CJ h|CxCJ h|Cx5CJhywh|CxCJhywh|Cx0J>*CJjhywhywCJUjhywhCJUhywhywCJ)v\ABQR & F8^8gdR & F@ ^@ gd ( ^ gd ( & F @ @ ^@ gd H & F @ @ ^@ gd Hp^pgd!!p^pgd ( & Fp^pgd (VWYZABQRSkl!lnuwн氦yr h|Cx6CJh|Cx5B* CJphh|CxB* CJph h0CJ h 6CJhS{h 6CJhS{hS{6CJ hS{CJ h|Cx5CJhRhRCJhRhR5CJ hRCJh+h+CJH* h+CJ h|CxCJh|Cx0J>*CJjh|CxCJU&#lnwjk-      & F^gd{  & F^` & F` & F@ `^@ `` & F@ ^@ ` & FǶNJveP?'/j[h+h|Cx5B*CJUaJph h+h|Cx5B*CJaJph)jh+h|Cx5B*CJUaJph h:h/5B*CJaJph'h:h|Cx0J5>*B*CJaJph'h:h:0J5>*B*CJaJph/jh:h|Cx5B*CJUaJph h:h|Cx5B*CJaJph)jh:h|Cx5B*CJUaJph h|CxCJh (h|CxCJOJQJh (h|Cx>*CJ(OJQJaJ( 678<=?@걢|dP||8P|/j=h+h$#5B*CJUaJph'h+h/0J5>*B*CJaJph/jҌh+h$#5B*CJUaJph h+h/5B*CJaJph)jh+h/5B*CJUaJphh+h:B*CJaJph h+h:5B*CJaJph'h+h|Cx0J5>*B*CJaJph'h+h:0J5>*B*CJaJph)jh+h|Cx5B*CJUaJph@\]^_hijkl®‰zeT*B*CJaJph/jh+h$#5B*CJUaJph h+h+5B*CJaJph)jh+h+5B*CJUaJphh+h:B*CJaJph h+h|Cx5B*CJaJph'h+h/0J5>*B*CJaJph'h+h:0J5>*B*CJaJph)jh+h/5B*CJUaJph/jh+h$#5B*CJUaJph h+h/5B*CJaJph       & ' ( + , - ̽̓̽̽|̓̽̽e̓̽̽N̓̽,jߏh+h|CxB*CJUaJph,jvh+h|CxB*CJUaJph,jh+h|CxB*CJUaJph$h+h|Cx0J>*B*CJaJph,jh+h|CxB*CJUaJphh+h|CxB*CJaJph&jh+h|CxB*CJUaJphh+h:B*CJaJph h+h:5B*CJaJph- . K L M X Y Z [ \ p q r t u x y  ꜍yjSy@yjyj$h+h|Cx0J>*B*CJaJph,jh+h|CxB*CJUaJphh+h|CxB*CJaJph&jh+h|CxB*CJUaJphh+h:B*CJaJph h+h:5B*CJaJph'h+h:0J5>*B*CJaJph/jHh+h$#5B*CJUaJph h+h+5B*CJaJph)jh+h+5B*CJUaJph                    ! + , 8 9 F G ճճճ{ui`YYRLCh?h|CxCJ h?CJ h?5CJ h|Cx5CJh[Th|CxCJhU#h|Cx>*CJaJ hQ!=CJhQ!=hQ!=6CJh|Cx h|CxCJh{ h:B*CJph,jh+h|CxB*CJUaJphh+h|CxB*CJaJph$h+h|Cx0J>*B*CJaJph&jh+h|CxB*CJUaJph,j(h+h|CxB*CJUaJph     ! G [        l v      2 I   ^gdQ!=^gd~'^^gdU#G Q [ g              l v {      $ 2 H I J d           ĺĶyg#jh[Th$#CJUaJjh[Th1 CJUaJh[Th1 CJaJh[Th|Cx5CJaJh[Th|CxCJaJhU#h|Cx5CJaJh|CxhQ!=hQ!=5CJ hQ!=CJ h+CJh[Th|CxCJhU#h|Cx>*CJaJ h?CJ h?5CJ h|CxCJ h|Cx5CJ(    de67hi & F8^8gd[T & FR p^gdQ & F^ & F^gdM & F^^gd[T^gd[TgdU#         67GI]^lmip Pd̵zpzzj hQ!=CJh~'hn8[5CJh~'h|Cx5CJ hn8[CJ h|CxCJH* hMCJh1 h|Cx5CJ h|CxCJh1 h|Cx5CJH*aJh1 h|Cx5CJaJh[ThMCJaJh[Th|CxCJaJh[Th1 CJaJh[Th1 0J>*CJaJjh[Th1 CJUaJ'deľ{n{^nRn{n{hMhM0J>*CJjhMhJCJUjhMhMCJUhMhMCJhMhM5CJ hn8[CJh1 h|Cx5CJ h|CxCJh1 h|Cx5CJH*aJh1 h|Cx5CJaJ hMCJhQ!=hMCJhQ!=hQ!=0J>*CJjhQ!=hQCJUhQ!=hQ!=CJjhQ!=hQ!=CJUXxY & FQ @ @ ^@ gdQ ^`gdM^gdM & F^gd{ & F^gdJ & F^gdM & F^ & F`gdM & F^ & F^gdQ!=./09:ghͽ͍ͭͣ}odXhMhMCJ\aJhM5CJ \aJ hMhM5CJ\aJhJhJCJH* hJCJj>hMhJCJU hMCJhJhM5CJjhMhJCJUjhMhJCJUhMhMCJhMhM0J>*CJjhMhMCJUjhMhJCJU"/W?TU67<ǽնxlhW1h|Cx5>*CJhW1hbq5>*CJ h|CxCJ hbqCJh:h|CxCJh:h|Cx5CJh?:hbq5CJh:hbqCJ hbq5CJh~'h1 CJ\ h~'CJ\ h1 h1 h1 CJ h CJ jhMCJmHnHu hMCJhMhMCJ aJ 'Yz>?TU'Bnp^pgd1 gd1 ^gd1  & F ^`gdM^gdM p^p`gdM6e9MNpq p^p`gd:gdbq^gdbq & F^gdM ^`gd: @ 0^@ `0gd:`gdbq & FSgdbq & F^`gdMgdbq`gdbq<Hdehps9<MNRVopqrvx|ƺwoe\e\eTƦhbqhbq5h:h|CxCJh:h|Cx5CJh|CxCJaJhbqhbq5CJaJhbqhbqCJaJhbqh|Cx5CJaJ h|CxCJ hbqCJhbq5CJ\h:hbqCJaJh:hbq5CJaJhbqhW1hbqCJ hW15CJhW1h|Cx5>*CJ hW1CJhW1h|CxCJhW1h|Cx5CJ KOPX(;QRST  랕wnnn jh|CxCJh|CxCJ4OJQJY(h|Cx5CJ4OJQJY( hMCJh[Th{ CJ h|Cx>*CJ h|CxCJH*h1 h|Cx5CJh1 h|Cx>*CJaJ h~'CJh~'h1 CJh~'h~'CJ\h~'h1 CJ\ h1 CJ h|CxCJ hbqCJh:5CJ\+ K'<Sbo & F^gdM p^p`gd1 p^pgd1 ^gd1  & F ^`gd:'(;PU  Hb^gdM & F< ^gdCjR & F; ^gdCjR & F8^8gdM & F^gdM & F^gdM.NO^< = V    & F^gd/ & F^gd/ & F$%DE= V   6!7!O!P!Q!a!b!!!!"H"I"U"d"u"#)#2#3#5#h#q#r#s########$$$$h/h/CJ hmfCJ\ h~'CJ\h/h/CJ\h/5CJ\h/h|Cx5CJ aJ hb"LCJ hG"CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJh|Cx5>*CJ jh|CxCJ h|CxCJ2  !!!!"".">"I"#)#4#h#s#######gd/ & F^`gdb"L & Fp^pgdb"L & F^gd/ & F^gd/ & F^gd/#$I$]$p$$$$%%E%^%%%%&&&9&E& & Fp^pgd/ & F^gd/ & F & F`gd/^gd~' ^`gd/^gd/^gd/$$4$5$6$G$H${$|$$$$$$$$$$$$$$$$$$$$$%%'%(%=%>%?%B%闎xh\h~'h~'0J>*CJjh~'h$#CJUh~'h~'CJjh~'h~'CJUh/5CJ\ h/CJjh~'h$#CJUjh~'h$#CJUjh~'h$#CJUh~'h/0J>*CJj(h~'h$#CJUh~'h/CJjh~'h/CJU$B%C%E%F%P%T%^%_%v%w%x%%%%%%%%%%%%%%%%%%&&&鴨|p|jbVjh/h/5CJaJh/CJaJ h/CJh~'h/5CJ\h~'h~'CJ\h~'h/0J5>*CJ\%jҘh~'h$#5CJU\h~'h~'5CJ\jh~'h~'5CJU\h~'h/0J>*CJjeh~'h$#CJUh~'h~'CJh~'h/CJjh~'h~'CJU&,&8&9&:&E&F&x&y&&&&&&&&&&&&&&''''''('E'F'G'c'd'e'x'y'''ȸίΦȖίΦ}qih/CJaJh/h/>*CJaJh/h/>*CJ\ h/CJ h|CxCJH*jh|Ch$#CJUh~'h|CxCJh|C0J>*CJj=h|Ch$#CJU h|CCJjh~'h~'CJU h|Cxh h~'h h|CxCJ h~'CJ hG">*CJ h|Cx>*CJ%E&x&&'''('F'd'x'''''(U(V(y((( & F^`gd{ & F^gd{ & F^gd/p^pgd/^gd/ & F^gd/ & Fp^pgd/  & Fp^pgd/''''''''''''''''(('()(*(G(H(I(R(S(T(U(y((())))"),)2)a)b)ȸѬȜѬޕysghzhX5>*CJ h "wCJhXhXCJH* hXCJ hG"CJ h|CxCJ h|Cx5CJjh/h$#CJUh/h/0J>*CJjh/h$#CJUh/h/CJjh/h/CJU h/CJh/h|CxCJ h~'CJh/h|Cx>*CJaJ'(b)c))) *,**T+V+++,F,G,k,, ^gd{ & F^gd{  & F^`gd{ gd9- & FT ppd]^pgdQd]^gd9-  & F^gd{ & F^gd{ b)c)u)v)))******+++ ++++,+6+P+T+V++++,,0,2,G,k,,,,h------V._.״ע׍|unuuu h|Cx>*CJ h|Cx5CJhn8[ h|CxCJH* h|CxCJ h9-h9-h9-h9-0J>*CJaJ#jmh9-h$#CJUaJjh9-h9-CJUaJh9-h9-CJ\aJh9-CJaJh9-h9-CJaJh9-h9-5CJaJh9-h9-5CJ]aJh|Cx+,g-h---V..#/./K//0`00023 ^`gd{ & Fp^pgd{  & F   ^ gd{ ^gd{ & F^gd{  & F^`gd{ & F^gd{ gd[T  & F^gd{ _../#/,/./W//////00`0s0000091=1J222222222223P3Q3`3a333334444Z5p555~ h{ CJhkhk0J>*CJaJ#jԛhkhkCJUaJjhkhkCJUaJhkhkCJaJ hkCJ hG"CJh|Cx6>*CJ h|Cx6CJh|CxCJmHnHu jh|CxCJmHnHu h|Cx5CJ h|CxCJ13344Z55567789999;;  & F^gd{ & F^gd{ & F^gd{ & F@ ^@ gd{ @ ^@ gd{  & F  @ ^@ gd{ p^pgd{ ^`gd{  & F   ^ gd{ 5555667-777777889999999:;;;+;1;2;3;4;\;d;;;;;;;;;;;;<<<<<<<H<jhZ )hCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx6CJ h|CxCJH* hrhr hrCJ hr5CJ hG"CJh|Cx h|Cx5CJ h|CxCJ h{ CJ3;3;;;;< =V=W=w===>>.>U>V>>>>>?^gdU#^gdU#^gd[T & F^`gd{ & F^gd{ & F^gd{ H<I<J<V<W<`<a<~<<<<<<<<<<<< = =V=W=w======>,>V>>>>>>>??F@[@@@A9AIARATAֵּ֌֌ֵֵ}ֵֵֵֵֵֵ hb"LCJhb"Lhb"LCJ h|CxCJH*hU#h|Cx5CJaJhU#h|CxCJaJh[Th|CxCJaJ h|Cx5CJj'h|CxCJUjh|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjߝhZ )hCJU0?E@F@[@@@AIABBBBBBB & F^gd/ & F^gd/ & F & F^`gd{  & F ^gd{  & F8h^8`hgd{ & F8^8gd{ & F^gd{ & F^gd{ TAdA{AAAAAAIBJBsBtBuBBBBBBBBBBBBBCCCBCCCCCȸѬ䙒{od{YQhrCJaJhrhrCJaJh/h/CJaJh/h|Cx5CJaJh/h|CxCJaJ h|Cxh h|CxCJH* hG">*CJ h|Cx>*CJh/h|Cx5CJ aJ hrh|Cx0J>*CJjhrhQCJUhrhrCJjhrhrCJU hrCJ h|CxCJhDhDCJH* hCJ hDCJBBCCCCCJDEEE&F'FMFNFFFFFG^gd/^gd/ & F & Fp^pgd{  & F^`gd{  & Fgdr`gd/gd/ & F^gd/  & F^gd/CIDJDrDDD~EEEF F&F'FMFG G G2G3GQGRG{G|G}G HHH;HHHHHHII)IWIXIYIgIhIsI|IIIIIJJJJKKRK[KbKź㨢㨘 h(CJ h+CJhh|Cx5CJ hrCJ hCJ h0CJ h9-CJh9-hbdWCJaJhbdWCJaJh|CxCJaJ h|Cx5CJ h|Cx>*CJ h|CxCJh|CxhrCJaJhrh|CxCJaJ7G G G GGGG*G2G & F$If & F & F`2G3G6G:GEGIG>4444 & F$Ifkdu$$Iflֈ4 R RFF04 layt/IGMGQGRGVG_G4kdN$$Iflֈ4 R RFF04 layt/ & F$If_GjGpGuG{G|G4kd'$$Iflֈ4 R RFF04 layt/ & F$If|G}GHH*CJ hG"CJ h|CxCJ h|Cx5CJ=OOOOONPOPPPPPDQEQRQSQQQQQ & F`h^hgd/ & F 88^8gdQ & Fh^hgd/ & F & F^gd{ & Fp^pgd{ & F^gd{  & F^`gd{ PCPDPEPKPLPMPOPPP_PaPPPPPCQDQEQPQyQ{Q|QQ˺˱yrylYMh/5B*CJph%jh/h/5B*CJUph h/CJ h+5CJ h+CJhRhRCJhRhRB*CJph hRCJh^lBhR5CJ h^lBCJ h|CxCJh=h=CJ h=h=0J>*B*CJph̙"jh=h=B*CJUph̙(jh=hfgB*CJUph̙h=h=B*CJph̙QQQQQQQQQQQQQQQQRRR־t_O7_.jnh[Th|Cx5>*B*CJUphh[Th|Cx5>*B*CJph(jh[Th|Cx5>*B*CJUphh[Th|Cx>*B*CJphh[Th|Cx>*hU#h|Cx5CJ$aJ$hU#hG"5CJ$aJ$ hRCJh+h$aCJ h+CJ h$aCJ h/CJ#h/h/0J5>*B*CJph%jh/h/5B*CJUph+jףh/h$#5B*CJUphQQQpRqRRRSSSS T T/T[TjTTTTT U!U^gd{  & F^`gd/ & F^gd/ & F & F^gd{ ^gd{ gdU#R3R4R7R8RZR[R\RmRnRoRpRqRrRRRRRRRRRعɔteOt=tete#h{ h|Cx0J5>*B*CJph+jh{ h|Cx5B*CJUphh{ h|Cx5B*CJph%jh{ h|Cx5B*CJUphh[Th|CxB*CJphh[Th|Cx>*B*ph.jh[Th|Cx5>*B*CJUphh[Th|Cx5>*B*CJphh[Th|Cx>*B*CJph(jh[Th|Cx5>*B*CJUph#h[Th|Cx0J5>*B*CJphRRRRRRRRRSSS,S-S/S0SSSTSUSZS[S]S^S~SSSSSSSSij֦֗֗֗k֗֗U֗֗+jh{ h|Cx5B*CJUph+jh{ h|Cx5B*CJUph+jh{ h|Cx5B*CJUphh{ h|Cx5B*CJphh{ h|CxB*CJph h{ h|Cx0J>*B*CJph#h{ h|Cx0J5>*B*CJph%jh{ h|Cx5B*CJUph+j h{ h|Cx5B*CJUphSSSSSSSSSSSSSSSS T T TTT U&U'U4U:U=UGUUU\UUUUUIJ֣֣֣zslflflflfYjh#R%hCJU hCJ h5CJ h|Cx6CJ h/CJ h|Cx5CJ h|CxCJ+jh{ h|Cx5B*CJUphh{ h|Cx5B*CJph#h{ hn8[0J5>*B*CJph#h{ h|Cx0J5>*B*CJph%jh{ h|Cx5B*CJUph+j#h{ h|Cx5B*CJUph!!U4U=UUUUQViVVWXX7YYY"\]] & Fxgd^gd & Fwgd & F^`gd{ & F^gd{ & Fp^pgd & F^`gd & F^`gd & F^gd{ UVVV V V V V!V"V#V%V&VQVVViVuVVVVVVWW W W WW"WXXX0XXXXX7YKYڸxrxrxrlblrxh#R%h#R%>*CJ h#R%CJ h|CxCJ h|Cx5CJh1Mh0J>*CJjh1MhCJUh1MhCJjh1MhCJU h5CJ hCJjh#R%hCJUh#R%h0J>*CJjh#R%hCJUjh#R%hCJUh#R%hCJ&KY[YkYYYYYYYYYYLZNZZ[[[[[\\\\ \"\.\0\7\8\A\B\C\ּ֬{r`"jhcqhB*CJUphhcqhCJh0J5>*B*CJph+jbhZ )h5B*CJUphh5B*CJphjh5B*CJUphh;'hCJH* h>*CJ jhCJ hCJhhCJ h5CJ hn8[5CJ h|Cx5CJ h|CxCJ C\g\h\i\l\m\q\\\ ]!]"]%]&]*],]0]3]?]W]]]]]]^"^m^˺˱yjcYcRLRLRL h|CxCJ h|Cx5CJhh5CJ h5CJh0J5>*B*CJph+jhZ )h5B*CJUphh5B*CJphjh5B*CJUph hCJhcqhCJ hcqh0J>*B*CJph"jhcqhB*CJUph(jhZ )hB*CJUphhcqhB*CJph]^w____``_``Raa%b;bobpb & Fp0^p`0gd{  & F) 8  ^ gd{ & F^gd{  & F^`gd{  & F@ `^@ ``gd{ & F^gd{ ^gd{ ^gd{ & F^gdm^s^u^w^^^^^^^^___E_v_w________```&`(`8`R`_`h`%b+b;bDbpbbbbccectccd?dRddddd6e:e|eeeeeeeﲹ﹜ hn8[5CJhG"hG"CJ h{ CJ h|Cx>*CJ h|Cx5CJ h#R%CJh#R%h#R%CJ hG"5CJ h=1?CJ h\ CJ hCJ h|CxCJH* h|CxCJhcqh|Cx5CJ=pbbccczcccd6e{e|eee3f~fffff&g'g & F^`gd{ ^`gd{ & F^gd{ & F^gd{ ^gd{ ^gd{ eeee3f7f~ffffffffffffg%g'g3gAg~gggggggg#hNhOhRhXh_hlhzhhhhhhhhhhhhhhѡїёѡ h6X5CJ hk1wCJhk1whH| 5CJh6XhH| 5CJhH| hH| CJ hH| 5CJ hZ.CJ h]CJhH| hH| 5CJ hH| CJh|CxhH| h|Cx>*CJ h|CxCJH* h|Cx5CJ h|CxCJ hG"CJ3'gAg~ggh>iJiijJjjjkk2kk@lm|m~mmfo p & F^gd{  & F 8^gd H^gd{ ^gd{ ^gd{ h*i,i=i>i?iHiijj'jJjKjjjjjjk2k>kklll$l0l2lѾѳ~ujb\RK h6X>*CJh-Sh-S>*CJ h-SCJh-SCJaJh-Sh-SCJaJh-S5CJaJhH| CJaJhH| hH| 5CJaJhH| hH| aJhH| h|Cx5CJaJhH| h|CxCJH*aJhH| h|CxCJaJ hG"CJ hH| CJ h|Cx5CJ h|CxCJh6XhH| 6CJh6Xh6X6CJh6Xh6X6>*CJh6Xh6XCJ2l>l@lRlmmzm~mmmnnnnndofo~o pFpJpdpeppppppppqr*r6rFr¼qc] hk1wCJh|Vh|Cx0J5>*CJ"j_h|Vh855CJUjh|Vh|V5CJUheah|Cx5CJh|Vh|V5CJ hG"CJ h|VCJh|Vh|Cx>*CJ h|CxCJ h|Cx6CJ h|Cx5CJhH| hH| CJaJhH| CJaJhH| hH| 5CJaJh6Xh-SCJaJ h6XCJ" pFp~ss3ttt;u*jh;'h;'Ujh;'h;'U h;'h;'h;'5CJaJh=h;'5CJaJh|CxCJaJ jh|CxCJmHnHu h|Cx>*CJheah|Cx5CJ jh|CxCJ h|CxCJH*hk1whk1w>*CJ hk1wCJ h|CxCJ hn8[CJ&2u3u4u8u9u:u;u*B*CJaJph,jhN rh-B*CJUaJphhN rhN rB*CJaJph&jhN rhN rB*CJUaJphhN rCJaJh[Th;'5CJaJh[Th;'CJaJh=h;'CJaJ h;'h;'h;'h;'0J>*jh;'h;'UjhEUwwww/x0x1x:x{?{@{A{R{`{p{{{T|[||||||||||||孡} h[TCJ h\ CJ h|CxCJ h|Cx5CJhU#h|CxCJaJhU#h|Cx>*CJaJhU#h;'CJaJhhCJH*aJh[Th;'>*CJaJh;'5CJaJh[Th;'5CJaJh[Th;'CJaJhCJaJh;'CJaJ1x1yzQz%{&{?{@{A{_{`{p{q{{{{|||B}C}D}U}V} & F^gd[T & F & F`gdU#^gd;' & Fgd;' & Fgd;'||}C}D}I}U}(~)~*~+~,~-~2~3~<~=~V~W~X~_~`~b~c~~~~~ǹǹp]F],jhBh|CxB* CJUaJph$hBh|Cx0J>*B* CJaJph,jGhBh|CxB* CJUaJphhBh|CxB* CJaJph&jhBh|CxB* CJUaJphhBh|CxB* CJaJphh|CxB*CJ8OJQJphh|CxB* CJ8OJQJph h#R%CJhhCJ$aJ$h"PCJ$aJ$ hCJ hG"CJ h|CxCJV}%~'~(~)~2~3~NO|}56с" & F^ & F ^gdB & F^gdB & F & F^gd~~~~~~~~~~~~~~~~~~9:;LMOݜ݅n_hBh|CxB* CJaJph,jhBh|CxB* CJUaJph,j'hBh|CxB* CJUaJph,jhBh|CxB* CJUaJph$hBh|Cx0J>*B* CJaJph,j3hBh|CxB* CJUaJphhBh|CxB* CJaJph&jhBh|CxB* CJUaJphOPjkltuxyݜ݅uiR,jhBh|CxB* CJUaJphh4uB* CJaJphh4u0J>*B* CJaJph,jhBh|CxB* CJUaJph,jhBh|CxB* CJUaJph$hBh|Cx0J>*B* CJaJph,jhBh|CxB* CJUaJphhBh|CxB* CJaJph&jhBh|CxB* CJUaJph!"CDEIJTUstuz{}~ĀŀɀʀճճճճճճnճճWճ,j͵hBh|CxB* CJUaJph,jbhBh|CxB* CJUaJph,jhBh|CxB* CJUaJph,jfhBh|CxB* CJUaJphhBh|CxB* CJaJph$hBh|Cx0J>*B* CJaJph&jhBh|CxB* CJUaJph,jhBh|CxB* CJUaJph"ʀ  +,-23567[\]ŲŲŲuauJa,jhBhB* CJUaJph&jhBh|CxB* CJUaJphhBh|CxB* CJaJph,j&hBh|CxB* CJUaJph,jhBh|CxB* CJUaJph$hBh|Cx0J>*B* CJaJph&jhBh|CxB* CJUaJph,jDhBh|CxB* CJUaJphhBh|CxB* CJaJph]\]tuv{|}̂͂#$%ȭȺvdWBd(jhBhfgB*CJUph̙hBhBB*CJph̙"jhBhBB*CJUph̙hBhBCJhUfh|CxCJhUfh|Cx0J>*CJj2hUfh$&%CJUhUfhUfCJjhUfhUfCJU h|Cx5CJ h|Cx5CJ h|CxCJhBh|CxCJaJ&jhBh|CxB* CJUaJph$hBh|Cx0J>*B* CJaJph"Â͂.ك)*3&'` & F^` & F^ & F` & F & F^%+,-./TUVjkك)2LMbcdghjk͕͕͕ri\ijhh|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU hn8[CJ hmfCJ h|CxCJhh|Cx0J>*CJjvhh9CJUhhpCJjhhpCJU h|Cx5CJhBhBCJ"jhBhBB*CJUph̙ hBhB0J>*B*CJph̙$̈́΄τ҄ӄ':;<PQRdegDžȅtk[tjhthCJUhthtCJjhthtCJU hG"5CJh|Cx0J5>*CJjh|Cx5CJU h|Cx5CJjh|Cx5CJUh|Cx56CJ hn8[CJhn8[0J>*CJj:h|CxCJUh|Cx0J>*CJjh|CxCJUjѺh|CxCJU h|CxCJ#':;gȅ=?S݆ކV \] & F`gd\c & F^`gd\c & F^gd\c` ^` & F` & F^ & F^` & F^ & F34?Sކ   )*+./12NOPSTUVó̧ufPf+jhreqhb*5B*CJUphh|Cx0J5>*B*CJph+jhreqhb*5B*CJUphhreq5B*CJphjh|Cx5B*CJUphh!gh|Cx0J>*CJj}h!gh HCJUh!gh!gCJjh!gh!gCJU h|Cx5CJ h|CxCJjhthtCJUhth|Cx0J>*CJ -./<=?@UVWZ[\]ƈ ޴Ԣ޴ԛ{ukubWhEuh|CxCJaJhEu56CJhEuhEu5CJ hEuCJh|Cx0J>*CJjh|CxCJUjh|CxCJU h\c5CJ"jh\ch5CJUh\ch\c0J5>*CJ"jh\ch5CJUh\ch\c5CJjh\ch\c5CJU h|Cx5CJ h|CxCJ h\cCJ"]؉ى#$5}efڋ)X & F^`gdU# & F^gdreq & F & F` '(JKL]^`a~؉ى#$535ef(ό ȍԍxr hn8[CJhg4h|Cx0J>*CJjhg4h&CJUhg4hg4CJjhg4hg4CJU hU#CJ h|Cx6CJh1Mh|CxCJ h|Cx5CJ h1MCJjh|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ,XьҌ8DSj}ȍɍՍ+ 6f & FgdEu & F^gdreq & F^gdreqԍ+,2w WXrst{|}~Ðɤɏvm]vQh'h|Cx0J>*CJj{h'h%szCJUh'h'CJjh'h'CJU hU#CJ hn8[CJh8h|CxCJh8hn8[0J>*CJh8h|Cx0J>*CJjh8h;~%CJUh8h8CJjh8h8CJU h|Cx5CJ h\CJ hEuCJhEuhEu5CJ h\5CJ h|CxCJC45NOޑFGj@C 8h^8`hgd`i<h^hgd`i< & Fdgd) & F & F^gdU# & F@ `^@ ``gdreq & F^gdreq ()5NOőݑ   !"23FGjkؒ@BCNøtl`íXlh|CxCJaJh`i<hG">*CJaJh`i<CJaJh`i<h|Cx0JCJaJ#j:h`i<hCJUaJh`i<hbXCJaJjh`i<hbXCJUaJh`i<h|CxCJaJh`i<h`i<CJaJh`i<h|Cx>*CJaJh`i<h)CJaJ h)CJ h|CxCJ hn8[CJ h|CxCJjh'h'CJUNOZ\x +,-3>?DFMX^opԔՔ 123yøyqh|CxCJaJh)hk[CJaJh)hUVCJaJh)hRCJaJh)hG"CJaJh)CJaJh)h|CxCJaJh)h)CJaJh[Th|CxCJaJhU#h|Cx>*CJaJh[Th`i<CJaJh`i<h`i<CJaJh`i<CJaJhk CJaJ+CxГpuՔ2}~+,^gdB^gdB`gd)gd)  h^ `hgd)8^8gd)^gd)h^hgd) ^`gdk gdk h^hgd`i<y|}~͕̕,CDEFstuxyz|ΖϖЖǴ}wqwh]QFhU#h|CxCJaJhU#h|Cx>*CJaJhU#h-DCJaJh-Dh-DCJ hG"CJ h-DCJ#ha?bha?b0J5>*B*CJph+jha?bh5B*CJUphha?bha?b5B*CJph%jha?bha?b5B*CJUphha?bha?bCJ ha?b5CJ h-D5CJ hn8[CJ h|CxCJ h|Cx5CJ h)5CJh)hUV,{ϖЖ9:*+q#^gdR ^`gd)^gd) ^`gd)^gd)gdU#^gdB*+#()PnКњkɜ?Z[ghԞĻʯʗyphEuhEuCJ hEu5CJ *hEuhEu5CJhRhRCJaJhRh|CxCJaJ hEuCJ hEu>*CJ hRCJ hn8[CJhRhRCJ h CJ hRCJ hR>*CJhRhR>*CJhU#hU#CJ h|Cx>*CJhU#h|CxCJ h|CxCJ,#)Qkɜ>?[gh gdEu & F gdR & F ^gdR^gdEu`gdEuh^hgd) & Fgd  & Fgd) & FgdRh՞֞+vwMNOPap+i0 & FgdS{ & F^gdS{ & FgdU#^gdR^gdEu^gdEuh^hgd) ^`gdEu ^gdEu*+<vwLMNOPU[_pqοδzpapOa=a#hh|Cx0J5>*B*CJph"jRhh|Cx5CJUjhh|Cx5CJUhh|Cx5CJhh~5CJhh~5CJPOJQJhh|Cx5CJPOJQJ hh)h)hRhRCJhRhEuCJaJhyhEuB*CJaJphhEuCJaJhEuhEu5CJaJh|CxCJaJ hEu5CJ hEuCJhEuhEuCJ ͠ΠѠҠ&'*,-BCD]^itu揧}pgWjhh|CxCJUhh|CxCJjhh|CxCJU"j(hh|Cx5CJU hS{CJ"jhh|Cx5CJUhh|CxCJ"jFhh|Cx5CJU#hh|Cx0J5>*B*CJph"jhh|Cx5CJUjhh|Cx5CJUhh|Cx5CJ"ϡСѡߡ   '(/01L¹˜ϒ؃ygUyNy hS{5CJ#hh|Cx0J5>*B*CJph"jhh|Cx5CJUhh|Cx5CJjhh|Cx5CJU hS{CJ hh|Cx0J>*B*CJphjhh5sCJUhh hCJjhh hCJUhh|CxCJhh|CxCJ hh|Cx0J>*B*CJphjhh|CxCJULMNhi¢ƢѢҢԢբ   ķħķĆuķeķUjhh|CxCJUj]hh|CxCJU hhG"0J>*B*CJphjhh|CxCJU hh|Cx0J>*B*CJphjshh|CxCJUjhh|CxCJUhh|CxCJ#hh|Cx0J5>*B*CJphjhh|Cx5CJU"jhh|Cx5CJU!0tm<Yإ|Iǩ  @a^ & F^ & F & FgdTB$ & F^a$gd`^  & F^`gd`^ & F^gdS{*+,/023UVWghmnţƣǣգ֣أ٣|ueUjhh|CxCJUjhh|CxCJU hS{5CJ#hh|Cx0J5>*B*CJph"jhh|Cx5CJUhh|Cx5CJjhh|Cx5CJUjhh|CxCJU hh|Cx0J>*B*CJphj3hh|CxCJUjhh|CxCJUhh|CxCJ!-./34:JLMklmpqwxظخءwgwjhh|CxCJU hh|Cx0J>*B*CJphj<hh|CxCJUhh|CxCJjhh|CxCJUhh|Cx5CJjhh|CxCJUjhhh|CxCJUhh|CxCJ hh|Cx0J>*B*CJphjhh|CxCJU$¤ƤǤΤϤ <=>IMVWXYZȸȨїȇvm^jhh|Cx5CJUhh|CxCJ hh~0J>*B*CJphjhh|CxCJU hhn8[0J>*B*CJphjhh|CxCJUjhh|CxCJUhh|CxCJ hh|Cx0J>*B*CJphjhh|CxCJUj0hh|CxCJU Zxyz¥ǥȥѥҥإ٥./ԹԋyԹlcSjhh|CxCJUhh|CxCJjhh|CxCJU"j[hh|Cx5CJUhh\ 5CJ"jhh|Cx5CJU"jhh|Cx5CJUhh|CxCJ#hh|Cx0J5>*B*CJphjhh|Cx5CJU"jhh|Cx5CJUhh|Cx5CJ /03467LMNQRTUjkloprs¦æʦ˦ظبؘ؈wnhh|CxCJ hhn8[0J>*B*CJphjhh|CxCJUjhh|CxCJUj!hh|CxCJUjhh|CxCJUjOhh|CxCJUhh|CxCJ hh|Cx0J>*B*CJphjhh|CxCJU*346HIabcijΧϧЧܧݧ񺱤q_Rjhh|CxCJU"jhh|Cx5CJU"j|hh|Cx5CJU hh|Cx0J>*B*CJphj hh|CxCJUjhh|CxCJUhh|CxCJhh|CxCJ#hh|Cx0J5>*B*CJph"jhh|Cx5CJUhh|Cx5CJjhh|Cx5CJU !-.01VWX[\^{|}ȸⲩ~lcVcFVjhh|CxCJUjhh|CxCJUhh|CxCJ#hh|Cx0J5>*B*CJph"jzhh|Cx5CJUhh|Cx5CJjhh|Cx5CJUh`^ h`^ CJ h`^ CJjhh|CxCJUhh|CxCJ hh|Cx0J>*B*CJphjhh|CxCJUjlhh|CxCJU&'(=>IJjkl{|ǩߩʜʜʃqʜkb[RhTBhTBCJ h|Cx>*CJhh|CxCJ hU#CJ"jlhh|Cx5CJU hS{5CJ"jhh|Cx5CJU#hh|Cx0J5>*B*CJph"jlhh|Cx5CJUhh|Cx5CJjhh|Cx5CJUhh|CxCJjhh|CxCJU hh|Cx0J>*B*CJph     @DHIJNPRUXZ^`ikz|:}s}}}f]heuheuCJjheuheuCJUhG"h\ CJH* h\ CJH* h\ CJhG"h|CxCJH*hG"hG"CJH*hKh|Cx5CJ h|Cx5CJ h|CxCJ h|Cx>*CJhTBhTB0J>*B*ph$jhTBh5NB*UphhTBhTBB*phjhTBhTBB*Uph hTBhTB̪IJϫ$z{٬ !/0AC & Fd7$8$H$ 7$8$H$^^` & F & F^` & F` & F^:;<FGUa{!/0DխܭCMޮ߮  >?]°ɰ̰n|лдлдллдЮдЧНАЃддддvjh:]|h:]|CJUh|Cxh|Cx0J>*CJj:h|CxCJUjh|CxCJU h|CxCJH* hG"CJ h|Cx5CJ h|Cx>*CJ jh|CxCJmHnHu h|CxCJheuh|Cx0J>*CJjheuheuCJUjrhZ )hCJU.>?]ɰ?no|ƱԲղ p7$8$H$^p7$8$H$^`7$8$H$ 7$8$H$`gdU# 7$8$H$^ 7$8$H$^(0Բ߲<>?ijknopȻȵnȵ_I+jhDhl5B*CJUphhDhD5B*CJph#hDhD0J5>*B*CJph+j(hDhl5B*CJUphhD5B*CJph%jhDhD5B*CJUph hDCJ hG"CJ h|Cx5CJ h|CxCJh:]|h|Cx0J>*CJjh:]|h:]|CJUjh:]|h^-CJUh:]|h:]|CJղ%.7qzdz &_IJtu`gdU#gdU# & Fd ^`^ijųƳ   $%&67WXY\]^_mnIJu¬–€ynbnhU#h|Cx5CJaJhU#h|CxCJaJ h|Cx5CJ+jhDhl5B*CJUph+jhDhl5B*CJUph+jjhDhl5B*CJUphhD5B*CJph h|CxCJ hDCJ%jhDhD5B*CJUph#hDhD0J5>*B*CJph%uDEfr$ 7$8$H$^ & F[7$8$H$7$8$H$ & F7$8$H$ ^`gdU#^gdU# h^`hgdU#gdU# ^`gdU# & FdgdU#Ef#ʷܷ޷'2=?JNVcpɸʸظ!NO׾׸׸׸תיייייף׃} hnCJ h|Cx>*CJhMWhMWCJ hMWCJhMWh|Cx5CJ h|Cx5CJhMWh|Cx56CJaJ hG"CJ hn8[CJhnh|Cx5CJhU#h|CxCJ h|CxCJh|CxhU#h|Cx5CJaJhU#h|CxCJaJhU#CJaJ-ʸ02r@нҽ 7$8$H$` & F h^`h & F 88^8gd H & F`gdU# & F[gdn & F[7$8$H$gdn2HJĺܺ.0BFH@jp̽νҽ!/67bjzǸ޲ެ׬ެަޠޠަސޠhnhIW5CJ hn8[CJhIWh5CJ hIWCJ hCJ h"CJ hG"CJh:]|h|CxCJ h:]|CJh:]|h:]|CJ h:]|5CJ h|Cx5CJ h|CxCJhU#h|Cx5CJaJ hU#h|Cxhnh|CxCJ4{#!eKz{K 7$8$H$^gdS 7$8$H$^gdS 7$8$H$^gd & F7$8$H$ 7$8$H$^ & F7$8$H$++-12cdeiKTfy{$%&úx"j/h|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJH* h|Cx6CJhU#hCJhh|CxCJhhCJhh5CJ h|Cx>*CJ h|Cx5CJ hCJ hG"CJhh|Cx5CJ h|CxCJ+&12KT $GPABFGLU[ݢݢݢݐyohhnp >*CJ hCJ hG">*CJhnp hnp >*CJ hnp CJ jhZH}hZH}CJ hZH}CJh|Cx h|Cx5CJ *h|Cx5B*CJph hOCJ h|CxCJH*hU#h|CxCJ h|Cx5CJ h|CxCJjh|CxB* CJUphh|Cx0J>*B* CJph*#L G ABM 7$8$H$`gdq 7$8$H$^gdU#7$8$H$ 7$8$H$^gdS & F pp7$8$H$^pgd H7$8$H$^`gdSij(Ekd$$Ifl0@$4 la $7$8$H$If !$7$8$H$If7$8$H$ 7$8$H$^ 456>?AB]^_fghiju FPUZ\^giqީ hMWCJ h|Cx5CJhG"h h|Cx5h|Cx h|CxCJjhZH}h/FCJUhZH}hnp CJhZH}hnp 0J>*CJjhZH}h/FCJUhZH}hZH}CJjhZH}hZH}CJU hnp CJ hG"CJ0hEkd\$$Ifl0@$4 la $7$8$H$IfEkd$$Ifl0@$4 la F\]^i#1hbTJJ & F7$8$H$hh7$8$H$^h`h7$8$H$Ekd$$$Ifl0@$4 la $7$8$H$IfEkd$$Ifl0@$4 la"#()014 9CflճճթբճճճճՖՖvo h|Cx5PJ h|Cx0J>*CJjh|CxCJUjh|CxCJU hKCJ hqCJ hq5CJhqh|Cx5CJ h|Cx5CJ hn8[CJ hMWCJhMWh|Cx5B* CJph3 h|CxCJhn8[B*CJphhMWh|CxB*CJphhMWhMWB*CJph)1 9f~2jk~LL & F^gd*8 & F^ & FgdlV & F^` & F^ ` & F 7$8$H$^ & F7$8$H$29-.RSThij~JLRT\bfpvz|L;ztzntnzhzhzn hIquCJ h*8CJ h/UCJh*8h*8CJ h*85CJ h_}5CJhKhlV5CJH* hlV5CJ hvX\5CJhKhK5CJ hlVCJhh|Cx0J>*CJjhhB=CJUhhCJjhhCJU h|CxCJ h|Cx5CJ h|CxPJ (;4v!O{ p7$8$H$^pgdS 7$8$H$^gdS 7$8$H$^gdS & FgdlV7$8$H$^` & F^ & FgdlV & F^gd*8;>DEFIJKLNQSX[^gruv4:;<?@DG񺴺ڞ񺕎{qqhKhlV5CJ jhlVhlV5CJ h|CxCJ h|Cx5CJhKh|CxCJ h*85CJhKhKCJ hn8[CJ hlVCJ hKCJ h_}5CJhKhK5CJH* hvX\5CJhKhK5CJ jhKhK5CJ hK5CJ hlV5CJ)GINQST\cuv{|}!>Gz{.<IQ  jh|CxCJmHnHu hn8[CJ h|Cx5CJ h|CxCJhKhlV5CJ hvX\5CJ hlVCJ jhlVhlV5CJhlVhlVCJ h\ CJ hYoCJ hYo5CJ h_}5CJ hlV5CJhKhlV5CJH*4"[\6 .<*a p7$8$H$^pgdS & Fp^pgdS7$8$H$^`gdS 7$8$H$^gdS & F^gdS p7$8$H$^pgdU# bhqu.]~$9oɿɟvjhTh|CxCJUaJhTh|CxCJaJhThCJaJh|CxhUh|Cx0J5>*CJ"jhUhs>L5CJUhUhU5CJjhUhU5CJU h|CxCJH* h|CxCJH* hn8[CJ hG"CJ h|CxCJ h|Cx5CJ+ab\q.Dw p7$8$H$^pgdS 7$8$H$^gdS7$8$H$^`gdS 7$8$H$^gdS D\]~#$9^gdT^gd^gd^gd & F^gdS & F^gdS 7$8$H$^gdS7$8$H$^`gdS 7$8$H$^gdSYbhivw9޷޷޷޷{m޷bWhTh hCJaJhTh CJaJhThG"0J>*CJaJ#jhTh|CxCJUaJhTh|CxCJH*aJhTh|Cx5CJaJ#jfhTh|CxCJUaJhTh|CxCJaJhThn8[0J>*CJaJhTh|Cx0J>*CJaJjhTh|CxCJUaJ#jhTh|CxCJUaJ"Y.=UVvv^gd%'gdU#^gd & F^gd^gd & FgdT^gdT "(.@FR~|~ 25}~ħ铧wl`lhTh|Cx>*CJaJhThTCJaJhThT5CJaJhTh|Cx0J5>*CJaJ&jNhTh5CJUaJ jhTh|Cx5CJUaJhTh 5CJaJhTh|CxCJaJhTh|CxCJH*aJhTh|Cx5CJH*aJhTh|Cx5CJaJhTh CJaJ"-./:;<=>?Uuv  \^`򮪢vjh|CxUjh|CxUh|Cx0J5>*CJjh|CxUjh|CxUh|CxhU#h|Cx5CJaJ h|Cxh h hCJjh|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJ.`rtvx >LNxz VWhnopucӼӚӎӀӀȀӎ jh%'h}jCJaJh%'h}j5CJaJh%'hK4=CJaJh%'hV(sCJaJh%'hV(s5CJaJh%'h|Cx5CJaJh%'h}jCJaJh%'h|CxCJaJjh|CxUh|Cxjh|CxUh|Cx0J5>*CJ-<>zibcz{4 ^`gd%'^gd%'^gd%' & F]gd%'gd%'cz49-89EH7F !"?M ./0,- !ѻѬњh%'h|Cx0J>*CJaJ#jh%'h|CxCJUaJjh%'h|CxCJUaJh%'hV(sCJaJh%'h_}CJaJh%'h|CxCJaJh%'h|Cx5CJaJh%'h%`CJaJh%'h%`>*CJaJ767F >?O  /- ^`gd%'^gd%'^gd%'*I3CR ^`gd%'^gd%'^gd%'!,4AYZ  "fs9st)*NOefgvwl h#CJjh|CxCJU hn8[CJh|Cx0J>*CJjfh|CxCJUjh|CxCJU h%'CJ h|CxCJ h|Cx5CJh%'h|Cx5>*CJaJh%'h|CxCJH*aJh%'h|CxCJaJh%'h|Cx5CJaJ2:lo57$8$H$^`gd|~ 7$8$H$^gd|~ & F 7$8$H$gd|~ & F^gd|~ & F 7$8$H$gd|~ 7$8$H$^gd.C 7$8$H$^ 7$8$H$`7$8$H$or6yz@C\egl34IPQZ[_afhùͥ h|~CJ h|CxCJH* h|~5CJh.Ch|Cx>*CJh.Ch.C>*CJ h.CCJ h hCJh|~h|CxCJ hG"CJ h|CxCJ h|Cx5CJh|~h|Cx5CJ?5z@\gl3P7$8$H$^` & F 7$8$H$ 7$8$H$`gd|~ 7$8$H$^gd|~ & F 7$8$H$gd|~ 7$8$H$^gd|~M N V       # , 7 9 C O P                 4 = ֲϋyooho^h<Wh<W5CJ h|CxCJH*h<Wh|Cx5CJh<Wh|CxCJh<Wh<WCJ h<W5CJ h)CJh)h|CxCJ h)5CJh)h)5CJh)h)CJ hG"CJh)h|Cx5CJh|Cx h|Cx>*CJ h|CxCJ h|Cx5CJ h|~CJ h#CJ h.CCJh.Ch.C5CJ$VM N        D E g  M  & F^gdS & F^gdSgd%' & F & F` & F & F^gd) gd.C7$8$H$?7$8$H$^`? 7$8$H$^ & F 7$8$H$gd.C= D G H X Y Z                # 8 ; C D E O P g h         M Q     DJLa>MQjlmƿƹ򹨹ƒh)h)CJ h|Cx6CJ hn8[CJh)h)>*CJ h|Cx>*CJ h)CJ h)5CJ h|Cx5CJh|Cxh<Wh<W5CJh<Wh|Cx5CJ h<WCJ h|CxCJH* h|CxCJ h<W5CJ9M  D=>I#$Q & F 8^gd H & F^`gdS & F^gdS & F^gdSmntuvw~IR $/0ADFGHfghqrv3QZ[ *h|CxCJh)h)6CJh)h|Cx6CJh|Cx0J>*CJj<h|CxCJUjh|CxCJUh|Cx56CJ h|Cx>*CJ h|Cx5CJ *h|CxCJ h|Cx6CJ hn8[5CJh)h|Cx5CJ h|CxCJ6[b   BC[i{ '2y'34Aɹҭ jh|CxCJh4h|Cx0J>*CJjh4h;CJUh4h4CJjh4h4CJU hn8[CJ h|Cx6CJ hQCJ h|CxCJ h|Cx5CJ@Yz{_4Zy @ ^@ `gdS ^`gdS ^`gdS & F^`gdS & F^gdS(VeuAg =} ^`gdS ^`gdS^gdSp^pgdS@ ^@ gdS @ ^@ `gdS p^p`gdSAJgp l|~ BC]^_fghμخwnwhn8[0J>*CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx>*CJ h|Cx5h|Cx h|Cx6CJh|Cx0J>*B* CJph"j*h|CxB* CJUphh|CxB* CJphjh|CxB* CJUph hn8[CJ h|Cx5CJ h|CxCJ hQCJ+}~Bggd8 & F^`gdS & F^gdS & F^`gdS ^`gdS ^gdS & F^gdShi./7:gp34589;<RSTXY[\qrsvwyzjh|CxCJUjqh|CxCJUjh|CxCJUjh|CxCJU h|Cx5CJh|Cx hQCJ h|Cx5CJh|Cx0J>*CJj"h|CxCJU h|CxCJjh|CxCJU7m0vw3k & Fh^h`gd\ & Fh^`hgd\ & F^gdS & F8^8gdS & Fh^hgdS & F & Fmv!"09wb d       !#!u!v!!!!!E"L"M"["""ټٵٯ٨ټ٢ٜ h=^CJ hQCJ h|Cx>*CJ hCJ h|Cx6CJ hn8[CJ hZCJhZhZ5CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjEh|CxCJU<   !!!M"""""##2$3$C${$|$ & F8^8`gdS & F^gdS & Fh^hgdS & F? p  ^ gdCjR & F8^8gdS & F8^8gd\ & Fh^h`gdS"""""##3$C$|$$$$$$$ %%%%f%t%%%%%%%%%&&X''((B(Z(_(m(((((())))))H*b*c*m*޹޲ަޝ h45CJhJQhJQCJ hJQCJ hZCJ hZ5CJ *h|Cx5CJhZh|CxCJhZhZCJhZh|Cx6CJ h|CxCJ h|Cx6CJ h|Cx5CJ h=^CJ h=^5CJ6|$$%%&((n(())) *G*H*c*+c+d+~+7$8$H$ h7$8$H$^hgdS & F^gdSh7$8$H$^h`gdS 87$8$H$^8gdS & F8^8gdS & Fh^hgdSm*n******%+4+E+P+d+~+++*->-|-}------....%.&.'.G.H.I.W.X.Z.[.|.}.~......ǹǹǹdzǩǜǍǩǀǩsǩj_h|CxCJUjh|CxCJU h|CxCJ(h|Cx0J>*CJjMh|CxCJUjh|CxCJU hn8[CJ h|Cx>*CJ h|Cx5CJ h|CxCJh4h|Cx0J>*CJjh4h;CJUh4h4CJjh4h4CJU-~+++;,s,--?-...%.&.F/G/\/// & F8^8gd  & Fh^hgdgd8 & F gd.C & F & F p7$8$H$^gd & F7$8$H$ 7$8$H$`7$8$H$............/////&/'/)/*/?/@/A/D/E/F/\///////////////000)0*05060:00ٿٲٮ٧١ٚ١٧ن٧٧٧ hn8[CJ h_}5CJ hQ5CJ h|Cx>*CJ hgvCJ h|Cx5CJh|Cxjah|CxCJUjh|CxCJUjeh|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU2///00600000"1#1@1r112-3 & F^gd.C & F^`gd.C ^gd.C & F^gd.Cgd8 & F & F^gd & F8^8gd8^8gd & Fh^hgd00000001111 1#1@111111222-3.3Q344a4445565Y5Z5l5m5n5555տ߹߹߳}s}fsj3h|Cx5Ujh|Cx5U h|Cx5 h%CJ h?_CJ h`^ CJh`^ h`^ 5CJaJhP5CJaJh.Ch.C>*CJ h.CCJ hQCJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJh|Cx h|Cx>*CJh8h.CCJ'-3.3Q3R33344a4c4455565Y5Z555g6h66  & F^gd.C & F^gd.C  & F^gd.C & F^gd.C & F^gd`^ gd`^  & F@ ^@ `gd.C & Fgd.C555555X6Y6g6h6t6u6v666666666 7 7\7h73848C8x8888888888˹޳޳ޭӧr`#hh0J5>*B*CJph+jhh$&%5B*CJUphh5B*CJph%jhh5B*CJUph hCJ h.CCJ hn8[CJ h|Cx0J>*jh|CxUjh|CxU h|Cx5CJhn8[ h|CxCJh|Cx h|Cx5jh|Cx5Uh|Cx0J5>*%67\748x88=9999:1;p;e<<<8=:=e====>>`> & F gd.C & F^gd.C & F^`gd.C & F^gd.C8=9>9e9f9g9}9~9999:::::::::::;;1;7;p;y;;;;;;;;<<<e<n<<===&='=(=5=6=7=8=:=>=@=A=W=X=ĸjlh|CxCJUjh|CxCJU hn8[CJh|CxB*CJphh|Cx5B*CJphhQ5B*CJph h|Cx5CJh|Cx0J>*CJj"hZ )hCJUjh|CxCJU h|CxCJ8X=Y=b=c==========>;><>=>R>S>T>]>^>>>???(?????1@F@G@H@]@^@_@o@p@q@r@@@@@@@AAA*A+Aߔj$h|CxCJU hn8[5CJh|Cx h.CCJjh|CxCJUh|Cx5B* CJph h|Cx6CJjRh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJU5`>>>>>5?@?W???0@1@r@@@?AAAAA/B0BBBgd[T & Fgd8 & F^gd.C & F^`gd.C & F^gd.C+A,AA?A\AaAAAAAAAAAA/B0BBBCBDBEBFBjBkBlB~BBBBBBBBBBBBBBBߺȍn%jlh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphjhZ )hCJUjh|CxCJU hd5CJ h|Cx5CJ h|Cxjh|CxCJU hDECJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJU)BBBBBCCCCCCC/C0C1C4C5C7C8CMCNCOCRCSCUCVCsCtCuCCCCCԱĢԏĢ|ĢiĢ_h|CxB* CJph%j&h|Cx5B* CJUph%jh|Cx5B* CJUph%jTh|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphjh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph BCSDTDUDDDEESEEEErFFHHGHHHjH@JAJNJOJ^gd?<^gd?<^gd.C & F^gd.Cgd8^gd.CCCCCCCCCCCCCCCCCCCCCCCDDDDDDD.DѸzgzTz%jh|Cx5B* CJUph%jh|Cx5B* CJUphh|Cx0J5>*B* CJph%j&h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUphh|Cx5B* CJph.D/D0D3D4D6D7DLDMDNDQDRDSDUDeDgDhDDDDDDDDDDܤ~l~^~UKBhdhdCJhdhd5CJhdh|CxCJh8h|Cx0J>*CJaJ#jAh8hCJUaJjh8h|CxCJUaJh8h|Cx>*CJaJh8h|CxCJaJh|CxB* CJph%jh|Cx5B* CJUphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%joh|Cx5B* CJUphDDDDDDEEEE!E"EKELEMEPEQESE\EEEEE F(F)FFFF龷pl`U`UJU`Uh?<hn8[CJaJh?<h|CxCJaJh?<h|Cx5CJaJh|Cxh|Cx0J5>*B*CJph+jhh$&%5B*CJUphh5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJhdh|Cx5CJ hdhd0J>*B*CJphjhdhc CJUhdhdCJjhdhdCJUFF G G_GdG|G}G~GGGGGGGGHHHHHHH$H%H&H'H9H:H;HDHEHGHĵģĵăwsks`kWksh|Cx0J>*CJjh|CxUjh|CxUh|Cxh?<h|Cx5CJaJ#jh?<h?<CJUaJh?<h?<0J>*CJaJ#j,h?<hSCJUaJjh?<h?<CJUaJh?<h?<CJaJh?<CJaJhv7CJaJh?<h?<CJaJh?<h|CxCJaJh?<hDECJaJ GHjHHHII/J0J:J;JAJNJOJrJsJJJJJJ.K4KGKIKJKvKwKxK{K|K}K~KKKŲ{ucVhshsB*CJph̙"jhshsB*CJUph̙ hsCJ#hy<hy<0J5>*B*CJph+j9hy<h'5B*CJUphhy<hy<5B*CJph%jhy<hy<5B*CJUph hy<CJ hDECJ h`CJ h@5CJ jh|CxCJmHnHu h.CCJ h|CxCJ h|Cx5CJ!OJJJZLLIMMNN(NONPNdNeNNNN`OOO & F^`^gd8gd8 & F`gd.C & F^gd.C ^`gd.Cp^pgd.C^gd.CKKKKKKZLaLbLiLLLLLIMRMMMMMNNN(NPNdNeNNNNNNNNNNNNN¼{thh8h|Cx>*CJaJ h|Cx0J>*jh|CxUjh|CxUh|Cx h hCJ hho;CJhho;hho;CJ hho;5CJ hn8[5CJ h|Cx5CJ h|CxCJ hsCJ hshs0J>*B*CJph̙"jhshsB*CJUph̙(jhshfgB*CJUph̙&NOOO)O*O+O@OIOJO`OiOkOlOOOOOOOOOOO:P;PRPSPTPYPZP[PnPPPPŻ|sc|__h|Cxjhkoh$CJUhkoh|CxCJhkoh|Cx0J>*CJjhkoh$CJUhkohkoCJjhkohkoCJU h|CxCJ h|Cx5CJhkohko0J>*hkoh|Cx0J>*jhkoh$>*Uhkohko>*jhkohko>*U h|Cx>* h|Cx5>*#O[PnPPP'QtQuQQQQHRRR SESSS+TT  & Fgdko & Fgdko & Fgdko ` & F gd. & F` & F^` & F^PPPPPP'Q,Q.Q/QUQVQWQbQcQuQQQQRFRiRjRRRRRRRRRRܽ汞ygQ+jRh.hb*5B*CJUph#h.h.0J5>*B*CJph+jh.hb*5B*CJUphh.h.5B*CJph%jh.h.5B*CJUph h.CJ hkoCJh|Cx0J>*CJjhZ )hCJU hCJjh|CxCJU h|CxCJ h|Cx5CJh|CxhUQhUQ5RRRRRRRR SDSESFStSuSvSSSSSS+TLTSTT$U0U*CJaJ#jhZ )hCJUaJjhkoh|CxCJUaJhkoh|CxCJaJhkohkoCJaJ h|Cx5h|Cx h|CxCJ h.CJ#h.h.0J5>*B*CJph%jh.h.5B*CJUph"T$UUtVuVVVV[WsWWW)XX:YZZ[n[ & F^gd.C & F^gd.Cgd[T 8^8`gd8^gd8 & F  88^8gdQ^gd8 ^gdko ^gdkoUtVuV|VVVVVVOWPWZW[WjWrWsWWWWWWWWWWWWWWWWWWXXX&X'X9X;XXXYվɾ}tm h|CxCJH*h|Cx0J>*CJjh|CxCJUjh|CxCJU hn8[CJ h|CxCJ h|Cx5CJhkoh|CxCJaJh8hkoCJaJh8h|CxCJaJh8h|Cx5CJaJh8h8CJaJh8h\ >*CJaJh8h|Cx>*CJaJh8h|Cx*YY3Y4Y5Y8Y9Y:Y=Y?Y@Y^Y_Y`YlYmYYYYYYYYYZZGZżŠzne[U hqCJjhqCJUhQ2h|CxCJhQ2h|Cx0J>*CJj- hQ2h/FCJUhQ2hQ2CJjhQ2hQ2CJUhGh|Cx0J>*CJj hGh CJUhGhGCJjhGhGCJU h|Cx5CJh|Cx0J>*CJjI h|CxCJU h|CxCJjh|CxCJUGZHZIZXZYZZZ`Z[ [n[[[[[[[[[[[\/\0\;\b\g\k\r\{\\\\\]]])]9];]>]?]@]E]G]L]N]R]}]]]]]]^^)^.^3^9^^^___(_̿ӹӹӳӳӪӪӪӪӪ̣ hn8[5CJ *h|Cx5CJ hSYGCJ hXCJ h7CJ h@5CJ h|Cx5CJ h|CxCJhHh|Cx0J>*CJjhqCJUj hZ )hCJU@n[o[[[[{\\\N]}]]]^^__ aaDa & Fgd' & F p^gdSYG & Fp^pgd.C & F^`gd.C & F^gd.C & F^gd.C^gd.C(_V_e_f_o_______`^`h````` aaaaa#a&aCaDayazaaaaaaab$bObPb۰yrke hb{CJ hb{5CJ h'CJH*h'h'>*CJh'h'5>*CJh'h'CJhSYGh'5>*CJh'hSYG5>*CJ hSYGCJ h75CJ hn8[CJ jhSYGhSYGCJ hB='CJ hDECJ h|Cx5CJ h'CJ jh\ h\ CJ h\ CJ h|CxCJ&DazaaabPbQbbbbbccc,dSde & F^gdSYG & F^`gdSYG & F^gdSYGp^pgdX^gd.C & F^gd.C & F^`gd.C & Fgd' & Fgd.C & Fgd#PbQbTbbbbbbcc(c8c9cQcecfchccccccccccccccccdSdfdddddde-e0eeeeeeef f,f5f;f*CJ h@CJ h@5CJhXhXB* CJph hXCJ hreqCJ h|Cx>*CJ hn8[CJ hn8[5CJ h|CxCJ h|Cx5CJhb{hb{CJ6ee*CJj h|Cx5CJUjh|Cx5CJU#h,oh,o5B* CJ\aJph h,oh|Cx5B* CJaJph h|Cx6CJ h|Cx5CJj( hZ )hCJUh|Cx0J>*CJji hZ )hCJU h|CxCJjh|CxCJUh|CxB* CJphh|Cx5B* CJph#hhhhhhhhhhhh i i iii5i*B*CJph+jn hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h,o5CJh|Cx5B* CJph h|CxCJ h|Cx5CJ#cjojpjjjjjjjjjjjokxkzkkkkkkkkkkll l'l(lllllllllllٴƩࣗم|o|jh)J^h)J^CJUh)J^h)J^CJ h)J^5CJhS{h|CxCJaJhS{h|Cx>*CJaJ h(CJh|Cx0J5>*CJ"jthZ )h5CJUjh|Cx5CJU h|Cx>*CJ h|Cx5CJ h|CxCJjh(h(CJUh(h,o0J>*CJ'lllllmmmmmnlnmnnnnIowoxogd[T & F^`gd[T & F^gdSYG & F^gdSYG & F^`gd2f & F^gd2f & F^gd2f & F & Fgd(llllllll3m5mmmmnnnnnnnnnnIowoxooNpTpVpWpppqprpypzp|p}pú|rer\rrh|Cx0J>*CJjh|CxCJUjh|CxCJU h[Th[ThS{hSYGh|Cx5CJh2fh|Cx6CJhS{h|Cx>*CJaJ h|Cx5CJ h2fCJ h|CxCJh)J^h|CxCJh)J^h|Cx5CJh)J^h)J^CJh)J^h)J^0J>*CJjh)J^h)J^CJUj9h)J^h{CJU$xooNpp?qXqqqq7rfrrrsbsssssgd8@ ^@ gd[T ^gdSYGp^p`gdSYG & F^`gdSYG  & F^gdSYG & F^gdSYG & F^gdSYG}pppppppppppppppppppppppp?qFqXq_qqqqqqqqqqq7rArr|nh hS{CJh|Cx0J>*B* CJph"j^h|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx h|Cx5 h|Cx5CJjh|CxCJUh2f0J>*CJj~h|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ(rrrssbsfsgshsssssss(t)t>t?t@tTtUtWtptt uu%uLu_u`uvuwuͽ๲sle[T h|Cx>*CJ h|CxB* CJph h|Cx>*CJ h|Cx6CJh|Cx0J>*B* CJph"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJ h|Cx5CJh2fh[Th|CxCJaJmHnHu% jh[Th|CxCJaJmHnHuh[Th|CxCJaJ jh|CxmHnHu h|Cx5h|Cx sssVtWtptt^u_u`uvuwuuuvvfwwZx]xx8^8gdS{ & F8^8gdS{ & Fh^hgdS{ & F  & F & F^gdSYG & F^gdSYGgd8wuxuuuuuuuuuuuuuuuuuuuuuuuuuuuuuuvvvvvvvvvvvvvvvww󲬲yjhZ )hCJUh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|CxCJ h|Cx5CJ hn8[0J>*jkh|CxUjh|CxUjh|CxU h|Cx0J>*j2h|CxUh|Cxjh|CxU/www1w2w3wAwBwDwEwZw[w\wdwewfwowwwwwwwwwww*CJj^hUhs>LCJUhUhUCJjhUhUCJUhUh|CxCJ h|Cx5CJjh|CxCJUh|Cx0J>*CJjvh|CxCJUjh|CxCJU h|CxCJ*xxxxx y!y"yyyyyyyzz^z`zrz ^`gdJIgd}`gd. & F  & Fh^hgdS{ & FX^`XgdS{ & F8^8gdS{ & F8^8gdS{\y]yyyyyyyzzzzzz@z\z`znzrztzvzzzzzzzzzzzzz̾{si\i\i\i\i\i\iU h}6hh}h}56>*hh}h}6hh}56hh|Cx56hhJICJaJh}h}CJH*aJh}h}CJaJh.CJaJh}CJaJh}h}5aJhhh}>*CJaJhhh|Cx>*CJaJh h}CJhh|CxCJ aJ h|Cx h|CxCJjh|CxCJU!zzz{{{{,{.{B{D{F{}~~(~~~~~~~~~~~~~~GJKLRTVwǺǺDztkk_h3/h>*CJaJhJICJH*aJh}hJICJH*aJh}hJICJaJhJIhCt5CJaJhJIhCtCJaJhCtCJaJhJICJaJh|CxCJaJ h|Cx5CJ h}CJ h|CxCJ h|Cx5h h,o6hh}h}6h h56h h}6hh}h}56>*h$rzF{H{{|@|X|o|||}q}}}}~e~~~~~~^gdCtgd^gd ^`gdJI ^`gdJI^gdJI^gdJI~~~~~*+uvw  01AB^gd.`gd.gd.^gd8^gd. & F gdJIgd`gdCt ^`gdCt p^p`gdCt    "ںں|h]UJ?h.hCtCJaJh.hJICJaJh.CJaJh.hCJaJ'h3/h3/0J5>*B*CJaJph/jRh3/h3/5B*CJUaJph h3/h3/5B*CJaJph)jh3/h3/5B*CJUaJphhJICJaJhJIhJICJH*aJhJIh3/CJH*aJh3/h3/CJaJh3/hCJaJhCJaJh3/CJaJ"/1A56JłƂ΂ς   >ѾѺypj]jfh|CxCJU hn8[CJh.h|CxCJ h|Cx5CJ h.5CJ h.CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJh|Cxh.CJaJh.h,oCJaJh.h|CxCJaJh.h|Cx5>*CJaJh.h.CJaJh.hJICJaJ$45_` JƂǂ=>de  & F^ & F` & F ^`gd^gdgd8gd. ^`gd.>Mbc΃҃'+1289@CILOPTUjk~քڄۄ݄ʅͅ򩝓 haCJhaha5CJhah|Cx5CJH*hah|Cx5CJ hh{5CJ jh|CxCJ jh|CxCJmHnHu hh{CJhC)hC)CJH*hC)h|CxCJH* h|CxCJH* h|CxCJ h|Cx5CJ3 &'OPzv'34^gd & F^gd ^`gd & F^`gd^gd & F^gd & F^ & F^ & F^`ͅ΅օ',MNxyz 4:;>?ABNY[\}~LJȇǷЫТЫsl h|CxCJH*hh{hh{0J>*CJjhh{h;~%CJU hn8[CJ hh{CJ h|CxCJH*hh{h|CxCJhh{h|Cx0J>*CJjhh{h;~%CJUhh{hh{CJjhh{hh{CJU h|Cx5CJ h|CxCJhah|Cx5CJhah|Cx5CJH*(4P@ tӉ$+7TՋt & F pp^pgd H & F^gd & F^gdh{^gd & F@ ^@ gd & F@ ^@ gdh{ & Fp^pgd^gd^gd>?@A`a 34TUklmqrtyƉщӉDEwxy݊*+4R_ۋtví hh{CJ hn8[CJh|CxCJmHnHuh|Cx h,oCJh|Cx0J>*CJj5h|CxCJUjh|CxCJU h|Cx5CJ h|CxCJH* h|CxCJH*h|Cx5CJH* h|CxCJ jh|CxCJmHnHu7tvT&'cӎ;ѐҐڑ^gd.^gd. ^`gd.`gd.gd.v  '68EbcƎǎ !"z{ɏˏ̏ϐА"$+甦{{h.h,oCJaJh.h|Cx0J>*CJaJ#jh.h|CxCJUaJjh.h|CxCJUaJh.h|CxCJH*aJ jh.h|CxCJaJh.h|CxCJH*aJh.h|Cx5CJaJh.h|CxCJaJh.h|Cx5>*CJaJ-&EQRstu7LlmvƻƛՒ{oib[b hn8[5CJ h|Cx5CJ h|CxCJh.h|Cx>*CJaJh.hCJaJh.h|Cx6CJaJh.5CJaJh.h|Cx0J>*CJaJ#jh.h{CJUaJh.h)J^CJaJjh.h)J^CJUaJh.h|Cx5CJaJh.h|CxCJaJ% jh.h|CxCJaJmHnHuڑՒ%&mߔ6/0=> & F^`gd. & F^gd. & F^gd & F^gd.gd.`gd.AB_`abjmno{|-0<=>μٮ~ocTM h|Cx5CJh.h.CJ OJ QJ aJ h.CJ OJ QJ aJ h.h|CxCJ OJ QJ aJ h.h.CJaJh.h85CJaJh.h|CxCJaJh.h|Cx0J>*CJaJh.h80J>*CJaJ#jh.h;~%CJUaJh.h5kCJaJjh.h5kCJUaJh.h8CJaJh.h.5CJaJ>Jo|Η@:ǙaFz( & F & F & F^ & F ^ & F^ & F^` & F``gd.ӖԖՖ89:HIJSozΗїҗDEۯ۟ۏxnx j *h|CxCJ *h|CxCJ jh|CxCJ h|Cx5CJjjht:h CJUjht:h CJUjht:h CJUht:h|Cx0J>*CJjht:h CJUht:ht:CJjht:ht:CJUht:h|CxCJ h|CxCJ+Ev:Ilmoyz{}ǙЙҙۙaeFYz~(3Ý  %;EFGhstuwz|}ʞ͞מ؞=Ľ˽Ľ h4CJH* h4CJH* h4CJ h|Cx6CJ h|Cx>*CJ h|CxCJH* h|CxCJH* h|Cx5CJ h,oCJ h|CxCJJF؞iBG & F^gd.gd8 & F h^gdQ & F & F^gd4 & F` & F^=>Z[\ghirtBRT]abvwޠߠDEǺǴǴǪǚǪDŽ}vǴmh;5>*CJ h|Cx6CJ hv6CJj'h|CxCJUh|Cx0J>*CJj^hZ )hCJUjh|CxCJU h;CJ h4CJ h|Cx5CJ h|CxCJhFXh|Cx0J>*CJjhFXhCJUhFXhFXCJjhFXhFXCJU*ENOYZabqrҡGM͢ 0<Wo ,KW]^_²߈߫z hn8[5CJ h|Cx>*CJ h,o>*CJh|Cxh8h|Cx>*CJaJh8h,o>*CJaJ h|Cx6CJh.h|Cx5CJ$OJ QJ aJ$ hvCJh;h;CJ h;5CJ h|Cx5CJ h|CxCJ jh;h;CJh;5>*CJ h;CJ00WL;<`ڥ  & F^gdgd8 & F^`gd & F^gd & F^gd & F & F^gd._Ȥ̤ͤդ<`¥ڥ9:GHIbzƦͦϦئڦ(>@Jbdȧɧʧѧ  #$KTXݨ˻Ѱh|CxB* CJph h|Cx6CJh|Cx5B* CJphh(h|Cx0JCJjh(hCJU h(CJjh(CJU h8z^CJ h|Cx>*CJh|Cx hn8[5CJ h|Cx5CJ h|CxCJ99:Gabz٦ڦ?@dɧ#$KݨiMN & F^gd & F^gd & F"%ivyѩNfªȪ@MW_dgʫ۫ܫ  !FGHPQȼ剙h|Cx0J>*CJj! hZ )hCJUjh|CxCJU h,o5CJ h,oCJh.h|Cx5CJ aJ hn8[5B* CJphh|Cx5B* CJphh|CxB* CJph h|Cx5CJ h|CxCJh) h|Cx5CJh) h) 5CJ24ȫɫʫ۫ܫ.  8r & F` & F^ & Fgd. & Fgd. & F^gd & F^gd & F^`gdQST}~ح8Ir{~567?@vw*`mntӱh|Cx6>*CJhh|Cx5CJ$aJ$ jh|CxCJmHnHuj"h|CxCJUj!h|CxCJU h|Cx6CJ h|Cx5CJ h,oCJh|Cx0J>*CJj hZ )hCJUjh|CxCJU h|CxCJ4r+_`mnu? 8^8gd h^h`gd & F h88^8gdQ & F h88^8gdQ & Fh^hgdgd & F^ & F` & F^ӱ34JUoβ CDYZ[rsϳг¹πtϐh/h/0J>*CJj#h/h/FCJUjh/h/CJUh2rhh/0J>*CJjO#h2rhhLCJUh2rhh2rhCJjh2rhh2rhCJUh/h/CJ h/5CJ hn8[CJ h/CJ h|CxCJ h|Cx5CJ h|Cx6CJ'`b|~ & F`gdmf & F^gdmf & F^gd & F^gdU & F & F8^8gd8, & Fh^hgd & Fh^h`gd & F8^8gd 8^8gd )*<csɵʵ`ʺʴʴí×ÍzqazUzhUhU0J>*CJj4%hUhs>LCJUhUhUCJjhUhUCJU hUCJhUhU5CJ h|Cx5CJ hWh|CxCJ hWCJ hW5CJ h8,CJh8,h|CxCJ h|Cx5CJ h|CxCJ h/CJh/h/0J>*CJjh/h/CJUju$h/h/FCJU!`b|~5Eʸոָ&'2p?@abcstٺٺٺٺٯ룗ٺً|j|\|hmfh|Cx0J>*CJaJ#j%hmfh|CxCJUaJjhmfh|CxCJUaJhmfh|CxCJH*aJhmfh,o>*CJaJhmfh|Cx>*CJaJhmfh,oCJaJhmfh|Cx5CJaJ% jhmfh|CxCJaJmHnHuhmfh|CxCJaJ h|Cx>*CJ h|CxCJ h|Cx6CJ hU5CJ"W'pu}5Cjվ; & F^gd & F^`gd^gdmf^gdmf^gd & Fgdmftu}¼5>CjƱti]R]R]R]R]JB]hy;CJaJhmfCJaJhmfhmfCJaJhmfhmf5CJaJhmfh*:CJaJ'hmfhBA0J5>*B*CJaJph/j0&hmfh5B*CJUaJph hmfhBA5B*CJaJph)jhmfhBA5B*CJUaJphhmfhBACJaJhmfhBA5CJaJhmfh*:5CJaJhmfhy;5CJaJhmfhy;CJaJr39:EFJKOPSTYZck<=DE[\]uvw}~j>'h|Cx5CJUh|Cx0J5>*CJj&h|Cx5CJUjh|Cx5CJUh|Cx5CJ4OJ QJ hCJ h|Cx>*CJh|Cx5>*CJ hn8[CJ h|CxCJ h|Cx6CJ h|Cx5CJ8;qrkx<=(2 7$8$H$^gd^gd & F^`gd2=>lBDE[\   +,{^gdB.gd & F3gd^gd^gd !@ABJKLMNlmnuvwxy;ͯ͠ڔͅڔvڔj*h|Cx5CJUj)h|Cx5CJUh|Cx0J5>*CJH*j)h|Cx5CJUj(h|Cx5CJUj$(h|Cx5CJU h|Cx5CJ h|CxCJh|Cx0J5>*CJjh|Cx5CJUj'h|Cx5CJU-  )*+23456STU[\]^_}~Ǹڬǝǎpj,h|Cx5CJUj},h|Cx5CJUj,h|Cx5CJUj+h|Cx5CJUh|Cx0J5>*CJH*j+h|Cx5CJU h|Cx5CJh|Cx0J5>*CJH*h|Cx0J5>*CJjh|Cx5CJUj*h|Cx5CJU,   '(+,;T)+)*Bƺഈഁz h|Cx>*CJ h|CxCJH* h_}CJh|Cx5CJH* h|Cx5CJ h5CJj-h|Cx5CJU h|CxCJh|Cx0J5>*CJH*h|Cx0J5>*CJjw-h|Cx5CJU h|Cx5CJjh|Cx5CJUh|Cx0J5>*CJH*,{:;@AABNOo 7$8$H$^gdB. & F 7$8$H$^gd.^gd.^gdB. 7$8$H$^gdB.BNO[^_`ghrs&5²˦˝퐇{ljh|CxB*CJUph h#CJ hFuCJhFuhFuCJ hFu5CJ hn8[CJhh|CxCJhh|Cx0J>*CJju.hh%quCJUhhCJjhhCJU h|CxCJH* h|CxCJH* h|Cx5CJ h|CxCJhUh|Cx>*CJaJ'&5AXw A@ ^@ gdFu p^p`gdFu ^`gdFu 7$8$H$^gdFu 7$8$H$gdFu^gdB. 7$8$H$^gdB. 7$8$H$^gdB.   /01>?AVXAyGS;F|}ѽѽtn hn8[CJhUh|Cx>*CJaJ h_}CJ h|Cxh h,oCJ h|Cx5CJ h|Cx>*CJ *h|Cx>*CJ(j}/hPhHwB*CJUph h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(j.hPhHwB*CJUphhPB*CJph+AyFGTUgu1$7$8$H$^`gdU1$7$8$H$^gdU^gdFu ^`gdFu`gdFu 7$8$H$^gdFuWk4@sp1$7$8$H$^`gd{_1$7$8$H$^gdFu 7$8$H$`gdFu1$7$8$H$^gdU1$7$8$H$^`gdU1$7$8$H$^gdU 7$8$H$^gdU<=^_`mnpuvw)-./09CPȾțwpjwddw h#CJ heaCJ h|Cx>*CJ *h|Cx>*CJ h{_CJ jh{_h{_CJh{_h{_CJh|Cx0J>*B*CJph(j0hPhHwB*CJUphhPB*CJphjh|CxB*CJUph h|Cx5CJ hFuCJhFuhFuCJ hFu5CJ h|CxCJ h,oCJ')CR_l1< & F^gdB. & F`gdFu^gdFu`gdFu1$7$8$H$^`gd{_p1$7$8$H$^pgdFu1$7$8$H$^`gdea1:;<=z&(:>@jlnp  ت~rh(h(56CJh(h(6CJ h|Cx>*CJhB.h|Cx>*CJaJ h|CxCJh|Cx5CJH* h|Cx5CJ hB.CJH*hUh|CxCJH* h,oCJhUh|Cx5CJ hn8[CJ hUCJ hB.CJ h|CxCJH* h|CxCJH* h|CxCJ h|Cx5CJ,z(lZ35{ 7$8$H$^gd(7$8$H$^gdB. & F` & F p^gdQ & F^gdB. 345LM'()GHabcno78мЁxh\ShbXhbXCJhFuh|Cx0J>*CJj21hFuhCJUhFuhFuCJjhFuhFuCJUh &6h|CxCJh &6h|Cx0J>*CJj0h &6h CJUh &6h &6CJjh &6h &6CJU h|CxCJH* h|CxCJ h(5CJ jhhCJ h(CJ hCJh(h(6CJ*G7Ga>8 & F @ ^gdQ^gd`i<@ ^@ gd`i< ^`gdp^pgd(7$8$H$^`gd( ^`gd(7$8$H$^`gd(`gd(89QRSno345:;DEGQRabzj^zzThw hw 5CJhv_hn8[0J>*CJj2hv_hCJU h|CxCJ hCJhv_h|CxCJhv_h|Cx0J>*CJj2hv_hCJUhv_hv_CJjhv_hv_CJU hbXCJhhbX0J5>*CJ"j1hh5CJUhhbX5CJjhhbX5CJUbkl<>np48`bŻww߲qqkk\jh;h;5CJU h ?CJ hZ[CJhZ[hw CJhZ[hw 0J>*CJj3hZ[hCJUhZ[hbXCJjhZ[hbXCJUhZ[hZ[CJhZ[hZ[5CJ h_TCJhw h|Cx6CJhw hw 6CJ hw CJhw hw CJ hw 5CJhw h|Cx5CJ 8`_Z-1;] ^`gdFu7$8$H$^`gdw 7$8$H$^gdw 7$8$H$^gd( ^`gd( & F  xx^xgdQ p^p`gd`i<b ij"#%&GHIMNZ[Խ{k_{{O_{j4hZ )hCJUhv_hv_0J>*CJj3hZ )hCJUhv_hv_CJjhv_hv_CJU hv_CJhv_hv_5CJ jhw hw CJhw hw 5CJ hw CJh;hw CJh;hw 0J5>*CJjh;h;5CJU"jg3h;h$&%5CJUh;h;5CJ[19:;\]g DFHIůxqjjcjjj h|CxCJH* h|Cx5CJ hw 5CJhw hFuCJhw hw CJhw hic'CJ hw CJhFuhFuCJ hFu5CJ h|CxCJ hv_CJj5hv_hCJUhv_h|CxCJhv_h|Cx0J>*CJjhv_hv_CJUjX5hv_hCJUhv_hv_CJ&.D3|ZeQ ^`gdFu ^`gdFu 7$8$H$`gdFu 7$8$H$^gdFu7$8$H$^`gdFu7$8$H$^`7$8$H$^` 38|Zcgiop  IKQZ )*+45bcr̷퍄} h,o5CJhbXhbXCJ hbX5CJ hic'5CJ h(CJh(h(5CJ hFuCJ h\ CJh|CxCJmHnHuhFuh|Cx5CJ jh|CxCJmHnHu h|CxCJH* h,oCJ h_}CJ h|Cx5CJ h|CxCJ hw CJ0*cTlyw7$8$H$ & F pp7$8$H$^pgd ^`gdFu 7$8$H$^gdFu & F pp7$8$H$^pgd & F pp^pgd 7$8$H$^gd(7$8$H$^`gdFu p7$8$H$^pgdFu V(*.2:>BRTV02MX]^ȾȞȾzsle^ h|CxCJH* h|Cx5CJ h_T5CJ h|CxCJH*hFuh|Cx5CJ hFu5CJ hic'CJH* hic'CJ h(CJhic'h(0J5>*CJ"jZ6hic'h5CJUhic'h(5CJjhic'h(5CJUhbXhbXCJ hbX5CJ hbXCJH* hbXCJ h|CxCJ h_TCJ$^gklnpy{tuab!"|ulhFuhFuCJ hFu5CJ hE6)CJ h hCJ jh|CxCJmHnHuh|Cx0J>*CJH*h|Cx0J>*CJj6h|CxCJUjh|CxCJUh?Mh|CxCJH* h(CJ h(5CJ h|Cx>*CJ h|CxCJH* h|CxCJH* h|Cx5CJ hbXCJ h|CxCJ(=t;kId>n & F^gd(7$8$H$^`gd(p7$8$H$^p`gd( p7$8$H$^pgd( 7$8$H$^gd(`gd(7$8$H$n#S~' 7$8$H$^gdFu & F^gdFu p7$8$H$^pgdFu 7$8$H$^gdFu ^`gdFu 7$8$H$`gdFu 7$8$H$^gd( & F^gd(7$8$H$^`gd("#*SVYe#~"$'012  ;Pv.hFuhFuCJ hFu5CJ h|CxCJH*h|Cx5>*CJh|Cx5CJH* h|Cx5CJhB.h|Cx5CJ h,oCJ h|CxCJH* hn8[5CJ h|Cx>*CJ h|CxCJ h|Cx5CJ hFuCJ:Cuv`:p^pgdPp^pgd. ^`gd.7$8$H$^`gd.^gd.^gd.7$8$H$ 7$8$H$^gdFu.0378`i!:`a8@ABN!s|uuuuu h|Cx5CJ hFuCJhFuhFuCJ hFu5CJ hptCJ h;YCJ h.CJ jh(CJmHnHu h(CJH* h(CJH* h(CJ h(5CJh|Cx5>*CJ hn8[CJhB.h|Cx5CJ h|CxCJH* h|CxCJ h?MCJH* h?MCJ.78B!\] & F_ 807$8$H$`0gdCjR 7$8$H$^ 7$8$H$`7$8$H$@ ^@ gd.p^pgd. ^`gd.7$8$H$^`gd.^gd.p^pgd;Yst~.0AC\]SUXY]^`JNPfgj~(,z| h|Cx6CJ hFu5CJ h?MCJ h|Cx>*CJh|CxCJH*OJ QJ h|Cx5CJ h|CxCJH*h|Cx5CJH* h|Cx5CJ jh|CxCJ h|CxCJ h|CxCJH*=Q C\k{ ^`gd;Y7$8$H$^`gd;Y p7$8$H$^pgd;Y ^`gd;Y 7$8$H$^gd;Y & F_ 807$8$H$`0gdCjR 87$8$H$^$3Jg?}~ & F 7$8$H$^gd;Y 7$8$H$^gd;Y 7$8$H$^gd;Y p7$8$H$^pgd;Y @ ^@ `gd;Y p^p`gd;YDfBCK`oN1 ?7$8$H$^1 `?gd;Yp7$8$H$^p`gd;Y p7$8$H$^pgd;Y ^`gd;Yp^pgd;Y & F pp^pgd;Y & F ^gd;Y|~NPTV`df~?@BCIK`!NS )*27inᲩjh|CxCJU jh|CxCJhFuhFuCJ hFu5CJ h|Cx5CJ h(5CJ h|CxCJH*h?Mh?MCJH*h?Mh|CxCJ h|CxCJ h?MCJH* h?MCJ jh?Mh?MCJ9 2i+A| & F_ p@ 7$8$H$^@ `gdCjR 7$8$H$^gd;Y@ 7$8$H$^@ `gd;Y7$8$H$^`gd;Yp1$7$8$H$^pgd;Y7$8$H$^`gd;Y p7$8$H$^pgd;Y)*ABVWXdehp+-35GJLgxz| , / 1     ٿٿٸٿٱٛٿٿٸٿٸٿٿٸٿٸَٕ hFu5CJ hn8[CJ h|Cx>*CJ h|CxCJh|Cx5CJH* h|Cx5CJ h|CxCJH* h|Cx5CJ h,oCJj7h|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjT7h|CxCJU4OZ,{r^gd;Y & F^gd;Y & F^gdFu & F^gdFu & F 7$8$H$^gd;Y & F_ p@ 7$8$H$^@ `gdCjR & F_ pp7$8$H$^pgdCjRp7$8$H$^p`gd;Y @ 7$8$H$^@ gd;Y ,-5Xg >   A f   p1$7$8$H$^pgd;Y7$8$H$^`gd;Y @ 7$8$H$^@ gd;Y p7$8$H$^pgd;Yp7$8$H$^p`gd;Y7$8$H$^`gd;Y^gd;Y^gd;Y    . / A E M f h t ~                    (          * j v w         귮񷒈hzhz5CJjhzhz5CJU hn8[CJ h|CxCJH*h|Cx56CJ h|Cx6CJ h|Cx>*CJh_}h|CxCJH* h_}CJ h\ 5CJ jh|CxCJmHnHu h|Cx5CJ h|CxCJhFuhFuCJ5       i j w      ' `    7$8$H$^gd;Y @ 7$8$H$^@ gd;Yp7$8$H$^p`gd;Y p7$8$H$^pgd;Y 7$8$H$^gd;Y^gd;Y 7$8$H$^gd;Y       &       &Xeg#5EGU]^_a?HIJ+.¼¼¼¼¼¼¼µµµµ§ µµ‹µ‹µ…… h_}CJ hB.CJ h.fCJhFuh.fCJ h.f5CJ h|CxCJH* hn8[5CJ h|Cx5CJ hzCJ h|CxCJhzh|CxCJhzh|Cx0J5>*CJjhzhz5CJU"j&8hzh~5CJU4#6iU_?Jp^pgd;Y ^`gd;Y7$8$H$^`gd;Y p7$8$H$^pgd;Y @ 7$8$H$^@ gd;Y7$8$H$^`gd;Y1$7$8$H$^gd;Yp7$8$H$^p`gd;YZ-% ^`gd;Y^gd;YgdYp^pgd;Y 7$8$H$^gd;Y & F 8  7$8$H$^ gd;Yh7$8$H$^`hgd;Y1$7$8$H$^gd;Y.7LXY   Ƽo_hw0J>*B* CJaJph$hYh|Cx0J>*B* CJaJph,j8hYh|CxB* CJUaJph&jhYh|CxB* CJUaJphhYh|CxB* CJaJphhYB* CJphh|CxCJPOJQJ h|Cx5CJ h,oCJh5kh|Cx5CJ h|Cx>*CJ h_}CJ h5kCJ h|CxCJ%89:NORShijnorsŲţwiWiMF h|Cx5CJhYhY5CJ#j9hYhYCJUaJhYhY0J>*CJaJ#j9hYhYCJUaJhYhYCJaJjhYhYCJUaJhYhYB* CJaJph$hYh|Cx0J>*B* CJaJph&jhYh|CxB* CJUaJph,j8hYh|CxB* CJUaJphhYh|CxB* CJaJph +,-9:<=abcvwyzub%j<h|Cx5B* CJUph%j)<h|Cx5B* CJUph%j;h|Cx5B* CJUph%j=;h|Cx5B* CJUph%j:h|Cx5B* CJUphh|Cx0J5>*B* CJph%j[:h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph%+,-.JKLVWYZz{|٤ّ~k%j?h|Cx5B* CJUph%j>h|Cx5B* CJUph%j>h|Cx5B* CJUph%j=h|Cx5B* CJUphh|Cx0J5>*B* CJph%j=h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJph&  '()/1FGIKLgwd%jZAh|Cx5B* CJUph%j@h|Cx5B* CJUph%j@h|Cx5B* CJUph%j?h|Cx5B* CJUph h|Cx5CJh|CxB* CJphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%j?h|Cx5B* CJUph!ghirsvwŲܣŐܣ}ܣfS$hfoh|Cx0J5B* CJaJph-jhfoh|Cx0J5B* CJUaJph%j"Ch|Cx5B* CJUph%jBh|Cx5B* CJUphh|Cx0J5>*B* CJph%j8Bh|Cx5B* CJUphh|Cx5B* CJphh|Cx0J5>*CJjh|Cx5B* CJUph%jAh|Cx5B* CJUph#$%&ABCLMNUWXмЫ|m\M9M&jhoCh|CxB* CJUaJphhoCh|CxB* CJaJph hoCh|Cx5B* CJaJphh|Cx0J5>*B* CJph%jCh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph hfoh|Cx5B* CJaJph'hfoh|Cx0J5>*B* CJaJph-jhfoh|Cx0J5B* CJUaJph/jChfoh|Cx5B* CJUaJph%N<Y2NTX^gd/^gd;Y ^`gd;Y p0^p`0gd;Y p`^p``gd;Y !",-/0Kճճճճճtճ]ճճ,j$FhoCh|CxB* CJUaJph hoCh|Cx5B* CJaJph,jEhoCh|CxB* CJUaJph,j>EhoCh|CxB* CJUaJphhoCh|CxB* CJaJph$hoCh|Cx0J>*B* CJaJph&jhoCh|CxB* CJUaJph,joDhoChB* CJUaJphKLMVWYZwxyճճճճճtճ]ճճ,jHhoCh|CxB* CJUaJph hoCh|Cx5B* CJaJph,jGhoCh|CxB* CJUaJph,jGhoCh|CxB* CJUaJphhoCh|CxB* CJaJph$hoCh|Cx0J>*B* CJaJph&jhoCh|CxB* CJUaJph,jFhoCh|CxB* CJUaJph !#$<=>EFHIefgqrtuճճճճճճnճճWճ,j1JhoChB* CJUaJph,jIhoCh|CxB* CJUaJph,jKIhoCh|CxB* CJUaJph,jHhoCh|CxB* CJUaJphhoCh|CxB* CJaJph$hoCh|Cx0J>*B* CJaJph&jhoCh|CxB* CJUaJph,jiHhoCh|CxB* CJUaJph"   ,-.3:;<=RSTŲŲŲqaUBa%jiLh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph$hoCh,o0J>*B* CJaJph,jKhoCh|CxB* CJUaJph,jmKhoCh|CxB* CJUaJph$hoCh|Cx0J>*B* CJaJph&jhoCh|CxB* CJUaJph,jJhoCh|CxB* CJUaJphhoCh|CxB* CJaJphTWXYZopq³‰³³r‰³³[‰³³,jMhoCh|CxB* CJUaJph,j;MhoCh|CxB* CJUaJph$hoCh|Cx0J>*B* CJaJph,jLhoCh|CxB* CJUaJphhoCh|CxB* CJaJph&jhoCh|CxB* CJUaJphh|CxB* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph !23JKLQRTUklmqrtuճճճճճճnճ^Rh|Cx5B* CJphjh|Cx5B* CJUph,jtOhoCh|CxB* CJUaJph,j OhoCh|CxB* CJUaJph,jNhoCh|CxB* CJUaJphhoCh|CxB* CJaJph$hoCh|Cx0J>*B* CJaJph&jhoCh|CxB* CJUaJph,jNhoCh|CxB* CJUaJph   ;<=LMNSt]tFt,j>QhoCh|CxB* CJUaJph,jPhoCh|CxB* CJUaJph$hoCh|Cx0J>*B* CJaJph,jXPhoCh|CxB* CJUaJphhoCh|CxB* CJaJph&jhoCh|CxB* CJUaJphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jOh|Cx5B* CJUphSTUstu  һᨕ~gP-jhoCh|Cx0J6B* CJUaJph,jRhoCh|CxB* CJUaJph,j8RhoCh|CxB* CJUaJph$hoChn8[0J>*B* CJaJph$hoCh|Cx0J>*B* CJaJph,jQhoCh|CxB* CJUaJphhoCh|CxB* CJaJph&jhoCh|CxB* CJUaJphh|CxB* CJph-./MNPQfgh NOZ[uֿ혉rlbXbRlKlKlKlKlKl h|CxCJH* h/CJhYhY>*CJhYh|Cx>*CJ h|CxCJ,jShoCh|CxB* CJUaJphhoCh|CxB* CJaJph&jhoCh|CxB* CJUaJph$hoCh|Cx0J>*B* CJaJph-jhoCh|Cx0J6B* CJUaJph,jLShoCh|CxB* CJUaJph$hoCh|Cx0J6B* CJaJphuv  $ % 6 d f       !!8!9!J!K!Q!R!X!Y!c!d!m!n!}!!"6"""""####7#@#R#S#p#q#### $ $/$0$=$>$G$H$L$M$򳧞hYhYCJhhI-5CJ aJ hI-CJ h/5CJ h/CJH*h/h/5CJ h|Cx5CJh/h|Cx5CJh/h/>*CJ h/CJ h|CxCJ h|CxCJH*=  $ % 6 7 r     L!M!N!}!~!!""6"s" & Fgd/8^8gd/ & Fgd/`gd/^gd/ ^`gd/gd/^gd/s"""""7### $ $G$H$s$t$$$$$%^gd|6^gd|6 & F gd`+gdYh`hgdgdI-`gd/p^pgd/ ^`gd/^gd/gd/ & Fgd/M$N$O$g$h$i$p$q$$$$$$$$$$$$$$%%"%~n`UMUAUh|6hI-5CJaJh|6CJaJh|6hI-CJaJh|6hY0J6CJaJh|6hY0J6>*CJaJh|6hI-0J6CJaJhYhY0J>*CJjThYhYCJUhYhYCJjhYhYCJUhY0J>*B*CJph(j.ThhlB*CJUphhB*CJphjhYB*CJUph hYCJ"%$%*%1%5%8%<%=%%%%%&g&h&z&{&|&~&&&&&''''))))) *,,skck]k]kW hx$CJ hCJh0JCJhI-0JCJh}WIh}WI0J>*CJaJ#j$Uh}WIh{CJUaJjh}WIh}WICJUaJh}WICJaJh}WIh}WICJaJh}WIhI-CJaJhhI->*CJ hI-CJh|6hI-CJH*aJh|6hI-5CJaJh|6hI-CJaJh|6hI-CJH*aJ"%%%%&&&&'''~(()))))*--gdI-^gdI- ^`gd^gd|6^gd & F gd}WIgd}WI`gd/^gdI-,-8-t----Z/[/d00000003161<1b1c1m1{11122 2 2 333444N4P4R4T4d4f4j4l4p444zjhwh`+CJU h`+CJh`+h/5CJh`+h`+5CJh/h`+5CJ h/5CJh/h/5CJ h/CJ jhI-CJhI-5CJH* hI-5CJhI-0J5CJ hI->*CJ hI-CJH*hI-0JCJ hI-CJ--W-X-//c0d00021311122233334^gdgzp^pgdgz p^p`gdgz^gdgz`gd/^gdI-^gdI-gdI-44P4R4`55@6666667477778S8888^gd1%n`gd1%n^gd`  & Fgd` gd1%n^gd^gdgd/44444555052545Z5\5`5b5r5t5x5z55566666666`7کڣvjaVP h` CJh1%nh` CJaJh1%n>*CJaJh1%nh1%n>*CJaJh1%nh}WICJaJhI-CJaJ h`+CJh`+h/5CJh`+h`+5CJ h/CJhwh/0J>*CJjUhwhCJUhwh/CJhwh`+0J>*CJjhwh`+CJUjUhwhCJUhwh`+CJ`7a777888888999:9;9=9R9S9T9s9t9u99999ƽkZKh/h/5B* CJph h/h/5B* CJaJph'h/hI-0J5>*B* CJaJph/j]Vh/hI-5B* CJUaJph h/hI-5B* CJaJph)jh/hI-5B* CJUaJphhI-0J6CJh/hI-CJ aJ hgzCJh1%nh1%n5CJ h1%nCJh1%nh1%nCJaJ h` CJ h` CJH*8889:9;9<9=9R9S999K:L:::::_;`;=C?D?^gdI-^gdgzgd/gdI-`gd1%ngd1%n ^`gdgz999999999999999999:::ݐ즃ydS;d/jWh/hI-5B* CJUaJph h/hI-5B* CJaJph)jh/hI-5B* CJUaJphhI-B* CJphheh/B* CJph+jUWh/hI-5B* CJUphh/h/5B* CJph#h/hI-0J5>*B* CJph+jVh/hI-5B* CJUphh/hI-5B* CJph%jh/hI-5B* CJUph:):*:,:;:<:J:K:L:M:c:d:e::::::::::::̽o]G]>h/0J6CJ+jXh/h/5B* CJUph#h/h/0J5>*B* CJph+jSXh/h/5B* CJUph%jh/h/5B* CJUphhI-0J6CJhehI-B* CJphh/h/5B* CJphh/hI-5B* CJphh/B* CJph)jh/hI-5B* CJUaJph'h/hI-0J5>*B* CJaJph::::::::;;;(;);+;8;:;;;U;V;W;\;];ɽɂm_Im7m#hwh{0J5>*B*CJph+jYhhqB*CJU\phh0J5B*CJph)jhwh{0J5B*CJUphhwh{0J5CJhwhw0J>*CJ"j)YhwhCJU\ jhwhw0J5CJUhwhw0J5CJhwhI-0J5CJhG+DhI-0JCJhw0JCJhI-0J56CJh/hI-5CJaJ];^;_;`;q;==C?D?k?AA"B/BBBBBBBYDjDDDEEFF0F=FHHHHH|J}JJKQNmNOPPPkPSTTTUUBUVVXX&YSYVZWZgZZH\Y\9^F^ҽʯҨҢʯ h/CJ hI-CJH*h/hI-0J6>*CJ hgzCJ hI->*CJhI-0JCJ hI-CJhI-0JCJhG+Dh{5CJhI-0J5CJhwh{0J5CJ@D?k?A"BBBBBYDEFF0FHHHJQNPPSUUBUVX&YVZWZ^gd^gdWZgZZH\#]9^^^^```abbbcc`dadtdudReefgg^^gd^gdF^^^````aaabbccadqdsdtdud~dRe\e]eeeeeffgg1g2gggghhhhhhhhhhhi&iǺ~ h)oCJ *hq4h|Cx5CJ h|CxCJH* hq4CJ hEIgCJhEIghEIgCJ hEIg5CJ h|Cx5CJ h|CxCJ hd}CJY(hn+:h|CxCJY(hI-0J5CJhI-0JCJhI-0J5CJhI-0JCJ hI->*CJ hI-CJ0ghYikCl?mvm^nooq.ttBvxuyz{}4 & F= 88^8gdCjR & FI 88^8gdCjR & FI 88^8gd?< & F_^&i'iXiYi_iaibiwixiyi|i}iiiii(jEjXj\jnjqjsjtjjjjjjjjjjjjɷө醓}pgWpjA[hDhHCJUhDhDCJjhDhDCJUh|Cx0J>*CJjZh|CxCJUjh|CxCJU h_}CJ hq4CJhq4h|Cx0J5>*CJ"jQZhq4h 5CJUhq4hq45CJjhq4hq45CJU h|Cx5CJ h|CxCJ h)oCJh)oh)oCJH*"jjjjkk*k+k,k0k1kkkClYl?mFmImJmhmimjmsmtmvmymmmmmnnnn=n>nVnзڰڰڰڡsڰmfڡ\hgzB*CJph hq4CJH* h,oCJh|Cx0J5>*B*CJph(jO\hZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph h|Cx5CJh|Cx0J>*CJj[hZ )hCJUjh|CxCJU h|CxCJ hq4CJjhDhDCJUhDhq40J>*CJ$VnWnXn[n\n^nannnnnnnnnn%o&o,o4oaooooooooppp p ppp(pǺܰǺǕǕDžycܰͅ+j]hgzh5B*CJUphhgz5B*CJphjh|Cx5B*CJUph hq4CJ(jq]hgzhB*CJUphhgzB*CJph hn8[CJ h|Cx5CJ h|CxCJh|Cx0J5>*B*CJphjh|CxB*CJUph(j\hgzhB*CJUph#(p)p*p.p/ptpvpzp\q]quqvqwqzq{q|qqqqqqqqqqqqqrrrr&t't.tAtCtǼܧnjܧjc]] hn8[CJ h|CxCJH*(j_hgzhB*CJUph h|Cx5CJ h,oCJ h)}CJ(j_hgzhB*CJUphhgzB*CJphh_}CJmHnHuh|CxCJmHnHu h|CxCJh|Cx0J5>*B*CJphjh|CxB*CJUph(j^hgzhB*CJUph$CtDt\t]t^tatbtttuuv@vBv^vNwPwwwwwwxxxxxxxxtyuyyyzz񽶽xrrke^ hmfhmf hmfCJ h|Cx6CJ hn8[CJhOh|Cx0J>*CJj`hZ )hCJUhOhOCJjhOhOCJU h)}CJ h,oCJ h|Cx5CJ h|CxCJh|Cx0J5>*B*CJph(j(`hgzhB*CJUphhgzB*CJphjh|CxB*CJUph#zzJzKzLzPzQzRzczzzzzzzz{{{{D{E{F{L{M{O{P{{{{{{{{{{{ɼɱpɼcjhohoCJU#j2ch?<h?<CJUaJh?<h?<0J>*CJaJ#j_bh?<h?<CJUaJjh?<h?<CJUaJh?<h?<CJaJ h|Cx5CJ h,oCJ h|CxCJ hmfCJhmfhmf0J>*jahmfhQU hmfhmfjhmfhmfU${{{{{{{{ | | ||||||"}#}$}*}+},}}}}}}~~~S~ȭ~sgs`\T\jh|CxUh|Cx h|Cx5CJh]NdhEIg5CJaJh]NdhEIgCJaJh]Ndh|Cx0J>*CJaJ#jseh]Ndh|CxCJUaJjh]Ndh|CxCJUaJh]Ndh|CxCJaJjdhohz CJU h|CxCJhoh|Cx0J>*CJjhohoCJUjdhohz CJUhohoCJS~T~U~Y~Z~[~e~f~~~~~~~~~~   234BѸ۱۟۟۟ۙۊk\h|Cx0J5>*B*CJph(jhhgzhB*CJUphhgzB*CJphjh|CxB*CJUph hn8[CJ h|Cx5CJjgh|CxU h|Cx6CJh|Cx0J>*CJjghZ )hCJUjh|CxCJU h|CxCJh|Cx h|Cx0J>*jh|CxUjDfh|CxU$   "#,\efӁ#$=>?EFPQReMOP]`b΃σكhq ąúÞ댅h|Cx h|CxCJH* hRGCJht^hn8[0J>*CJht^h|Cx0J>*CJjNiht^h$CJUht^ht^CJjht^ht^CJU hCJ hmf5CJ hRG5CJ h|Cx5CJ h|CxCJjh|CxB*CJUph2fӁRӂσRhȄąŅ^gd ^`gd^gd & FgdRG^ ^`` h^h`ąڅ # ();<͇·χՇևˈ%If‰ĉʼnƉ'()BCҹ򧜘zlzj khZ )hUh%w0J5>*CJjjh%wUjh%wUh%wh%w0J56CJhh%w5CJ(aJ( hmfCJh0J>*CJjihZ )hCJUjh|CxCJU jh|CxCJh|Cx5CJH*h|Cx h|CxCJ h|Cx5CJ*Ņ  #Pk;hˈHIfgd%wgd & F{ pp^pgd H^gd^gd^gd ^`gdCFGpqrck <=>GHKMNs{}~üõëáõÑÁxrhrõ^jhCJUh*wh*wCJH* h*wCJh%w0J>*CJjlhZ )hCJUjh%wCJU hCECJhCEhCE5CJhCEh%w5CJ h%w5CJ h%wCJH* h%wCJh%w0J5>*CJ$jkhZ )hB* Uphh%wB* phjh%wB* Uphh%w"c sύ^_ďŏΏ֏܏ $$Ifa$gdn |8]|^8gd%w^gdo8^8gd%w^gdCE ^`gdCE^gd%w~ی܌݌!"HIJSTUʥ|ofVoJofh}ho0J>*CJjohZ )hCJUh}hoCJjh}hoCJUh%w0J>*CJjohZ )hCJUjh%wCJU h%wCJh}h0J>*CJj5nhZ )hCJUh}hCJjh}hCJUh0J>*CJjhCJUjhmhZ )hCJU hCJUVW|}~ύԍ֍׍꽴ꌁwqawXwqOh}hCECJhCE0J>*CJjqhZ )hCJU hCECJjhCECJUhohoCJaJhoho5CJaJh~8h%w0J>*CJj[qh~8h%wCJUh~8h%wCJjh~8h%wCJU h%w5CJh%w0J>*CJjphZ )hCJU h%wCJjh%wCJU hoCJ012=>?@\xB]^_cefstďŏǾǝzqqqhh%w5>*CJho0J6CJh%w0J56CJh%w0J6CJ hCJh%w0J>*CJjh%wCJU hoCJ h%wCJhohoCJaJhJ hCECJ hCECJh}hCE0J>*CJjrhZ )hCJUh}hCECJjh}hCECJU$ $$Ifa$gdnnkdLs$$Ifl\2 <f4 la8ytn)24>GHQR^`jquvwݐ+,-4567Ѿʠzndh h CJ]h=h=0J>*CJjfwh=h_1CJUh=h=CJjh=h=CJU h=CJh%w5B*CJphh%w5B*CJphh%w5B* CJph h%w5CJh%wB* CJphh%wB*CJphh%wB*CJph h%wCJh%wB* CJph$)3 $$Ifa$gdnnkds$$Ifl\2 <f4 la8ytn34>HR_ $$Ifa$gdnnkdxt$$Ifl\2 <f4 la8ytn_`jkqu $$Ifa$gdnnkdu$$Ifl\2 <f4 la8ytnuvwx $$Ifa$gdnnkdu$$Ifl\2 <f4 la8ytn $$Ifa$gdnnkd:v$$Ifl\2 <f4 la8ytnݐ7>k)œϓ~vvvvvma~  ^gd%w`gd  & Fgd ^gd%w`gd%wnkdv$$Ifl\2 <f4 la8ytn 78WXYfghilm=>LMjkst羸zqhz\qhz\qz\qh|h%w0J6CJh 0J6CJh%w0J6CJh%w0J56CJh h CJ]h h 0J>*CJjTxh hCJUjh h CJU h CJh h CJh h 0J5>*CJ"jwh h5CJUh h 5CJjh h 5CJUϒВђ)-œϓXZ:=hiÕNQʖ˖sＶymaXGX! jh*wh*wCJmHnHuh*wh*wCJh*wh*w0J6CJh*wh%w0J6CJh%w0J6H*h%w0J56>*h|h%wCJH*h|h%wCJ h%w5CJ h%w0J6h%w0J56 h%wCJh%w0J6CJh'h%w0J>*CJ"jxh'h%szCJU]h'h'0J6CJ jh'h'0J6CJUϓJÕtuҗ=h hj,v^gdgz^gdF & Frgd*w^gd%w^gd*wgd%w & Fgd%wstu}~җӗ<=h hƸƜƑ؂ظyky_yUHh*wh*wB* CJphh*wh*wCJ] jh*wh*wCJh*wh*w0J56CJh*wh*wCJ jh*wh*w0J6CJh*w0J6CJ]h*wh*w0J>*CJjbyhZ )hCJUh*wh*w0J6CJ]#jh*wh*w0J6CJU]h*wh*w0J6CJ h%wCJ h*w5CJh*w0J6CJ h*wCJhj89:=>RV͜ΜϜ %&MNORSvhn8[0J>*CJj9}h|CxCJUjj|hZ )hCJU h|CxhhhCJj{hZ )hCJUjzhZ )hCJUh|Cx0J>*CJj#zhZ )hCJUjh|CxCJU hCJ h|Cx>*CJ h|CxCJ.F]jx%ĝ:= @ `^@ ``gdgz^gdF^gdF^gdgz^gdgz>KƞǞȞ՞=>defop9Jó̧̞xh\U h|Cx>*CJh~8h|Cx0J>*CJj8h~8h*{5CJUh~8h~8CJjh~8h~8CJUjo~hZ )hCJUha /h|CxCJha /h|Cx0J>*CJj}ha /hfgCJUha /ha /CJjha /ha /CJU hCJ h|Cx5>* h|CxCJjh|CxCJUh|Cx0J>*CJǟ89JKàmEvmnã^gd^gd^gd^gd}WI^gdgz^gdF^gdgzJKLstuàĠHIJVWmnxhjhghgCJUhghgCJjhghgCJUjۂhZ )hCJUj hZ )hCJUj=hZ )hCJUjphZ )hCJUh|Cx0J>*CJjhZ )hCJU h|CxCJjh|CxCJUh|6h|CxCJ(%&''(),-mn 1:OPiʰףלףztjt]ThthtCJjhthtCJUhohS5CJ hSCJhS0JCJhHhSCJhHhS5CJ hS5CJ h|Cx5CJh|Cxho0J>*CJjmhZ )hCJUjhoCJU hoCJ ho5CJ h|CxCJhgh|CxCJjhghgCJUhgh|Cx0J>*CJOФڤ!-i̦ͦ© ^`gd ^`gd^gdgd|6 & Fw pp^pgd H^gdijkrs!*LM̦ͦڦۦܦ6@Dзгvpfp]phFi|hCJh$ah5CJ hCJh0J>*CJ"jhZ )hCJU]jh0J6CJUh0J6CJh0J56CJhShhSCJ hQoCJhohS5CJ hSCJhthS0J>*CJjhthtCJUj*hthOCJU!DFZ\©کީ56WZíLMO]Uacd{ŹůŦŜůŹń}}}v}}}œ} hmf5CJ h5CJh0JCJ jhh hhhFi|h5h jhCJhFi|h5CJ jhFi|hCJ hCJh0J5CJh0JCJ jhFi|h0J5CJhFi|h0J5CJhohCJ. |W U{ֵ p^p`gd & Ft pp^pgd H ^`gd & F pp^pgdQ^gdp^pgd^gd & Fs pp^pgd Hɵʵ˵Եյֵ׵ͶζǷȷɷº˻̻ZǻǧǝǐwkaaYPhvhCJh0JCJhvh5CJhgzh0J>*CJj3hgzhCJUhgzhCJjhgzhCJUhz+8h5CJ jhCJh0J56CJhFi|h0J6CJ hCJh}h0J>*CJjjhZ )hCJUh}hCJjh}hCJUֵ׵+:CZ[@ ^`gd^gd4dU^gd ^`gd^gdZf<=>GH[dǾ־ﵪ|p^|R|ph"4Yh0J>*aJ"j^hZ )hU]aJh"4Yh0J6aJ jh"4Yh0J6UaJh"4YhaJhh"4Yh5aJh h>*CJh0J56CJh0JCJhvh0J>*CJjhZ )hCJUhvhCJjhvhCJU hCJhvh5CJ@L5AJS` U\^k¸§xnh`hnhnhnhnhnh`hh0JCJ hCJhQDxh5CJh"4Yh0J56CJaJhCJaJh"4YhCJaJh"4Yh5CJaJh"4Yh]aJ h4dUaJhh"4Yh4dUaJhh"4YhaJhh"4Yh5aJhh"4Yh0J6aJhh"4Yh0J6aJh"4Yh0J6H*aJ$45AUUR./mn~%v^gdDl & F:gdDl & F9gd4dU^gd4dU^gd^gdUbR[])-./;Աå뜑}ssic]Th4dUhgzCJ hCJ h4dUCJh4dUh4dU5CJh4dUh5CJh4dUh4dU0JCJh4dUhCJh4dUh0JCJh4dUh4dUCJhh0J>*CJ"j)hhB=CJU] jhh0J6CJUhh0J6CJh0J56CJh0J56CJh0J6CJ;<=cdejkl~vHKMһxoe___e_e_____ hDlCJhDlhDl5CJhgzhCJhgzh0J>*CJjhgzhB=CJUhgzhDlCJjhgzhDlCJU hCJh0J56CJ,jhgzhB*CJUaJphhgzhB*CJaJph&jhgzhB*CJUaJphhgzhCJaJ%H  UVgh;Blm'~^gd^gd|6gd|6^gd^gdDl & F;gdDl^gdDl @ABOPRSstuxy{|  %&'GݸԨݸԘݸsbs jhgzh0J6CJUhgzh0J6CJh0J56CJhDlhDl0J6CJ]jhDlhB=CJUj5hDlhB=CJUhDlhDl0J>*CJjxhDlhB=CJUhDlhDlCJjhDlhDlCJUhDlhDl5CJ hDlCJ hCJ GHIRSTUVghk /7lm}~ź|qiaVO h(`5CJh(`h|CxCJ4aJ4h|6CJaJhCJaJh&hCJaJh&h5CJaJ h&hh0JCJ hCJhg/h5CJh|6h0J6CJ h0J6h0J56CJhgzh0J6CJhgzh0J>*CJ jhgzh0J6CJU"jhgzhCJU]5?C^,0 24^gdN]^ & F; p^gdQ^gd4u^gd(`gd(`gd|6 <Ϲٳwlcw[Sch{>CJaJh4uCJaJh4uh4uCJh4uh4uCJaJh{>h4u5CJaJ h4uCJh8 h8 0J>*jՎh8 h_1Ujh8 h8 U h8 h8 h8 CJh|Cx0J>*CJjlh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJ h(`CJh(`h(`CJh(`h(`5CJ45>?BC]^,/0: 24B68:Hdǽ͈ͤ́́́wwq h_}CJhN]h|Cx5CJ h|Cx5CJ h|Cx>*CJh(`h(`0J5CJh(`0J5CJh(`h(`0JCJh|Cx0JCJ hwLCJh`x6hwL5CJ h{>CJ h|CxCJ hq:CJhq:0J5CJhq:0JCJ h(`CJh(`0JCJh{>0JCJ,4~68V bd!p^pgd8 `gdf ^`gdN]^p^pgdN] ^`gdN]^gdN]^gdN] p^p`gdN] ^`gdN]  "bd !"9KYDEZ[\_`ǽǴ֭wkUw+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx0J>*CJjh|CxCJUjh|CxCJU hfoCJ h|Cx5CJhN]hN]CJhN]hN]>*CJ hN]CJ jhfCJ hfCJhf56CJ jhfh hfhhf56h h|CxCJ !"K@1efp^pgdZp^pgd5 ^`gdfop^pgdfogd|6^gdfo ^`gdfo^gdfogdf$+,hk~/8?`ɹɗ~rfr`YR h|Cx6CJ h|Cx5CJ h>CJh>h>0J>*CJh>hfo0J>*CJjh>h$&%CJUh>h>CJjh>h>CJUhN]hN]CJ hN]CJ h/g7CJh/g7h/g7CJ hfo6CJ hfoCJ hfo5CJh|Cx h|CxCJjh|Cx5B*CJUphh|Cx0J5>*B*CJph `dtuv&0128def}'Q^ؿحvfj1hH{hFCJUhH{hH{CJjhH{hH{CJU hH{CJhfo0JCJ hfoCJ hfo6CJ hfoCJ hfo5CJhZh|CxCJaJhZhZCJaJ h^t5CJ h|Cx6CJ h|CxCJ h5CJ jh5h55CJ h55CJ h|Cx5CJ%-Q !1 9Xajy^gdH{^gdH{ ^`gdH{^gdH{p^pgdfo^gdfo !18WXrstxy@ǀyrkrrрreee h -UCJ hn8[5CJ h|Cx5CJ h|Cx6CJ h|Cx>*CJht^ht^0J>*CJaJ#jht^ht^CJUaJht^ht^CJaJjht^ht^CJUaJ ht^CJ h|CxCJh|Cxh|6h|CxCJ hfoCJ hH{CJjhH{hH{CJUhH{hH{0J>*CJ'y>@W opCD^gdvH^gdCh^gdZgdZ ^`gdH{p^pgdH{^gdH{ ^`gdH{ ^gdH{@JW QqrstǾwaw+jhvHh#,5B*CJUph#h(hvH0J5>*B*CJph+jhvHh#,5B*CJUphhvH5B*CJph%jh(hvH5B*CJUphh(hvHCJ hvHCJhhZ5CJ hChCJhZ0JCJ hZCJ h|CxCJ h|Cx5CJ h5CJnop%6Dw xz{|ֻ|rkb|Ubjh?hZCJUh?hZCJ hZ5CJh`x6hZ5CJ hJ\CJ jhhZCJht^hZCJ h{>CJhZ0JCJ hChCJhChhCh5CJ hZCJh(hvHCJ#h(hvH0J5>*B*CJph%jh(hvH5B*CJUph+jQhvHh#,5B*CJUphDwzJK^Kcd & F^`gd; ^`gdLp^pgdL & FvgdL^gdL^gdJ\^gdZ^gdZDK^ʶЮФКufOu,jhLhSB*CJUaJphhLhLB*CJaJph&jhLhLB*CJUaJphhLhLCJaJ hLCJhLhL5CJhfhZ5CJhZ0JCJh`x6hZ5CJhJ\hJ\5CJ hJ\CJ hZCJh?hZ0J>*CJjh?hZCJUjhZ )hZCJU }~;<=vpj]TD]j h;h$&%CJUh;h;CJjh;h;CJU h;CJ hZCJhfhZ5CJhLhLhL0J>*B*ph$j`hLhSB*UphhLhLB*phjhLhLB*Uph hLhL hLCJhLhLCJaJ&jhLhLB*CJUaJph$hLhL0J>*B*CJaJph=FGHIbd<=>CDEHtgRtDthL0J>*B*CJph(j_hLhSB*CJUphhLhLB*CJph"jhLhLB*CJUph h;5CJh;h;5CJh>hL0J>*jh>hSUjh>hLU h>hLhLhL5CJ hLCJ hZCJ h;CJh;h;CJjh;h;CJUh;h;0J>*CJHuwx12KLw5 $)36pqwsjh|Cx0J>*CJj"h|CxCJUjh|CxCJUhd~Vh|Cx5CJ h|CxCJ h$CJhhCJ h|Cx5CJhfhZ5CJ hZCJhLhL5CJhLhZ5CJh;h;5CJh;h;CJH* h;CJh;h;CJh;hLCJ(!JvwlmgdZ^gd`q^gdZp^pgdL^gdZ & Fgd; & F^`gd; & Fp^pgd;p^pgd;qAs^./tU ^`gd`q @ ^@ `gd`q p^p`gd`qp^pgd`q^gd`q ^`gdp^pgd^gd^gd$`gd(`'()?@ADFacds./2缲}wpwf`f`Zp}} h8 CJ h`qCJh`qh`q5CJ h|Cx5CJ hbdCJ jh|CxCJmHnHuhMhM0JCJhMCJaJhMhMCJaJhMhMCJhd~VhM5CJ h|CxCJh<hM0J>*CJjh<h$CJUh<h<CJjh<h<CJU hMCJ hd~VCJ#  :;<?@AUW  !'(BCIJRSjkvwɶԧ렛~thhCJH*hh5CJ h|CxCJH* hCJ hCJ h|Cxh h|Cx5hhgzh|Cx0J>*B*ph$j$hgzhB*Uphhgzh|CxB*phjhgzh|CxB*Uph hgzh|Cx h|CxCJ jh|CxCJmHnHu+U'j=gd ]^gd^gd ^`gd^gd^gd`qp^pgd$p^pgd & F @ @ ^@ gd H ^`gd`q4/01;<EO   09²˦욎|n|d|ZZh]h|Cx5CJh0 h0 0J>*jVh0 hjUjh0 h0 U h0 h0 h:h|Cx5CJaJ h ]CJ h_}CJh)h|Cx0J>*CJjߙh)h<<CJUh)h)CJjh)h)CJUh|Cx hCJhh5CJ h|CxCJ h$CJ h|Cx5CJ#0V{*`8n  & F 8^gdQ h^`hgdb^gd0^gd0 & Fq^gdO^9V[{*6'c`i8d nqýё~uhOh|CxCJhOhOCJhOh|Cx5CJhO0J5CJh00JCJ h0CJ h05CJ h|CxCJH* h|Cx5CJ hOCJ hO5CJ h]5CJhO0JCJhOhO0JCJ hn8[CJ h]CJh]h|Cx5CJ h|CxCJ. R`ah  > ? - . 9 : ; E F c d    ɽѫѫ핌yp`yj1hzKhCJUhzKh0CJjhzKh0CJU h0CJh00J5CJh00JCJ hb5CJ hbCJH*hb0J5CJhb0J6CJ jhb0J6CJhb0JCJhb0JCJhbhb5CJhbhb>*CJ hbCJ h|Cx5CJ h|CxCJ" - . : ; c    >@E$xA 8^8`gd]8^8gd] & Fgd0 & Fgd] & Fgd0 & Fgd0 & Fgd] h^`hgdb^ & F 8^gdQ                       =>?klm|}úڱڛ˛ڱykYkNkh00J5>*CJ"jhZ )hCJU\jh00J5CJU h]CJhzKh]0J>*CJjhzKhCJU h0CJjhzKhCJUhzKh0CJh00J5CJh00JCJ h|CxCJhzKh|CxCJjhzKh0CJUhzKh|Cx0J>*CJhzKh00J>*CJ}$%NOP\]^"/ !x%&APZ[hir|u|u||k|htht5CJ h|CxCJH* htCJhth|Cx5CJ h|CxCJ h0CJH* h05CJh00J5CJh00JCJ h0>*CJhzKh0CJhzKh00J>*CJ%j]hzKh5CJU\hzKhb0JCJjhzKhb0JCJU h0CJ*A[ 89Tlijy ^gdO^gdgz^gd8^8gd & F^gdQ`gdt 8^8`gd]^gd]8^8gd]  9ST9:jxyMOZ^tjbhO0JCJhOB* CJphhO5B* CJph hCJ#hh5B*CJ\aJphhh|CxCJaJ h|Cx>*CJ h>*CJ h]CJhtht>*CJhth|Cx>*CJ htCJH* htCJ ht5CJhtht5CJhth|Cx5CJ h|CxCJH* h|CxCJ#AY  (| ,/BJKiKLMVW_afgn}ȶҨhO0J5CJ jhOCJ hO>*CJhOh~8hO0J5>*CJ"j,h~8hO5CJUh~8hO5CJjh~8hO5CJU hO5CJ hOCJhO0JCJhO0J5CJ2{|ABNO LQ"  & Fgdx$ & Fgdx$^gd:^gd:^gd:^gdO^gdO^gdO234KLOdfg LTöæ̓yoyyooyhx$hx$5CJhx$hI-5CJ hx$CJ hI-CJhI- hO5CJhOhO0J>*CJjfhOhNM#CJUjhOhOCJUhOhOCJhMhO5CJhO0J>*CJjhZ )hCJU hOCJjhOCJU+! # 8 !!!!!"""###'#)###########$$$$$νڵڦ~u~~f\fh0h ]5CJjh0h ]5CJUh0h0CJh0h ]0J5CJh0h00J5CJ h0CJh0h05CJ h&"CJhA40J5CJh ]0JCJ hA4h ]5B*CJaJphhA4h ]5CJaJ h ]CJhI-B*CJphhhI-5CJ hx$CJ hI-CJ"" # 8 9 : @ Q i r ~     $IfgdNM#^gd^gd:         e\\\\\\\ $IfgdNM#kd$$Iflֈd g R&,+ (4 layt        !!!$!e\\\\\\\\\ $IfgdNM#kd$$Iflֈd g R&,+ (4 layt $!%!O!Q!W!a!b!g!p!u!!e\\\\\\\\\ $IfgdNM#kde$$Iflֈd g R&,+ (4 layt !!!!!!!!e\\\\\\ $IfgdNM#kd'$$Iflֈd g R&,+ (4 layt!!!!!!!!!"e\\\\\\\\ $IfgdNM#kd$$Iflֈd g R&,+ (4 layt ""/";"M"V"["\"_"`"e"e\\\\\\\\\ $IfgdNM#kd$$Iflֈd g R&,+ (4 layt e"f"{"""""""e\\\\\\\ $IfgdNM#kdm$$Iflֈd g R&,+ (4 layt""""""""e\\\\\\ $IfgdNM#kd/$$Iflֈd g R&,+ (4 layt""""###$$e\WRWIII^gdA4gd:gd ]^gdkd$$Iflֈd g R&,+ (4 layt$$$$$$$$$$$$%%% %"%?%@%C%P%Z%a%x%y%z%%%%%%%%~&&&>'ȾȲȲȲxȋooici h0CJ h ]CJh0h0CJh0hZCJ\h0hZCJh0h ]CJh0h"[-CJh10J5CJh0hZ0J5CJh0h00J5CJh0h ]5CJh0h ]0J5CJh0h ]0J5CJH*jh0h ]5CJUjh0h ]5CJU$$%y%%;((()))+H,,,B112m22222 & F  ^gdQ & F! ^gdQ^gdA4^gdA4 & F" ^gdQ>'|';(C(((y)|)}))))))))))))))*K*M*`*c*r*u*****_+`+Ŷ䰦䉀tkakakakakXkah&"h&"CJh&"h ]CJH*h&"h ]CJh&"h ]0J5CJh10J5CJ h1CJh1h&"5CJ h15CJ h ]CJh0h ]5CJ hH0[CJh0h ]5B*CJphh0h05B*CJph h0CJh&"B*CJph h&"CJh&"h&"5CJ h_CJ h"[-CJ"`++++G,H,U,W,X,v,w,x,,,,,,,,,,,,-... / /000A1B1F1p1ېᆀwwwwwqhq^hA4ht^5CJh0h0CJ h0CJht^ht^CJ ht^CJhA4hH0[5CJ h ]5CJh1h10J>*CJ"jUh1hFCJU\h1h10J5CJ jh1h10J5CJUh10J5CJ h1CJ h ]CJh ]0JCJh10JCJh&"h ]CJ#p1r1s1111111111111122222a2b2m2}2222222yslf^Rh1h ]0J5CJh ]0JCJ h0CJ h ]5CJ h ]CJ hH0[CJ hA4CJH*hA4ht^5CJ ht^CJH*ht^ht^CJ ht^CJhA4hH0[5CJ#hA4hA40J5>*B*CJph+jЩhA4hA45B*CJUphhA4hA45B*CJph%jhA4hA45B*CJUph hA4CJ222222223;3G3`3a33334h4i4s4~44444444 5 5455565@5ǻzqazUhIGhIG0J>*CJjhIGh_1CJUhIGhIGCJjhIGhIGCJUhIGhIG5CJh10J6CJhA4hA40J6CJhA40J6CJhA4h10J6CJhA4h ]0J6CJhIG0J6CJhIGhIGCJH* hIGCJh1h15CJ h ]CJ h1CJh10J5CJ!23a334h44o5p55X6n66677e7788q9^gdA4 & F$  gd_ ^`gd_^gdA4 ^`gdA4^gdIG & F# pp^pgdQ@5A5f5g5n5o5p5}55555556686@6K6L6g6h66666777e777778888ýý{{n{jfhA4h ]CJUjhA4h ]CJUhA4h ]CJhA4h ]0J5CJhA4h1CJh&"h1CJH* hA4CJ h1CJH* h1CJhth15CJhA4hIG0J6CJhIG0J6CJhIGhIGCJH* hIGCJjhIGhIGCJU%885868K8L8l8m8n8}8~888888888839p9q9r9s999~rnfafafafXRKR hA45CJ hA4CJhA40J6CJ h_5ht^ht^5ht^hA4h10J5CJhA4hA40J5CJh"PhA40J5CJh"PhA40J>*CJ"jh"Ph%szCJU\h"Ph"P0J5CJ jh"Ph"P0J5CJUhA40J5CJhA4h&"0J5CJhA4h ]0J5CJhA4h ]0J5CJH*q9s999H:::;;`<<==>>>>{>>1?? & F)gdi^gd^gdgd:gd ]^gd; ^gdYgd; ^gdA4`gdA4gdA49999999:::;;;3<_<=#===>>>>>#>/>0>1>2>r>÷÷ï÷÷ã~ribWShijhihiU hihihi0J5CJhh0J5CJh0JCJ hCCJhA4h ]CJaJhA4h ]>*CJaJht^h; 0J6CJhYCJaJh; h; 5CJaJh; h; CJaJh; hA4CJaJhA40J>*CJjhA4CJU hA4CJjhA4CJUr>s>t>x>y>z>{>>>>>>>>>>>>>>???? ? ?1?:?;?ƽxo_xSxJha?bhiCJha?bhi0J>*CJjha?bhCJUha?bha?bCJjha?bha?bCJUhih?0J>*CJjͮh?hCJUhih?CJjhih?CJU hiCJhhTqCJhhTq5CJh0JCJ hihihihi0J>*jhihiUjhU;?*CJh?hTq0J>*CJjUh?hCJUh?h?CJjh?h?CJUhhTqCJ"?@BSC_C|CCC4D@DDD8EpEEFFFGG^gdTq^gdTq`gd ] & Fgdd & Fgd H & Fgdd ^`gdd & Fgd^gdBCCRCSC\C^C_ChCiCnC|CCCCCCC3D4D=D?D@DRDDDDDD"E2E7E8EEEEEEEдЫ֡ЄxijhdhdCJUaJhdhd5CJaJhdhdCJaJhhCJhh ]CJhh ]5CJhhdCJ h?CJ hCJ hiCJh?hi5CJ hdCJhhTq5CJhhTqCJhhTq0J5CJhhTq0JCJ&EEEEEFFFFGGGUHoHHHHIIJJJJJJ+Jƽqf\MGA h|CxCJ hgzCJhgzh|Cx6B*CJphhgzh|Cx6CJhI-h|CxCJ aJ hI-h|CxB*CJ aJ phhI-h|Cx>*CJ aJ hTqhTqh10JCJ h1CJh10JCJ hTqCJhTq0JCJ hCJhdhdCJhdhdCJaJhdhd0JCJaJjhdhdCJUaJ#jhdhdCJUaJGGHHHIIJJJJ,JuJJ*K+KSKTKKgd|6^gd|6 8^8`gdgz & FC 88^8gdQ^gdgdTq^gdTq^gdTq^gd1^gd1+J,J=JtJ~JJJJJJJJJJJSKTKYKmKnKKKKKKKKLLGMHMMM N N7Nuooe^ h ]5CJhOh ]5CJ hn8[CJh|Cx0J5>*B*CJph+j0hgzh5B*CJUphhgz5B*CJphjh|Cx5B*CJUph hCJh|Cxh|Cx0J>*CJjghZ )hCJUjh|CxCJU h|CxCJH*h|CxB* CJph h|CxCJ hgzCJ#KKKKKK0L1LNLLLLLLMM(MAMfMgMsMM N N+N O+O^gdgz^gdgzgdgz^gd7N+O3OOOPPQQQQQ RRJRKRLRMReR}RRSSSTTT)U*UGUZUsUtUUUUUWV`VcVgVWWWWWXlYuYYYY%Z3Z4Zh|Cx>*CJaJh h|Cx>*CJaJh ]h ]CJh ]h ]5CJ h ]CJH* h CJh?<h ] h ]5 h9CJH* h9CJh9h9CJh9h ]CJ h ]5CJ h ]CJ6+OOPPPEQQR.SSTT)UsU6VWVcV WWW^gdgz & Fn pp^pgd H & Fm pp^pgd H^gdgzp^pgdgz & Fl pp^pgd H^gdgzWWWX>XYlYYYYY$Z%Z4Z5ZMZ\%\\3]]p^pgdgzgd: & Fp pp^pgd H & Fo pp^pgd H^gdgz^gdgz4ZMZYZZZZZZZZ[[>[A[K[[[[[\#\%\5\7\A\\\c\\\]$]]]]]^ ^!^#^.^/^;^<^U^Ⳮztnn hn8[CJ hiCJh h 5CJh hi5CJhC!0J6CJhC!0JCJ hCJh|Cx0JCJ h CJ h|CxCJhgzhgz5CJhgzhC!5B*CJph hzCJhgzhC!5CJ hgzCJ hC!CJhhC!5CJh|Cx0JCJ+]]^U^v_a$aaabtccdfRgpj{jjk & F p^pgdQ & F p^pgdQ@ ^@ gdgz & FD   ^ gdQ^gdgz ^`gdgz ^`gdgzU^d^f^i^^^^^__`_a_f_g_h_v__T`U``````abbhbbbbbbtc}ccccccdd}dddddd著|v hCJhh5CJhh|Cx5CJ hzCJhzhzCJhgzhgz5CJ hgzCJ hC!CJH*jhC!CJUjhC!CJUhC!hC!5CJ jhC!hC!CJ h|CxCJhC!h|CxCJ hC!CJhC!h|Cx5CJ.dddddd,e7efgRgUgWgXglgmgng}g~ggggghh)h*hEhhhSiTiUiViWieifiiiiiij}vlvjlhCJU hCJH*jʶhCJUjhCJUh0JCJhYh0J>*CJjchYh%szCJUhYhYCJjhYhYCJUhh5CJhh|Cx5CJhhCJ *hkh|Cx5CJ hCJ h|CxCJ*j1jHjpjyjzjjjk'k)k>kBkPkRkkkmknkkkkkkkkkkl1lllmm nnnnn(n:n;nAnCnDnֱܿ{u hCJhh5CJaJhhCJaJhCJaJhh ]CJaJhh|Cx>*CJ aJ hXh|Cx5>*CJ aJ hn8[0JCJhhCJ hYCJ h CJh 0JCJhh5CJ h|CxCJ hCJ hCJ+kQkRkmkkkkmmm n nnn;nvpwppcq^gd & F8 88^8gdQ^gdgd^gdgzp^pgdgz^gdgz ^`gdgz & F p^pgdQDnEnnsouospupvpwppppppppppCqbqcqdqvqqqqqqqqqqrr(r)r5r6rJr¹}umchVhV5CJh|Cx0JCJhV0JCJ jhVhVCJ hVCJ h|CxCJhh0J5CJ\hh0JCJhhV0JCJhhCJhVh|Cx5CJhVCJaJhCJaJhhCJaJhh|CxCJaJ hCJ hCJH*&cqqqqr6rNrSr`rr)s*s5s6s{stNttttt?u^gd&gdo^gd&^gd8^8gd 8^8`gd & F8 88^8gdQJrKrSrTr`rarrrss(s)s*s4s5s6sJsKsLsVsWsbscsds{sssssttttMtNtQt÷zqka[k[kkk hHCJhHhH5CJ h|CJh|h|CJhHh|0JCJhHh|5CJhHh|CJhHh|CxCJhHh|Cx0JCJhoh|CJaJhCh|Cx5CJ aJ hXh|Cx5>*CJ aJ h&h|CxhVh|Cx0J6CJ] h|CxCJ hCJ hVCJ hVCJH*#QtTt_t`tktrt~ttttttttttttttttttu u u u u1u2u3uu?u@uúrfh&hS0J>*CJ"jh&hnCJU\h&hS0JCJjh&hS0JCJUh&hS0J5CJhS0JCJh0JCJhHhCJhHh5CJ h5CJhHhH5CJhHhHCJ hHCJ hH5CJ h|CxCJ h|CJ$?u@uXuuuu!vw?wrwswwwOxxxPyzzb{!| & FHgd?^gdY#gd: & F 8^gdQ^gd& ^`gd& ^`gd&^gd&@uVuWuXuuuu!v$vJvww w?wHwJwQwqwrwswwwwwwwOxsx|xxxxxxxxNyPyȽvk`k`k`h?hICJaJh?h|CxCJaJhY#hICJhY#hI5CJhY#hY#0JCJhY#hY#CJhY#h|CxCJhY#h|Cx0J6CJhY#hI0JCJhY#h|Cx0JCJhXh|Cx5>*CJ aJ hhXh|Cx0J6CJhhXhhX5CJ hhXCJ h|CxCJh|Cx0JCJ%Pyayky~y0{1{!|"|8|:|F|S|U|k|q|r|{|}||}}_~`~a~b~k~m~x~y~z~~~U\13{܀݀ͽͳͪ͗ͳͪͪͪͪͪͪͪͪͪͪͪͪh|Cx0J6CJ]hY#hn8[CJhY#hY#5CJhY#hY#CJhY#h|Cx5CJ hY#CJhY#hI5CJhY#h|CxCJhY#hICJh?h?CJaJh?hICJaJh?h|CxCJaJ2!|9|F|r|}||b~m~܀݀zm & FIgd:^gd:gd:gdY# & FF ^gdQ & FG ^gdQ^gdY# & FE ^gdQ݀ y{υӅ46lm}ψ؈ω݉/@AOPmȼȼȴȴȴȴȴȴȴȴȪ|uo hwCJ h:>*CJh|6h:CJh:h:5CJ$aJ$h;}h:>*CJh;}h:CJ h:CJh;}h:5CJh:CJaJhw^h:5CJaJhw^h:CJaJhw^hmfCJaJhmfCJaJh:h:>*CJ aJ h:h:5>*CJ aJ 'wψ./@AOPǧ)<q ^`gdw^gdw^gdwgd: & Fgd:gd|6^gd: & FJgd: & FKgd:mňό)5;<@r滯m_Th h:CJaJh hw0J>*CJaJ#jh hCJUaJjh hwCJUaJh hwCJaJh h:5CJaJh8%h:5CJh8%h:0J5CJh:0J5CJhfh:0JCJhw0J56CJhjh:0J5CJh:0JCJ h:CJ jh}h:CJqr10Mxy}~gd: ^`gd:p^pgdw & F p@ @ ^@ gdQ ^`gdw^gd  ^`gdwpy}~Ґtv̒ΒВܒޒv“ēГғ;<DE궪{sa{#jh?`h:CJUaJh:CJaJh?`h:0J>*CJaJ#jh?`h:CJUaJjh?`h:CJUaJh?`h:5CJaJh?`h:CJaJh:0J5CJ hw>*CJ h:>*CJh:0JCJ *hEFh:CJ h:CJhEFh:5CJ hwCJ&Ґ)Mtvtvؓ;<DE”gd: @ `^@ ``gd:`gd: ^`gd:8^8gdw & FA pp^pgdw ^`gdw^gd:EPQ͔Δϔ*+,=OP^op|~:@BDFHXs#%?BamCG~3տմyh}h:5CJhbnh:CJhth:5CJ *h8%h:5CJh4cgh:5CJh:0JCJh|6h:CJaJ hh:hh:5 jh:h: hw>*CJ h:>*CJhh:5CJ jh:CJ h:CJ/Hpq|~abCrљ3|՚ ^`gd:^gd:^gd:gd:^gd|6^`gd:374RS&'Hhw*PU`a亂uj^h/Lh:0J5CJh/Lh:0JCJh/Lh:5CJh:h:0J>*CJjh:h:CJUh:h:CJjh:h:CJU h:CJH*h:0JCJh{Ph:>*CJaJhnAh:CJH*aJhnAh:5CJaJhnAh:CJaJ h:CJh}h:5CJ$<GHhiw S*OPa؞p^pgd: ^`gd:^gd:^gd:gd:؞ٞݞ'cd̟ϟ'ܠݠ ^`gd:p^pgd:^gd:^gd:ڞܞߞ&)*d$%&'ݠZt{Σϣݣޣõè̘xpep[h:B*CJph jhwh:>*hwh:>*hwhw>*CJh:5B*phh:B*phh: h:0J5h:0J>*CJjmh:CJUjh:0J5CJUh:0J5CJh:0JCJh{Ph:>*CJaJhuh:5CJ hwCJh/Lh:5CJ h:CJ##̢[Σϣ)a()3BȦt & Fqgd=^gd=^gd:^gd:^gdw^gd: & F pp^pgdQ67klƤǤ'(+26?HJKklmz{Ǧuٻ豥xfXh=h=0J>*CJaJ#jh=h_1CJUaJh=h=CJaJjh=h=CJUaJh=CJaJh=h:CJaJh=h:5CJaJh: h:CJh:0J>*CJ(jԼhZ )h:B*CJUphjh:B*CJUphh:B*CJph jh:B*CJphtuܧ*+Ө(dezԪrVp^pgd:^gd: & FH pp^pgdCjR^gd:^gd: ^`gd:gd:@ ^@ gd: ^`gd:gd|6u!+4Ө(/0BCDdez"#V`abx|}~9:Q żżПhEFh:0J5CJh:5>*CJhbnh:CJ jh:0JCJh:0J5CJhth:0JCJ h:>*CJ jh:CJ h:5CJh:0JCJ h:CJhh:5CJ9Vx9:Q߭*cܰ׳سgd|6^gd:^gd:p^pgd: & F p@ @ ^@ gdQаѰҰٰڰ۰ܰسSZu{ȵɵʵԵյ*<1𽵮znh#$h:0J5CJh:0J>*CJjhZ )h:CJUjh:CJU h:>*CJh: h:CJ h:5CJh:0JCJhEFh:0J5CJhEFh:0J>*CJj4hEFh:CJUhEFh:0JCJjhEFh:0JCJU&tu)*=2"QҸ2^gd:^gd:p^pgd: !"и(4  FHSdAB~v㽷uih:h:>*CJ aJ hXh:5>*CJ aJ hth:>*CJ jh:CJhth:5CJ h:>*CJ h:CJH*h:0J6CJ h:CJh:0JCJh#$h:0J>*CJ"jhh#$h:CJU\h#$h:0J5CJ jh#$h:0J5CJU& f(*4 RSd}~uvgd:^gd:^gd:p^pgd:HINOfQ:z & F pp^pgdQ^gdX^gdXgd: @ `^@ ``gd:^gd:^gd:IR`asuMOQ[nosuxz:Czzqzqhh:CJhh:5CJhh:0J6CJhh:0J56CJh:h:5CJaJh:h:CJaJh:h:5CJ$aJ$hXh:CJ aJ hXhXCJ aJ h:0JCJ h:CJH* h:CJH* h:5CJ h:CJ hjhCJ,9Btuv./<HltBFI_bq 3459ºº³}hX0J>*CJjhXCJUjhXCJU *hXCJ jhXCJ hXCJ hX5CJhX56h hX6hhX0J56CJh:0J6CJ]hMh:5CJh:0JCJhh:CJ h:CJ19u<lBq  & FG pp^pgdCjR^gdXgdY# & F pp^pgdQ^gdX^gdX & F pp^pgdQ9:BC^`a(5Ʋ|ƲmV|O hY5CJ,jhxh'B*CJUaJphhxhxB*CJaJph$hxhx0J>*B*CJaJph,jNhxh'B*CJUaJphhxB*CJaJph&jhxhxB*CJUaJphhxhxCJaJhxhX5CJaJhxhXCJaJ hX5CJ hXCJjhXCJUBC(_q)^4l & FgdY ^`gdX ^`gdX p^p`gdXp^pgdX & FgdY^gdx^gdX5@AB_lvwx&'GHILMN)0^b꼳سthh`+hX0J>*CJjhZ )hXCJUh`+hXCJjh`+hXCJU hXCJ hX5CJhY5B*CJphhYhYCJ jhYhY5CJhYhY5B* CJph hYCJ jhYhYCJ hY5CJhYhY5B*CJph(4 efgp_`cdnpŷ|h|Cx0JCJ h|CxCJH* h|CxCJ hJCJhJh|Cx5CJhJhJ5CJhJhJ0J6CJhJhJ0J6>*CJh|Cx0J6CJhJh|Cx0J56CJ,aJ,hY#hX0J6CJ] hYCJ hXCJ hX5CJ-f_ h^`hgdTE & F pp^pgdQ^gdTE^gdTEgdY# & FgdY$ h&CDZ\ORTUh :ͽӵͦӞ͔͍ӦӃͦͦͦh%3Sh|Cx5CJ h|CxCJH*h%3ShJ5CJh%3S0JCJ h%3SCJh%3S0J5CJh|Cx0JCJhh5CJ haWBCJ h|CxCJ hJCJhJhJ5CJ hJ5CJh|Cx0JCJhh|Cx0J6>*CJ0hDh?r >T8^8gdTE 8h^8`hgdTE & F ^gdQ h^h`gdTEh^hgdTE & F pp^pgdQ & F ^gdQ^gdTE:=*5T\q{}  <>\`bdj ST] ߼ߤ~ߊ߶߶߶ jh%3Sh%3SCJhhX0J5CJhhX0JCJh%3S0J5CJh|Cx0JCJhh|Cx5CJ hhXCJhhhX5CJh%3Sh|Cx0JCJh%3S0JCJ hn8[CJ h|CxCJhCh%3S5CJ h%3SCJh%3Sh%3S5CJ1 ?HRS ),MO-=@VwwlwwhoChoC0JCJhoChoCCJhhoC5CJhh5CJhhCJhhoCCJhh|CxCJ hoCCJhoChoC5CJ hCJhh%3SCJaJhh)5CJaJhhX0JCJ hhXCJh%3Sh|Cx5CJ h%3SCJ h|CxCJ*GHS  >GxUM h^h`gdTE ^ gd-k & Fgd-k^gd-k & F   ^ gdQ8^8gdTE^gdTE'HNOXx  >DF`aefrtwxGQ^_wx߼֤ujbZhCJaJh]CJaJh-kh]CJaJh]h]5CJaJh]h-k5CJaJh]h5CJaJh-khCJaJh-kh5CJaJ jhoChoCCJhoChoC5CJhh5CJ hoCCJhoChoCCJ hCJ h]5CJhoCh|CxCJhh|Cx5CJ#x@BTUa125BLMR ·sokokch|Cx0JCJhaWBh|CxhaWBh|Cx5CJaJ haWBCJhaWBhaWB5CJhaWBhaWBCJhaWBCJaJhaWBhaWB5CJaJhaWBh|CxCJaJhaWBhaWBCJaJ hCJhh5CJh-khoCCJaJh-kh5CJaJh-kh-k5CJaJh-khCJaJ#M !5?hit x & FI pp^pgdQp^pgdTE^gdTE^gdTE^gdTE & F p  ^ gdQ !45:$%HPVgistz  giĻıĻĻĻĻĻ૟haWBCJaJhaWBh|CxCJaJhaWBhaWBCJaJhaWBhaWB5CJaJ h|CxCJhaWBhaWB5CJhaWBhaWBCJhaWBh|CxCJhaWB0J6CJhTEh|Cx5CJhTEhTE5CJh|Cx0JCJhh|Cx0J6>*CJ/&'vx$[\n3RSTk&'U(7bd|Ļ~njmh]h{CJUh]h]CJjh]h]CJUh1 h|Cx0JCJh1 h1 CJh1 h|CxCJH*h1 h|CxCJh1 h)[CJh|Cx0J56CJh|Cx0JCJh)[h)[CJh)[h|CxCJ h|CxCJ h)[CJh)[h)[5CJ'x\STk)|=>^gdTE  ^gdTEgd^gdp^pgdTE^gdTE & FI pp^pgdQ ^`gdTE & F p@ @ ^@ gdQ kl .FI8:<=>HѽѴѽѽѽѽѽѽѽѽ{pgh|Cx0J56hh|CxCJaJh?`h|Cx5CJ$aJ$hTE5CJ$aJ$hh|CxCJaJh|Cx0JCJ h|CxCJh1 h|Cx0JCJh1 hn8[CJh1 h1 CJh1 h|Cx0JCJh1 h|CxCJjh]h]CJUh]hn8[0J>*CJh]h|Cx0J>*CJ&HJK`abefhi|}~#&)gprh|Cx0J5CJh|Cx0JCJ hHCJh|Cx0J6CJ h|CxCJ h|Cx5CJjh|CxUj!h|CxUjh|CxUjOh|CxU h|Cx0J>*jh|CxUjh|Cx0J6U h|Cx0J62gro-.Q & FH pp^pgdCjR^gd?` ^`gd?`^gd?` & F^gd?`gd|6 & Fy pp^pgd H^gdTE ^`gdTEr{ 4:;Iox,ɽɶɧ~nb~hJhJ0J>*CJjhJh_1CJUhJhJCJjhJhJCJU hJCJ h|Cx5CJ h|CxCJ h|Cx>*CJh|6h|Cx h|60J6h|6h|Cx0J56 h|Cx0J6hH0J5>*CJhH0J5CJh|Cx0J5>*CJh|Cx0J5CJh|Cx0JCJ&,-.4@QY  5:/ 3     T V _ h   ] f   )2dgos!"Hhn8[ h|Cx5hTE0J56CJh|Cx0J56CJh|Cx0JCJ h|CxCJH* h|CxCJH*h|Cx5>*CJ jh|CxCJ h|Cx5CJhHh|Cxh|Cx0J5CJ h|CxCJ= /   _  ]  )doHI^gdTEgd|6  ^gd?`^gd?` ^`gd?`^gd?`HIRTU\^_sv|5;-6ghi!%.7ý͆}}}}r}}h|Cx0J5>*CJh|Cx0J5CJh|Cx0JCJ h|CxCJ h|Cx5CJh|CxhTEh|Cx0J6CJ]hH0JCJh|Cx0JCJ hTECJh|6h|Cx5CJh|Cx0J6CJhTE0J56CJh|6hTE0J6CJh|Cx0J56CJ h|Cx0J6,5-hi.j5O ^`gd?` & F^gd?`^gd?` ^`gd?`^gd?`^gd?`5617AJ )*& ' ( 6 7 @ A N O | } ~   Ƚ𚪑~jh|CxCJU hn8[CJh|Cx0J>*CJjhZ )hCJUjh|CxCJU jh|CxCJhuThHCJaJhuTh|CxCJaJ h|Cx0J6 h|Cx5CJ h|Cx5 hTECJh|Cx h|CxCJh|Cx0J6CJ1&1A M!"j$&2'v'(5(6(a( & FH pp^pgdCjR & FagduT & FbgduT^gduT^gd?`gduT^gd?`   M!Q!""##\#b####($L$N$j$p$&&&&v''((5(6(C(`(a(((((((((ȼȴȼȨznehyh|CxCJhyh|Cx0J>*CJj*hyhCJUhyhyCJjhyhyCJUh|Cx0JCJhuTh|Cx>*CJaJhuTCJaJhuTh|CxCJH*aJhuTh|CxCJaJhuTh|Cx5CJaJ h|Cx5CJh|Cx0J6CJh|Cx0J56CJ h|CxCJ'(((((((4)=))*M*N***[+^+?,C,W,Y,q,t,,,-%---....K.R.a.e.u.x.../ /)/K/j/l//////0/00022żז׮h|Cxh|Cx0JB* CJphh|Cx0JB* CJphh|Cx0JCJ hTECJh|Cx6>*CJh0J56CJ h|CxCJH*h|CxB* CJph h|Cx5CJ h_}CJ hn8[CJ hHCJ h|CxCJ9a(4)**[+ ,?,q,,--...///000222#3^gd?` ^gd?`^gd?`gduT^gd?`^gdTE22222#3h3i333/404E4F4G4J4K4R4{44444444444555 5'5,55566+6.6T6w666Ժ~~~w~~ h|CxCJH* h/MLCJh/MLh/ML5CJh/MLh|Cx5CJh/MLh/MLCJaJh/MLh/ML5CJaJh/MLh|CxCJaJh|Cx0J5>*CJjh|Cx5CJUjh|Cx5CJU hn8[CJ h|Cxh h|CxCJ hn8[5CJ h|Cx5CJ,#333R4{44445666l7m77M8899::[;^gduT^gd?`^gd?` & Fgd/ML^gd/ML ^`gd?`^gd?`666667>7m771848C8M8P8x8y88889999:: ;;;;R;S;T;X;Y;Z;[;;;;;;ܷܰܠܙvogh|Cx0JCJ h|CxCJH*hih|Cx0J>*jhih|CxUjhih|CxU hih|Cxh?`h|Cx5CJ hACJ hA5CJhuTh|CxCJaJ hn8[CJ h|Cx0J6h|Cx0J6CJh|Cx h|CxCJ h|Cx5CJ h/MLCJh/MLh/MLCJ h/ML5CJ([;;w=J> ????@@+AAAIBC>>>>>>>>>??????L???@ @y@z@@@@@@@@+A﫧闋ufh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx h|Cx5 h|Cx6CJh|Cx0J6CJh|Cx0J56CJ h|CxCJH* jh|CxCJ h|Cx>*CJ h|Cx5CJ h|CxCJ hACJhAhA5CJ(+A.AAAAABIBRBBBoCDDDDDDEEEEEF4F7FFFFFFFFFFFFʿʿ޹򮠙xh\xxh!9hx$0J>*CJjh!9hx$CJUh!9hx$CJjh!9hx$CJU hx$CJ h|Cxh h|Cx5hhuTh|Cx0J6CJaJh]0J6CJaJ h:CJhAhACJaJhAh|CxCJaJ jh|CxCJ hACJ hA5CJ h|Cx>*CJ h|CxCJ h|Cx5CJ$7FFG@GGH|HHIZIIIJJgK5M6NNPP^gd?` h^`hgd?`  ^gd?`^gd?`p^pgd?`^gd?`^gd| & FB pp^pgdQFFFF G GGGGGGGHH{H|HHIIIIIJJ$JJJJJJgKpKzKKKKKKLLuoooeohphp6CJ hpCJ *hph|Cx5CJ hCJh"h|Cx5CJ h|Cxh h|Cx5hhuTh"CJaJ huThuT h"CJ h"5CJ h|CJh!9h|Cx0J>*CJjh!9hW CJUh!9h"CJjh!9h"CJU h|CxCJ hx$CJ&LLMLjLkLlLsLtL5M8MMMMMMM6N>NNNPPLPMPPPQQR2R]RRRRS$S&S5S6S*h\h|Cx h|Cx5h"0J>*CJjph"CJU h"CJjh"CJU/PPP;Q]RRRR%S&SWSSBTCTsTTTT(U ^`gd?`p^pgd?`^gd?` ^`gd|p^pgd|^gd|^gd?` & FA pp^pgdQ^gd?`(U)UpUW7XXYYYZ\w]] ^^^c_^gduT & FgdZ & Fgd & FL pp^pgdQ & FO 8^gdQ & FM pp^pgdQ & FN 8^gdQ^gdZ^gdZgd~(U)U@UPUoUpUvUxUUUV*VVVVVWWX X(X7X[X^XXXXXXXYYY1Y3Y4YRYSYTYú̺̺̐vd"jh~hiNCJU\h~h~0JCJjh~h~0JCJUh~h~5CJ h~CJh~h~CJ hCJh~h|Cx0JCJh~h|CxCJh~h5ZwCJh~h|Cx5CJh~CJaJh~h~CJaJh~h|Cx5CJaJh~h|CxCJaJ&TYjYkYqYYYYYYYYYYYYZZZ\\\N\O\w]]]]]]]^ ^m^^^^^^ǼǶүҶҤҶҶҚҐҊҁҊҊwҊkh~h~5CJaJhh|Cx5CJh~hn8[CJ hCJh~h~5CJh~h|CxCJH*h~h|Cx0JCJ h~>*CJ h~CJh~hn8[CJaJh~h|CxCJaJh~h|CxCJh~0J5CJjh~h~0JCJUh~h|Cx0J>*CJ%^ __"_-_J_c_g_j_o_______U`V`W`Z`\`]`q`r`s`u`v`x`y````````нбwlZwl#jhdqhiNCJUaJhdqh|CxCJaJhdqh|Cx0J>*CJaJ#jdhdqhiNCJUaJhdqhdqCJaJjhdqhdqCJUaJh~h~5CJaJhh5CJh~hCJ hCJ h5CJh~h|Cx0JCJaJh~h|CxCJaJh~h~CJaJ#c__W`abbcccoccddef fNffdggiii ^`gdZ ^`gdZ^gdZgd~^gdZ^gduT^gd & Fgd````````aa.a/a0aFaGaQaRagahaiaaaaaaaaaaabbƸԭԭԭ~sh]hQhshh~h|Cx>*CJaJh~hn8[CJaJh~h|CxCJaJh~h~CJaJhdqh~CJaJ#jRhdqhiNCJUaJ#jhdqhiNCJUaJhdqh|CxCJaJhdqhn8[0J>*CJaJhdqh|Cx0J>*CJaJjhdqhdqCJUaJ#jDhdqhiNCJUaJhdqhdqCJaJbbbQb_bhbmbbbbb,c0cTcacccocqcccccccccccc d dddd$d4dddee*e.e_eceeeeeȿȲȿxhZh|Cx5CJhZh|Cx0JCJhZh|CxCJhZhZ0J>*CJjhZhiNCJUjhZhZCJUhZhZCJ hZCJ h|Cx>*CJhCJaJh~h|CxCJaJh~h~CJaJh~h~5CJaJ/ef f ff.fMfOfWfffff$g0gdghgggggg_hjh*CJhZhZ>*CJhZhZCJhZh|Cx0J6CJhZh|Cx0JCJhZhn8[CJ hZCJhZh|Cx5CJhZh|CxCJ4ijjjkk6lmLmmmm%nn6oo$p%p&p'p(p2p3pp & F^gduT & F & Fgd"Pgd"P & FPgdZ^gdZ^gdZ7lelfljlqlllllmmKmymmmmmmmmm nn o o5ooooo&p(p2p3p4pOpPpQpr+jHh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3f h|Cx5CJh}vh|CxCJ`OJQJaJ` h|CxCJh"Ph"P5CJ h"PCJ h'CJh"Ph"P5CJ$aJ$ hZCJhZhZCJhZh|CxCJ%Qp[p\p`papvpwpxp{p|p~pppppppppppppppppppppppqqqq˵˟ˉs]+jh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3f+j&h}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f$q q!q"qDqEqFqWqXqZq[qyqzq{qqqqqqqqqqqqݟݓq[qIq#h}vh)J^0J5>*B* CJph3f+jh}vh)J^5B* CJUph3f%jh}vh)J^5B* CJUph3fh}vh)J^5B* CJph3fh|Cx5B* CJph3f+jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3fp!qZqqq;r#h}vh}v0J5>*B* CJph3fh)J^0J5>*B* CJph3f+jUhZ )h5B* CJUph3fh}v5B* CJph3f%jh}vh}v5B* CJUph3f+jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f+joh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3fh)J^5B* CJph3f4r5r9r:r;r*B* CJph3f+jh}vh|Cx5B* CJUph3f%jh}vh|Cx5B* CJUph3fh)J^5B* CJph3fh}vh|Cx5B* CJph3f%jh}vh}v5B* CJUph3f#h}vh}v0J5>*B* CJph3fh}v0J5>*B* CJph3frrrrrrrrsss;ss?s[s\s]sfsgshsiskslsssssָ֚֚֚n\֚֚F+jh}vh|Cx5B* CJUph3f#h}vhn8[0J5>*B* CJph3f+jWh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3fh}vh)J^5B* CJph3fh|Cx5B* CJph3f#h}vh|Cx0J5>*B* CJph3f%jh}vh|Cx5B* CJUph3f+jah}vh|Cx5B* CJUph3fssssssssssssssssssssssssstttttt2t3t4tHtItKtȹȹȹȹȹȹwȹȹaȹ+jh}vh|Cx5B* CJUph3f+j+h}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3f+j;h}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f#h}vhn8[0J5>*B* CJph3f$KtLtatbtctftgtitjttttttttttttttttttݟ݉vgQv+jPh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3f+jjh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3fttttttttuuuuuuu!u"u$u%u;u*B* CJph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f%jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3fZu[u\u_u`uaubuuuuuuuuuuuuuuuuuuuֵzkkUֵ?+jih}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f#h}vh|Cx0J5>*B* CJph3f+jsh}vh|Cx5B* CJUph3f%jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f#h}vh|Cx0J5>*B* CJph3f%jh}vh|Cx5B* CJUph3f+j h}vh|Cx5B* CJUph3fuuuuuvvv"v#v%v&vMvNvOv\v]v^v_vvvvvvڿڿڿڇteOt=t#hF/h|Cx0J5>*B* CJph+jhF/h|Cx5B* CJUphhF/h|Cx5B* CJph%jhF/h|Cx5B* CJUphhuT5B* CJph3f+jch}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3fhF/5B* CJph3f%jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3fvvvvvvvvvvvvvvvvvvw w w wwwww˟˟o˟cP%jh}vh|Cx5B* CJUph3fh|Cx5B* CJph3f/j]hF/hI<5B* CJUaJph/jhF/hI<5B* CJUaJph'hF/hF/0J5>*B* CJaJph/j{hF/hI<5B* CJUaJph)jhF/hF/5B* CJUaJph hF/hF/5B* CJaJphhF/hF/5B* CJphw+w,w-wAwBwCwDwEw_w`wawiwjwlwmwwwwwwwwwwȶ񧔧~lVl@+jh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3f#h}vh|Cx0J5>*B* CJph3f+j9h}vh|Cx5B* CJUph3f%jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3f#h}vh|Cx0J5>*B* CJph3f%jh}vh|Cx5B* CJUph3f+jh}vh|Cx5B* CJUph3fh}vh|Cx5B* CJph3fwwwwwwwwwwwwwwwwxx xx˼wjXjCX2 h-khA/0J>*B* CJph3f(jh-kh6GnB* CJUph3f"jh-khA/B* CJUph3fh-khA/B* CJph3f h-kh|Cx0J>*B* CJph3f(jh-kh|CxB* CJUph3f"jh-kh|CxB* CJUph3fh-kh|CxB* CJph3fh}vh|Cx5B* CJph3fh}vh|Cx5B* CJph3f#h}vh|Cx0J5>*B* CJph3f%jh}vh|Cx5B* CJUph3fxxxxx?x@xAxSxTxgxhxsxxx y!yyyyyzz|zzzzz{{{${ԭœԕ~wnndWdNh|Cx0J>*CJjh|CxCJUjh|CxCJU jh|CxCJ h|Cx>*CJ hn8[CJ h|Cx5CJ h|CxCJh|Cx hA/5CJ h-kh|Cx0J>*B* CJph3f(j~h-kh|CxB* CJUph3f"jh-kh|CxB* CJUph3fh-kh|CxB* CJph3fh-khA/B* CJph3f"jh-khA/B* CJUph3fgxhxsxxxxyylzz{{Q}Y}Q~W~h~i~|~~ & F^gd-k & F^`gd-k & Fz pp^pgd H & Fp^pgd-k & F^gd-k  & F^gd-k & F${&{{{{{{{{{{,|-|Y|a|||||||||||| }}-}5}Q}X}}}Q~U~h~|~Áҫ"jLhA/h6Gn5CJUhA/hA/5CJjhA/hA/5CJU hA/5CJjh|CxCJU h|Cx>*CJ hCJ hn8[CJ h|Cx5CJh|Cx0J>*CJjlh|CxCJU h|CxCJjh|CxCJU.~j _wȁRׂ & F^gd-k & F^gd-k & Fp^pgd-kÁƁǁȁɁ:;<PQRSxyzٵٚوvoh h|Cx5CJ hA/5CJ"jhA/h6Gn5CJU"j.hA/h6Gn5CJU"jhA/h6Gn5CJUhA/hA/CJ"j(hA/h6Gn5CJU"jhA/h6Gn5CJUhA/hA/5CJjhA/hA/5CJUhA/hA/0J5>*CJ(݂ނ89:NOrsw124;dez{|JTmȼȭțȉނ|r|lchA/hA/CJ h7 CJhA/hA/5CJ hA/CJ hA/5CJhQ[uhQ[uhQ[u0J>*CJaJ#j hQ[uh_%CJUaJjhQ[uhQ[uCJUaJhQ[uhQ[u5CJaJhQ[uhQ[uCJaJ h|Cx>*CJh|Cx h|Cx5CJ h|Cx5h h|Cxh jh|CxCJ h|CxCJ$ׂ9:rs12IJU~^gd-k & F pp^pgdQ & F^gd-kgduT & F^gd-k  & F^gd-k & F^`gd-kmt$%ч҇Ӈևׇ؇هڇ !@AceɈʈ²zqqqkekq h_}CJ hn8[CJ jh|CxCJ h-k5CJh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h-kCJ h|Cx>*CJ jh|Cxh|Cx h|CxCJ h|Cx5CJ hA/5CJhA/hA/CJhA/hCJ'$%هڇˆ4^gd-kp^pgd-k ^`gd-k & F^ & F & F^gd-k & F^gd-kʈԈՈ݈ވ   +3]^{|+,BMWXei67LM]^~*67NOZhivwߌKZ\lю܎ºµ hpMh jh|Cxh h|Cxh h|CxCJH* h|Cx5CJ h|Cx>*CJh|Cx h|Cx5 h_}CJ hpMCJ jh|CxCJ h|CxCJG45DoΉ@be67LM*Zp͌ߌ & F^`gd-k  & F^gd-k & F^gd-k & F^gd-k & F  & F^gd-k^gd-kߌKюPU & F^gd-k^gd-k ^`gd-k^gd-k & F8 ^gdCjR & Fh^`hgd-k & F^gd-k܎Qbӏԏ'(;AGQ\zڒےܒBCPjh|CxCJU hpMCJh(*h|Cx5B* CJphh(*h(*5B* CJph h|Cx5CJ h|CxCJH*h|Cx5B* CJphh|Cx0J>*CJj(h|CxCJUjh|CxCJU hn8[CJ h|Cx5CJ h|CxCJ2()QzCDH @ & F^gd-k & F^gd-k & F^gd(* & F` & F & F^`gd-kHQefg ?@L;D_ۖ0<g}—ʗۗ3팅 h|Cx>*CJ h(*5CJ h(*CJh(*h;%5CJ h;%5CJh;%h;%5CJh;%h;%CJ hbCJhbhb0J>*jhbh+<UjhbhbU hbhb h|Cx5CJ h|CxCJ h;%CJ3@;ږۖ01giИј & F@ ^@ gd-k & Fp^pgd-k & F^`gd-k & F^`gd-k & F^gd-k & F^gd;%3@Иޘ /1iřә OPYZcqϛћ ϼɲɐt"jh;eh$5CJUh;eh$5CJjh;eh$5CJU h$6CJh;eh$6CJH*h;eh$6CJ hpM5CJ h;eCJ h$CJ h$5CJ h$5CJ h$ hn8[CJ hpMCJ h|Cx5CJ h|CxCJ h_}CJ-јޘ12Luřƙә.K}5AO & F^gd-k & F^`gd-k & F^gd-k & Fp^pgd(* & F^`gd-kOPYZ:ҞӞ۞ܞ5ğ5q & FE p^gdCjR & Fgd;e & F^gd$ & F`gd$ & F^gd$gduT & Fgd$gd$567=>@A[\]fgijҜӜԜӽݰӽݣӽݖӽ݉ӽ|ӽjh$CJUj0h$CJUjh$CJUjPh$CJUjh$CJUh$0J>*CJjph$CJUjh$CJU h$CJjh;eh$5CJUh;eh$0J5>*CJ/ 45689:?MVÝĝŝϝН)*,-Fó̧̡xm`Wh$0J>*CJjYh$CJUh$0J5>*CJjh$5CJUjh$5CJU h$>*CJ h$5CJ h$CJh;eh;e0J>*CJj{h;ehMCJUh;eh;eCJjh;eh;eCJU h;eCJh;e0J>*CJjh$CJUjh$CJU"FGHPQSTijklnyz|ўҞӞó̧̐ي}td}X}RK h$5CJ h;CJh;eh;e0J>*CJjh;ehMCJUh;eh;eCJjh;eh;eCJU h;eCJhKCh$CJhKCh$0J>*CJH*hKCh$0J>*CJjChKChFCJUhKChKCCJjhKChKCCJU h$CJh$0J>*CJjh$CJUjh$CJUӞ۞FPğ՟5@ܠޠҡӡ (@DGLX^`aj٢ū裟{ jh$h'T}h$5 hpMCJ h'T}CJ h$H*h$h'T}h'T}h'T}5h$0J5>*CJj'h$5CJUjh$5CJU h$CJH*h$5CJH* hpM5CJ h$CJ h$5CJh;eh$>*CJ, (@G٢37AB & Fgd$ & F^gd$ & F^`gd'T} & Fgd'T}  & F gd'T} & F ^gd$ & F^`gd$ & F`gd;e & FE p^gdCjR"#$12367AOǤoȥɥ˥̥֥ץѻѮ~wndnwdh6yh6y5CJh6yh6yCJ h6y5CJhuTh$CJh$0J>*CJj h$CJUjh$CJU h$>*CJ h$CJ h$5CJ h'T}CJh'T} h'T}h'T} h'T}5h$hy*jhy*CJjXh$CJUjh$CJUh$0J>*CJjh$CJUjh$CJUh$5CJH* h6y5CJ h$5CJ h$CJh6yh6y5CJ h6yCJ3ͧΧNOfgUMN^_o5l & F^gdk & F^gd$ & F`gd$ & Fgd$ & F^`gd$ & F^gd$(TU` CDEKLN^_o5>delu{ǫȫϫzphkh$5CJhkhkCJ hkCJH*hkhkCJH* hkCJhkhk5CJ h$5CJhuTh$CJ h$>*CJjhZ )hCJUh$0J>*CJjhZ )hCJUjh$CJU hpMCJ h%};CJ h$CJ,l!ijEFW & F^gd$ & Fgd$ & F^`gd$ϫԫݫޫ!jxz{۬ܬݬ6EFW!"#.9ʮѮ hpMCJ hn8[5CJ h|Cx5CJ h|CxCJ h|Cx>*CJ h$h$B* CJph h$>*CJjh$CJUh$0J>*CJjSh$CJUjh$CJU h$5CJ h$CJ8Gv8 ͵[ & F^`gd3 & F pp^pgdQ & F^gdF} & Fp^pgd3 & F^gd3 & F^gd3 & FgduT6>AJuwvʰ۰)8A   (?noü~ݦ h>CJ h$CJh$h$0J>*CJjGh$hMCJUjh$h$CJUh$h$CJ h$5CJhZh$5CJ hZCJhZhZ5CJ hF}CJ jh|CxCJ hpMCJ h|CxCJ h|Cx5CJ-³ijϳгҳӳ /79:^_`Ƿ֩ǙВqgUq"j hZ )h5CJUhrvhhrvh5CJjhrvhhrvh5CJU hF}CJ h;eCJ h|CxCJ h|Cx5CJjh$h$CJUh$h$0J>*CJH*j9h$h$CJUh$h$CJ h$CJh$h$0J>*CJjh$h$CJUjh$h$CJU`ijlx&͵ε\mwx°ݪݠݐxxqxxxxxxqx hn8[5CJ h|Cx5CJ h|CxCJh h;e0JCJjh h;eCJUjh;eCJU h]CJ"jhZ )h5CJUhrvhhrvh5CJ hF}5CJh;eh;e5CJ h;eCJjhrvhhrvh5CJUhrvhh;e0J5>*CJ,[\~>lmVCrs & F^`gd3 & Fp^pgd3 & F^gd3 & F^gd3V_CGais|}~)3@ü׼ؼBluENPQcdí h^qYCJhn8[0J>*CJh|Cx0J>*CJjRh|CxCJUjh|CxCJU h|Cx5h|Cx hn8[5CJhlhlCJ hlCJ hl5CJ h|Cx5CJ h|CxCJ9s)BlEQ0 & F^`gd3 & F1 pp^pgdQ  & F^gd3 & F pp^pgd H & F pp^pgd H & F^gd3 & F^gd3deԾվ0h¿п+,BMUi}w hpMCJh|Cx56CJ hpM5CJ h|Cx>*CJ h|BCJ h|Cx5CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h^qYCJh(KSh^qY0J>*CJjh(KShI<CJUh(KSh^qYCJjh(KSh^qYCJU,,-Chi^_w & Fp^pgd-k & F^gd-k & F^gd-k & F & F^`gd3 & F^gd3 & Fp^pgd{ _wx  1=@Cen1@\drtw%xzǹ䴰ǹ hn8[CJ h|Cx>*h|Cx h|Cx5 hn8[5CJ h|Cx6CJ h|Cx5CJhuTh|CxCJ h|Cx>*CJ hpMCJ h|CxCJh|CxB* CJphh|Cx5B* CJphAwx   evw & F^gd-k^gd-k ^`gd-k^gd-k & Fp^pgd-k  & F^gd-k  & Fp^pgd-k & Fp^pgduT & F^gd-k & Fw45WFGf  & F^gd-k  & F^gd-k & F^gd-k & FgdV & F^`gd-k & Fp^pgd-kijw5UGfg|}(2ABRWX]ft ׸ưƥ h|Cx0J>*jh|CxUjh|CxU h5CJ h|Cx5hh|Cx h|Cx6CJ hpMCJ h|Cx5CJ hVCJhVhVCJ hV5CJ hn8[CJ h|CxCJ>fg|}R?} & F/gd.9 & F^gd.9  & Fp0^p`0gd.9 & Fp^pgd & Fp0^p`0gd & F^gd & Fp^pgdjT* & F^`gd-k  & F^gd-k & F^gd-k >? 78]^_ghsOmitAL`ath|Cx5B* CJphh.9 h|CxCJh.9 h|Cx0J5>*CJ"jh.9 h75CJUh.9 h.9 5CJjh.9 h.9 5CJU h|Cx5CJ h|Cx>*CJh|Cx hA5CJ hACJ h_}CJ hpM5CJ h|CxCJ h.9 CJ hpMCJ,~7NOm\ & F^`gd & F pp^pgd H & Fp^pgd & Fp0^p`0gd & F^gd & F^gdA & F^gdAIJ^_K ^`gd^gd>l^^ & F^ & F^ & F & F^gd & F^gdJ^ghikl$JKɳ|h^h^CJaJh^h>lCJaJh^h>l5CJaJh>lh|Cx hpMCJ h|CxCJH*h|Cx0J>*CJjh|CxCJUjh|CxCJU hn8[5CJ h|Cx>*CJh|Cx5B* CJph h|Cx5CJ h|CxCJ hn8[CJ.KO!"#7>?H\^`istȻȒ͋{ocXcLohu/hu/5CJaJhu/h\CJaJhu/h\5CJaJhu/h|Cx5CJaJ hn8[CJ h|CxCJh|Cx h>lh>l h^hh^h>l0J>*hjTh^h7Uhh^h^hjh^h^Uh h>lh h|Cxhh^h|CxaJhh^h|Cx5aJhh^h^CJaJh^h^5CJaJ"#7GHt<=i_`y & F^gd-k & F^^gdu/^ & F^  & F^gd>l^gd>ltu|}NR<=iz~>?`ny PQ»´h|Cx0J>*CJj!h|CxCJUjh|CxCJU hn8[CJ hpM5CJ hn8[5CJ h|Cx5CJ hpMCJh|Cx5B* CJphh|Cx56CJ h|Cx5>*huTh|CxCJ h|CxCJ h\CJ3yCMY 5c\M & Fp^pgd-k & F^`gd-k ^gd-k & F^gd-k & F ^gd H & F^gd-k+,-1245JKLOPRSuvw|}ٿٲwjahqhqCJjhqhqCJUjh|CxCJUhYh|CxCJhYh|Cx0J>*CJjhYh%szCJUhYhYCJjhYhYCJUjZh|CxCJUjh|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU#CLNOdefijLMVYZпвУЙУɐЁ{uoueueuohjhhjhCJH* h/*CJ hjhCJ hc CJ hmCJhhCJhh|CxCJh|CxB*CJph hCJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJhqh|Cx0J>*CJjhqhqCJUjhqh`iCJU' 56CFgr\dx{A .1 h>lCJh|Cx0J>*CJj)h|CxCJUjh|CxCJU jh|CxCJ h|CxCJH* hpM5CJh$h|Cx hpMCJ h|Cx>*CJ hc CJ h|Cx5CJ hc 5CJ h|CxCJ:1MP   89DEGJ~gT$h-kh|Cx0J>*B*CJaJph,jMh-khB*CJUaJphh-kh|CxB*CJaJph&jh-kh|CxB*CJUaJphh-kh|CxCJaJ h>lCJh|Cx0J5>*B*CJph+jh-kh5B*CJUphh-k5B*CJphjh|Cx5B*CJUph h|Cx5CJ h|CxCJ MGqNc# & F pp^pgd H & F^`gd-k & F p@ @ ^@ gd H & F pp^pgd H & F^`gd-k & F^gd-k & Fp^pgd-kuvqw*-NSTac#)˸򯨯򛕛 h|CxCJH*h|Cx hACJ hA5CJ hn8[CJ h|Cx6CJh|Cx56CJ hpM5CJ hpMCJ h>lCJ h|Cx5CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|CxCJH*1#$CDT2kl & F^gd-k & F^ & F^gd-k & F p@ @ ^@ gd H  & Fp^pgd-k & F^`gd-k!"#HIJKRS$CDTov&'2U^|ppdp^ hpMCJhn8[5B* CJphh|Cx5B* CJph hCJh|Cx hn8[CJh|Cx0J>*CJh-k0J>*CJj hZ )hCJUjh|CxCJU h|CxCJH* h|CxCJhpM0J5>*CJh-k0J5>*CJ"jUhZ )h5CJU h|Cx5CJjh|Cx5CJU$^bjkl./0CD_`}~ fgopqs˵˯˵xng h|Cx>*CJh$ h$ >*CJh2qhpM5CJ h$ CJh2qh|Cx5CJhuTh|CxCJh|Cxj`hZ )hCJU hCJh|Cx0J>*CJjh|CxCJUjh|CxCJUhuTh|CxCJaJh|Cx5B* CJph h|Cx5CJ h|Cx6CJ h|CxCJ(Vfgqp^pgd$  & F} 88^8gd H  & Fh^h`gd-k & F 88^8gd H & FcgduT & Fh^hgd-k & F & F^gd-kq=>?GHi~Pm & F~  & F^ & Fp^p & F^` & F^ & F & F`h^hgd$ >?GHM  %&%&2#,?H͘͢ h|Cx5hAh|Cx5 hpMCJhAh|Cx5CJ hACJ h$ h$ h|Cx5>*h|CxB*CJphh|Cx jh|CxCJ h|Cx5CJ h*CJ h|Cx>*CJhuTh2qCJh2qh2q5CJ h2qCJ h|CxCJ0 %&&? & Fp^pgd$ & F^gd$ & F^gd$ gd$  & F^gd$  & F & Fp^pgd* & F^ & Fp^p & F^ & F~?X"  & F^gd$  & Fp^p`gd$  & F/   ^ gdQ & F}gd* ^gd$ & F^gd$ & F^gd$ & F^`gd$ & F^gd$  & Fp^pgd$   WX#4M^deŻѵѯѢ}q}hѯh2qh|CxCJh2qhn8[0J>*CJh2qh|Cx0J>*CJj h2qhWbCJUh2qh2qCJjh2qh2qCJU hn8[CJ hpMCJhh>*CJ hCJ h*CJ h|CxCJh|Cxh|Cx0J5>*j h|Cx5U h|Cx5jh|Cx5U&"#4LM^23JN& & F^gd$ & Fp^pgd$ & F^gd$  & F^`gd$  & F^gd$  & Fp^p`gd$ 3VX`NTrxyz &/6ST3򶬶򶬶xhuThCJaJ hCJhuTh5CJaJh|Cxh>h>h>CJ h_}CJh>hn8[5CJh>h|Cx5CJ h>CJ h>5CJh+{-h|CxCJh+{-h+{-5CJ h+{-CJ hpMCJ h*CJ h|CxCJ h|Cx5CJ-T34KEFOP & F^gd & F^gd ^gd^gd & FgdgdgduT & F^gd$ & Fp^pgd$  & F^`gd$ 34KFNPRhijlmo0123=WX_z{WXag~Ǿh|CxB* CJ(OJQJphh|Cxhh;%CJh;%h;%5CJ h;%CJ h;%5CJhh5CJ h>*CJ hCJ h5CJhBPij)*3X{VW & Fp^pgd & F/gd & F/gd;% & F^gd & F^gdWfg~}~ & F^gd$  & FgduT & F^`gd & Fp^pgd & F^gd & F^gd;% & F^gd789MNPQԼԓjVL8&jh`Ph`PB* CJUaJphh`PB* CJph'h`Ph`P0J5>*B* CJ aJ ph/j| h`Ph`P5B* CJ UaJ ph h`Ph`P5B* CJ aJ ph)jh`Ph`P5B* CJ UaJ ph'h`Ph|Cx0J5>*B* CJ aJ ph/j h`Ph|Cx5B* CJ UaJ ph h`Ph|Cx5B* CJ aJ ph)jh`Ph|Cx5B* CJ UaJ ph h|CxCJQklmuvxyŲŲŲsdZF&jh$ h`PB* CJUaJphh`PB* CJphh`Ph`PB* CJ aJ ph h`Ph`P5B* CJ aJ ph,j h`Ph`PB* CJUaJph,jb h`Ph`PB* CJUaJph$h`Ph`P0J>*B* CJaJph&jh`Ph`PB* CJUaJph,j h`Ph`PB* CJUaJphh`Ph`PB* CJaJph*+,9:;<bcdpqŲ𨓂jV>V/j@ h`Ph|Cx5B* CJ UaJ ph'h`Ph|Cx0J5>*B* CJ aJ ph/j h`Ph|Cx5B* CJ UaJ ph h`Ph|Cx5B* CJ aJ ph)jh`Ph|Cx5B* CJ UaJ phh`PB* CJph$h$ h`P0J>*B* CJaJph&jh$ h`PB* CJUaJph,j@ h$ h`PB* CJUaJphh$ h`PB* CJaJph;56r:VWlm@ ^gd$  & Fu & F & F & Fv ^gd H & F^gd$  & F^`gd$ & F^gd$ qrtu#ȱמȇמpמYמ,j"h`Ph|CxB* CJUaJph,jh`Ph|CxB* CJUaJph,jRh`Ph|CxB* CJUaJph$h`Ph|Cx0J>*B* CJaJph,j h`Ph|CxB* CJUaJphh`Ph|CxB* CJaJph&jh`Ph|CxB* CJUaJphh`PB* CJphh|CxB* CJph #$%3467VWXpqrWlռysis\iSJSisC h|Cx5>*hn8[0J>*CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJh|CxB* CJphh|Cx0J>*B* CJph"j h|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJ$h`Ph|Cx0J>*B* CJaJph&jh`Ph|CxB* CJUaJph,jh`Ph|CxB* CJUaJphlm@ A ] ^ a                & E j m   & 6              C кк񘧍zt htCJhtht5CJh|Cx56CJh|Cx0J6>*CJjh|Cx6CJUjh|Cx6CJU h|Cx>*CJh|CxB* CJphhn8[5B* CJphh|Cx5B* CJph hjT*CJ h|CxCJh$ h$ CJ h|Cx6CJ h|Cx5CJ-@ A ]       % & E    /       B C c  & F^gdt^gdt & F^ & F^gdjT*C c d ~         4 K u    *=@FSrstemow|}-.Crs򢯙hn8[0J>*CJh|Cx0J>*CJjgh|CxCJUjh|CxCJU h|Cx6CJhuTh|CxCJ hn8[CJ hpM5CJ hACJhAh|Cx h|Cx5>* h|Cx5CJ h|CxCJ h|Cx>*CJ8c d ~        3 4 K t u      *s & F^` & F & F^ & F` & F` & F^8^8s-.Crs*7@LM^gduT & F`gd`PgduT & F & F^ & F^ & F^gdAMZ[\]{|} #%@IRS_a78%к jh|CxCJhAh|CxCJhF/h|Cx5CJhF/hF/5CJ hF/CJhuTh|CxCJaJh|Cx0J>*CJjh|CxCJUjh|CxCJU hK5CJ h|Cx5CJ h|Cx>*CJh|Cx h|Cx6CJ h|CxCJ3S+u%&4 & F^gd$ & Fp^pgd$ p^pgd$ p^pgduT ^`gd$ ^gd$ ^gd$ ^gduT%&45BCV]} <AOZg{ "2N\:B_h<Fox9C'=>huTh5)5CJaJhuTh|Cx5CJaJ h\ CJ hpMCJ hA5CJ hpM5CJ hF/CJhF/h|CxCJ h>CJhF/h|Cx5CJhF/hF/5CJ h|Cx5CJ h|CxCJ;:_<o&'dp^pgduT^gduT^gduT & F^gd$ & Fp^pgduT & Fp^pgd> & F^gd$ ^gd$  & F^`gd$ >?GQRTcp  09D P G!Q!g!s!t!!w"""""#ҭҭޡuhuTh5CJaJhuTh|Cx>*CJaJh>CJaJhuTh|Cx6CJaJhuThjT*6CJaJhuTh5)CJaJ jhuTh|CxCJaJhuTh5)6CJaJhuTh5)5CJaJhuTh|Cx5CJaJhuThpMCJaJhuTh|CxCJaJ+0D  !t!!!!e""""#)$$%m%%%%^gduTp^pgduT ^`gduT^gduT##P#R#####)$/$8$:$%%m%v%%%&&&&&&''''''''''''''ym^jh|Cx5CJUjh|Cx5CJUh|Cx0J5>*B*CJph+jUhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJhuTh5CJaJhuThpMCJaJhuTh|Cx5CJaJhuTh|CxCJaJhuThCJaJ$%/&&&&*((:))*** +!+F+G+++++,,,p^pgd$ ^`gd$ ^gd$ ^gd$ ^gduTp^pgduT ^`gduT'' ( (*(6((((:)>)A)e)))**>*?******* +!+9+:+E+F+G+V+W+X+x+y+z++++++++̹̭̭̭̩vp h>CJh|Cx0J>*CJjUh|CxCJUjh|CxCJU h|Cx5CJh$ h|Cx>*CJaJh|CxhuTh|CxCJH*aJhuThI=CJaJhuTCJaJhuTh|CxCJaJhuTh|Cx5CJaJ h|CxCJh|Cx0J5>*CJjh|Cx5CJU,++,,,(,),+,,,,,,,,,,,,1-2------------------.. . .&.'.(.2.3.5.C.Y.Z.].^....j5h|CxCJUh|Cxjh|CxCJU hn8[CJ h|CxCJH*jUh|CxCJU h|Cx5CJ h>CJh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU6,,------. .4.5.]........5/6/h/ & F^gd$ ^`gd$ gduTp^pgd$ ^gd$ .....i// 00000$0H0]000000000000000@1A1b1c1d1h1i1222*2+21232Ϸϥxr hGCJ hG5CJj8hZ )hCJUh|Cx0J5>*CJh>0J5>*CJ"jshZ )h5CJUjh|Cx5CJU h>CJ hn8[CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU*h/i//0G0H0]000022+242l2334444p^pgd$ ^gd$  & F & F^`gd$  & F^`gd$ & Fp^pgd$ & F^gd$ & F^gd$ 324292;2<2B2D2K2h2l2m2w2222222233 3!3)3*343T3\3^3f3h3t3v3333ſ{o]#h`Ph`P5B*CJ\aJphh`Ph|Cx5CJaJh`PhwECJaJh`Ph|CxCJaJh`Ph`PCJaJh`Ph.kCJaJh`Ph.k5CJaJh`Ph`P5CJaJ hwECJh`PhwE5CJ h`P5CJh.khwE5CJh.kh.k5CJ h`PCJh.kh`P5CJ h.kCJ#333333333444L4444444444444555B5555566ɾɾ|uoho\Q\huThCJaJhuTh5CJaJ h|CxCJH* h|CxCJ h|Cx5CJh.kh.kCJh hh h6>*CJ h hCJh hh.k6>*CJ h.kCJ h.k5CJ h`PCJh.kCJaJh`Ph`PCJaJh`Ph`P5CJ\aJh`PB*CJaJphh`Ph`PB*CJaJphh`PB*CJ\aJph4555$8o9p99::);f<u<<=8==>>,@2A & Fu pp^pgd H & F^gd$ & F^gd$ ^gd$ ^gduT^gd$ & F^gd$ 6L6N6R6^666$8-88888888;9<9Z9[9\9h9i9o9p9999::::::);5;;;f<r<4=ļıԅxqkq hpMCJ h|Cx5CJ h|Cx>*CJ hn8[CJ h|CxCJ h hhSh hhS0J>*jh hh5sU h hh hjh hh hUhShS>*hSh.kh.k>*h.kh|Cx h|Cx5huTh5CJaJhuThCJH*aJhuThCJaJ(4=5===>><>R>>>>?@@,@9@O@P@p@q@r@@@@@@@@@@'A0A2A*CJjrh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJ h|CxCJH*62A|AA]B!CDoE5FFFFGCGGDHHHH^gd$ ^gd$  & F p0^p`0gd Hp^pgd$  & Fu^`gd H & Fu p^`gd H & Fu ^`gd HIDJDKDSDTDYDZDDDDDDDDDDDDDFFHHHIPIIIJJJIKJKVKXKfKmKoK|KKKKKL%L>L?LALֲֲֲֶ֥֬օ|vv֘֘v hCJhh|CxCJhh|Cx5CJh%05h%05CJ h%05CJ h%055CJ h|Cx5CJ hpMCJh|CxjhZ )hCJUjhZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU.HHiIIIIJJJJJK{LLMWMMMM4NgNiNjNuNvNgd & Fp^pgd$ p^pgd%05^gd$ p^pgd$ ^gd$ AL]L{LLLLLLLLMMWM`MaMMM4N=NiNjNuNvNwNNNNNNNNNNNNNNNNNʾ林{rha[h|CxCJjha[h|CxCJUhF0J>*CJjh|CxCJUh|Cx0J>*CJj/h|CxCJUjh|CxCJUhh|Cx5CJ4aJ4hh|CxCJ(aJ(h|Cxh%05h%05CJ h%055CJ h%05CJ h|CxCJhh|Cx5CJ'vNNNO9O:OaObOOOOIPSPPPP Q Q & F@ ^@ gdA/ & F^`gdR & F^ & Fp^p`gdR & F@ ^@ gdR & F^gdR & F^`gdA/gduT & F & FVNNNOOOO'O(O)O7O8O:OaObOcOOOOOOOOOýçýk[OC= ha[CJhRh|Cx5CJaJhRhA/5CJaJh,4hA/0J5>*CJaJ&j h,4h6Gn5CJUaJh,4h,45CJaJ jh,4h,45CJUaJh|Cx h|Cx5CJh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJUha[h|CxCJha[h|Cx0J>*CJjha[h|CxCJUjha[h|CxCJUOOP&P8P:PJPRPUP^PlPnPPPPPPPPPPPPQQ QMQNQdQmQnQ{QQQQQQQQQQERORrRRRR㻮xhRh|Cx5CJ hR5CJhShA/0J>*CJjhSh%CJUhShSCJjhShSCJU hA/CJhRhR5CJhRh|Cx5CJ aJ hRhR5CJ aJ hpMCJ hRCJ ha[CJhRha[5CJ. QQ(RrRRRRS;SSSS TyTTT$U & F`gd,4 & F & FgdR & F@ ^@ `gdR & Fp^p`gdR & F^ & F^`gdR & Fp^p`gdA/ & F@ ^@ gdA/RRSS#T(T)T8TTTTTTTTTTTTTTT U U U!U"U#U$U%U(U*UU˾ˮui_Y h0CJhl~h|Cx5CJhl~hl~0J>*CJj hl~hI<CJUjhl~hl~CJUhl~hl~CJ h|Cx>*CJhA/hA/0J>*CJj# hA/h6GnCJUjhA/hA/CJUhA/hA/CJ hA/CJ ha[CJhRh|Cx5CJhRhR5CJ hRCJ h|CxCJ $U%UyUUU0VAV]VVVVVVW^WWXXXXX & F^ & F & F` & F^gdl~ & F^gd0 & F^`gd0 & F^gdl~ & FUUUUUUUUUUU0V3VAVDV]VdVVVVVVW^WgWhWWWWXXX!XXXXXYYYYYYYY謧茬rj!hZ )hUhjh|CxUh h|Cx5h h|Cx5CJ hpM5CJ hn8[CJ hn8[h h|Cxh h|Cx>*CJ hDCJ hl~CJhl~h|Cx5CJh0h0CJ h05CJhl~h05CJ h|CxCJ h0CJ jh0h0CJ,XXY YtYYYnZZ1[S[[A\k\l\v\\\\Y]] & Fp^pgd,4 & F^gd,4 & F| & F|  & F| & F| & F` & F & F^`YYZZZmZnZZZZ0[:[A[[[[ \\\=\?\l\v\\\]]^]_]]]]^^^^^żҦҜ̐̊̐̄ztjcj hl~>*CJhl~hl~>*CJ h`CJhRh`5CJ hl~CJ hpMCJ jh,4h,4CJh,4h,4>*CJ hCJ h|Cx>*CJhh|CxCJhhCJ h5CJ h,4CJ h|CxCJ h|Cx5CJh|Cx h)h h|Cxhh|Cx0J>*hjh|CxUh$]]]^^^^^^```KaLawaaNbgb & F0gd^qY $ & F0a$gdI & F^gd^qY & Fgdl~gdkA[ & F^gdl~ & F`gdl~ & F^gd` & F^gd` & F^^^ ___ _$_4_^_`_i_{_____2`4`;`=`U`[`]`e`g`n`````````aa!a"aCaDaEaHaIaJaMadagah^qYhl~5CJ#hIhI0J5>*B*CJph+j!hIh#,5B*CJUphhI5B*CJph%jhIhI5B*CJUph hICJhl~ hl~CJH* hl~>*CJ hl~CJ hl~6CJ hl~5CJ/gavawaaaaaaaaaaaaaaa b"b#bFbGbHbKbLbNbgbhbzbbb宛vd^TMT h05CJh0h05CJ h0CJ#hIhI0J5>*B*CJph+j"hIh#,5B*CJUphhIhI5B*CJph%jhIhI5B*CJUph hICJ jhl~hl~CJ hl~CJh^qYhl~5CJH*h^qYhl~5CJh^qYh^qYCJ h^qYCJh^qYh^qY6CJh^qYhl~6CJgbhbbbbbbGcHccccd d5dWdXdod & Fh^hgd,4 & F8^8`gd,4 & F ^gd H & Fh^h`gd,4 & F8^8gd,4 & F^ & F^gd0^gd0bbbbbbbbb5c7cHcZcccccccdd*d+d,d-d5dWdoddde;eieueeeeeeeeeffhfffffggggggܿ㧝㧝h|Cx h|Cx5CJh|CxB* CJphh|Cx5B* CJph hFCJ h(KSCJ hn8[5CJ hpM5CJ hpMCJ jh|CxCJ h|Cx5CJ h|CxCJ h|Cx>*CJh0h0CJH* h0CJ6odee;eheieweeeeeefgfhffffff & F^`gd,4 & F^gd,4 & F^gd,4 & F & Fh^h`gd,4 & Fh^hgd,4 & F8^8gd,4fggggIgJgXgggNhmhh iniii & F^`gdy*CJj #h|CxCJU h|CxCJjh|CxCJU/iiiiiijjj$j%j1j^j_j`jrjsjjjjj2k & F8^8gdy*CJj#h|CxCJUjh|CxCJUh|Cxhh|Cx5CJ hCJhh5CJ hn8[CJ h|Cx>*CJ h|Cx5CJ jh|CxCJ h|CxCJhkA[h|Cx5CJ-m n.n[n\nonn/oXoooodppqsqs*CJh?hn8[CJh?h|CxCJh?hbCJhtht56CJhtht6CJ h|Cx5CJh;sth|Cx5CJh?h?CJ h?6CJ h?CJ h|CxCJ hCJhkA[h|CxCJh|Cxhn hnCJhnhn5CJ+Vt_u`u~uuvowzwxy@zz|{||}j}}}4~5~L~^gdyz@zVzzz|{{|4|8|@|k||||||||||}}}$}j}}}}}}}4~²hbhbCJ hb5CJ jhbhbCJ h_p5CJ h!]_CJh!]_h!]_5CJ hbCJhbhb5CJ h_pCJhtht5B* CJph3 htCJhth|Cx5CJ hn8[CJ h|CxCJ h|Cx5CJ hy*CJaJ#j$hxIhpKCJUaJhxIhxICJaJjhxIhxICJUaJhxICJaJhxI hxIhxI hxICJ Y( h|CxCJ Y( h|Cxh h|CxCJh|Cx%L~~~~~~~~PQ%&8^8gd> h^h`gd>h^hgd> & F 88^8gd>`gdxI & FgdxI ^`gdy*CJh|Cx0J>*CJj%hZ )hCJU h|CxCJjh|CxCJU hxICJ-&5{|ہՂJK˃Ȅ-./gdy ^`gd> ^`gdy^gd>^gd>9:;<CDKUV]Ȅф؄-./JK\ǽǭǑDŽDŽ~Njzpj^Y h|Cxhh|Cx5B* CJph h>CJh>h>>*CJhy*CJh@*0J>*CJjr'hZ )hCJUjh|CxCJU h|CxCJh@*h@*0J>*CJj&hZ )hCJUh@*h@*CJjh@*h@*CJU"/JK\؅ ZȆɆ݆)oljȉ^gd> & F^`gd> & F^gd> & F^gd>^ ^``gd>gdy*CJj)hZ )hCJUh_}0J>*CJj9(hZ )hCJUjh_}CJU h_}CJ h_}5CJ h|CxCJ h|Cx5CJ8ȉA45WLM\ٌڌ ^`gdy & F^gd>^gd>^gd> ^`gd>^gd>5E<=LM[\׌،.jtwxÍ  vocXhh|CxCJ$aJ$hh|Cx5CJ$aJ$ h5CJh>h>CJh>h>CJH* hQFVCJ hxICJ h>CJhxIh>CJ hz5CJ hxI5CJ h>5CJ hy*CJj<*hbhMCJUhbh|Cx0J>*CJj)hbhMCJUhbhbCJjhbhbCJU h~i5CJ htCJ hn8[CJh|Cx h|Cx5 h|CxCJ h|Cx5CJ h~iCJh~ih~iB*CJph$LWΏϏԏ ΐϐА,-|]“" & F pp^pgdQ^gd^gd^gd^gd~ip^pgd~i ^`gd~istuxyzÐĐ̐͐ϐА-9{|l\]ar“ғ"678Xeʫʝʗʝʑʗʗʗʝʋʝʝʝʗʗʝʝʝ hn8[CJ h_pCJ hKrCJ h|Cx5CJ h|CxCJY( h;eCJj+hthMCJUhthtCJ h|CxCJ htCJhtht0J>*CJjhthtCJUj*hthMCJU6"XߖXYO & F pp^pgdQ ^`gd p^p`gd@ ^@ gdp^pgd^gdWpǗȗNOk  "06ABCdefijklh|Cx0J>*CJj+hZ )hCJUjh|CxCJUh|Cx5CJH* h|CxCJH* h_pCJ hKrCJhKrhKr5CJ hKr5CJ jh|CxCJ hn8[CJ h|Cx5CJ h|CxCJ: (6,-yS*+7:^gdp^pgd^gd^gd ^`gd,FGIyϜSV+4pqΞݞ?@AEFGH͟~:C\_¥ h^qYCJhn8[0J5>*CJ"j,hZ )h5CJUh|Cx0J5>*CJ"j),hZ )h5CJUjh|Cx5CJU h|CxCJH* h|CxCJ h|Cx5CJ>:\jkvABRإ٥#$Jͦئ/ ^`gd^gdp^pgd ^`gd^gd  Jhktv|}6=NZǤBR٥$J%.٧ʨhho65CJ h|Cx5CJ h_pCJ h_}CJ hF}CJ h|CxCJH* hbCJhbhb5CJhbh|Cx5CJH*hbh|Cx5CJ h|Cx5CJ hn8[CJ jh^qYh^qYCJ h^qYCJ h|CxCJ4/ا٧*h̩\]|ݪ()M & F^` ^` & F^ & F=gdo6`gdo6 & F^ & F^gd^gdʨ*fhʩ̩ީѪҪݪު(89Lwxy}ī(*:<ĬƬx~ʭܭүưưh;eh|Cx5CJj".h|CxCJUh|Cx0J>*CJj-h|CxCJUjh|CxCJU h|CxCJH* jh|CxCJ hn8[CJ h|CxCJ ho65CJ h|Cx5CJ ho6CJ<*xʭ԰9hԲղ޲bcy³ó & F^ & F^^ & F>gdo6TUyz{԰ 9A~ղ޲߲cyóӳԳճ,-QR_no56пйРп hCJ hn8[5CJ hn8[CJ h_pCJ hZFCJ ho6CJh|Cxj^/h|CxCJU h|Cx5CJh|Cx0J>*CJj.hZ )hCJUjh|CxCJU h|CxCJ8ó׳,-QR_45]ζ·˷gd^gdc^gd^gd & F^gd  & F^gd & F & F^` & F`6@ABCеӵ?@JP\]ĶŶƶ˶̶Ͷﺮxp^xPxphUXfhUXf0J>*CJaJ#j0hUXfh9CJUaJhUXfCJaJjhUXfhUXfCJUaJhUXfhUXfCJaJhUXfCJaJhcCJaJhUXfh>*CJaJhUXfhCJH*aJhUXfhCJaJhh0J>*j/hh9UjhhU hh hCJhh5CJ6@FZ[v|·˷~shaUP h|Cx5hh|Cx5CJ aJ hhhhCJaJhUXfhcCJaJ#j1hUXfhUXfCJUaJhUXfhcCJH*aJhUXfhcCJaJhUXfhc5CJaJhUXfhUXfCJaJhUXfhUXf0J>*CJaJ#jW1hUXfh9CJUaJhUXfCJaJjhUXfhUXfCJUaJhUXfhUXfCJaJ˷ $mкѺ!";<Fռ-Vgd~i ^`p^p^^gd^ & F7"+-mtuv<E`ozúкѺٺ";<CDFƻӻռݼ  -67Ȳ hn8[CJ h|Cx>*CJ hn8[5CJh~ih|Cx5CJaJh|Cx0J>*CJj2h|CxCJUjh|CxCJU h_p5CJ jh|CxCJ h_pCJ h|CxCJH* h|Cx5CJ h|CxCJh|Cx97>Wghl-.08YZhtſƿ')2Ļğ򌂌|phqNhPu5CJaJ hPuCJhPuh|Cx5CJ hPu5CJhh|Cx5CJ$aJ$hth|Cx0J>*CJj3hth|CxCJUhth|CxCJjhth|CxCJU jh|CxCJ hn8[CJ h_pCJh~ih|Cx5CJaJ h|CxCJ h|Cx5CJ*VWghh() ? ^`gdPu ^`gdPu & F7p^p^gd~i^2KLuvw  JKZZc|uuuuuoi h_pCJ h&6CJ h|Cx5CJ hPuCJhqNh|Cx5CJh|CxB* CJphhPuh|Cx5B* CJph h|CxCJH* h|CxCJhPuh|Cx5CJhPuOJQJ^JhPuhPu0J>*CJaJ#j3hPuhqNCJUaJjhPuhPuCJUaJhPuhPuCJaJ'?KZ#$2Snx ^`gd^gd^gd^gd&6^gd&6^$2 "x6H1=vx5>   0@q}3<~=> h4DeCJh|Cx h|CxCJH* h_pCJ hn8[CJ h_}CJ jh|CxCJmHnHu h|Cx5CJ h|CxCJ h|Cx>*CJH56Hwx5/0@q3<=>J & F^gd ^`gd^gd>JKLM[]fhy NW_`|}驣ynch55h0@CJaJh55h55CJaJh55h0@5CJaJ h0@CJh0@h0@>*CJaJ h|CxCJ h|CxCJ8 h_pCJ8h|CxhL' hL' 5CJ jh>h>CJhok5hok5CJaJ hok55CJhok5h>5CJh>h>5CJ hL' CJ h>CJh>h>CJ8aJ8 JKL[yLB078 & F^gd0@^gd55 & F^gdL' & F^gdok5 & F   :;<?@BHIJKwxy|}~ﰖthRt@t#h(hvH0J5>*B*CJph+j5hvHh#,5B*CJUphhvH5B*CJph%jh(hvH5B*CJUphh(hvHCJ hvHCJ h0@CJ&j4h55h#,5CJUaJh55h0@CJaJ'h55h0@0J5>*B*CJaJph&j@4h55h#,5CJUaJh55h0@5CJaJ jh55h0@5CJUaJ~89GHIJrstؑ}rc[Ic#j7h;^h#,CJUaJh;^CJaJjh(h;^CJUaJh(h;^CJaJ h;^5CJ h|Cx5CJ h?zCJ+j7h(h0@5B*CJUphh(h0@CJ#h(h0@0J5>*B*CJph+jG6h(h0@5B*CJUphh(h0@5B*CJph%jh(h0@5B*CJUph h0@CJtwxy]hi˵ˀznczzYOzch0@h95CJh9h95CJh(h0@CJaJh(h0@5CJaJ h0@CJh0@h|Cx0J5>*B*CJph+jj8hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h9CJ h|CxCJh(h;^CJaJjh(h;^CJUaJ'h(h;^0J5>*B*CJaJph8z & F^gd9 & F^gdk^gd0@ & F^gd0@  & F^gd0@ & F^`gdk & Fgd0@ijwWXYZ𷱷𷱙w𷙏pgh9h9CJ h95CJ#j[:h0@h#,CJUaJ hb.CJh9h95CJ h9CJ#j9h0@h#,CJUaJ h0@CJh(h0@CJaJ'h(h0@0J5>*B*CJaJph#j8h0@h#,CJUaJh0@CJaJjh(h0@CJUaJ(BCDKLNOxų͟ܙsgTHh0@5B*CJph%jh(h0@5B*CJUphhbOCh0@0J>*CJj;hbOChbOCCJUhbOChbOCCJjhbOChbOCCJU h0@CJ'h(h;^0J5>*B*CJaJph#j;h;^h#,CJUaJh;^CJaJjh(h;^CJUaJh(h;^CJaJ h;^CJ h|CxCJ h|Cx5CJ h9CJxyz}~:NOPuvyz־}sg`ZTH?h555CJaJh55h|Cx5CJaJ h55CJ hn8[CJ h|Cx5CJh|Cx5B* CJphh|CxB* CJphhbOCh|CxCJhbOCh_p0J>*CJj)=hbOCh?rCJUhbOCh55CJjhbOCh55CJU h|CxCJ h0@CJ#h(h0@0J5>*B*CJph%jh(h0@5B*CJUph+j|<h0@h#,5B*CJUph"#8yzA klw ^`gdk^gdk & F^`gdb. & F^gdb.^gd55`gd55 & F^`gdk & F^gdk & F^gd?z9:;>?@AGI[\mn  luǵϡޚ~wkg` *h|Cx5h|Cxh0@h0@>*CJaJ h|Cx5CJ h_pCJ hn8[CJ h|CxCJhb.hb.5CJ hb.hb.'h(h0@0J5>*B*CJaJph#j=h0@h#,CJUaJh0@CJaJjh(h0@CJUaJh(h0@CJaJ h0@CJ hb.CJh9hb.5CJ#h0d !e & F7 pp^pgdCjR ^`gdk  & F^gdkgd~i  & F^gdk  & F^gdk & Fgd0@gd0@ & F^gdk %&'EFfghq01<FOcd{u{ hn8[CJ h|CxCJ *h|Cxh *h|Cx5h h|Cxh h64h|Cxh64h640J>*aJj>h64h_UaJh64h64aJjh64h64UaJ h64h64 h645h64 hb.5hb.hb.5hb.h|Cx *h|Cx5 *h|Cx-)*+WXY\]_`}~񼫟wcw&j@hh5CJUaJ'hh0J5>*B*CJaJph&je?hh5CJUaJhh5CJaJ jhh5CJUaJhhCJaJ hWCJhh|CxCJaJh5CJaJhh|Cx5CJaJh|Cx h|CxCJ jh|CxCJ!&'OWXk ^`gdkgdk  ^gdk^gdk^gdk  & F^gdk  & F^gdk & F^gdk & F^gdk^gdgd^gdk '/078>?FNO]txyۼ۰ۼzzpjjbha[h|Cx5 ha[CJh8h|Cx5CJ h8CJhh|Cx h_pCJ h|CxCJhCJaJ&j@Ahh5CJUaJhh5CJaJhhCJaJ'hh0J5>*B*CJaJph jhh5CJUaJ&j@hh5CJUaJ%>?@]^_bcef<=QRSо׬К׬Ј׬{uldYdjCh|CxUjh|CxUh~ih|CxCJ h|CxCJ h|Cx5CJ h8aJ"jCh8hp5UaJ"jlBh8hp5UaJ#hh80J5>*B*aJph"jAh8hp5UaJ h85aJjhh85UaJhh8aJh|Cxh8h|Cx5B*ph"SUVWXkt!'?G]i<=tvwûóua'h+h+0J5>*B*CJaJph/jDh+hA-5B*CJUaJph h+h+5B*CJaJph)jh+h+5B*CJUaJphh+CJaJhmfCJaJhkhkCJaJhkhkCJ\aJhkhk5CJ\aJhkh|Cxjh|CxU h|Cx0J>*"!?] %b KL]{^gdk`gdk^gdk^gdk^gd?z ^`gdk^gd0@ %L]|罴~t~iZjh(h0@CJUaJh(h0@CJaJh0@h0@5CJ h0@CJh0@h0@>*CJaJ h|CxCJH* h|CxCJ h|Cx5CJh|Cxh0@h|Cx>*CJaJh0@>*CJaJhkhkCJhmfCJ\aJhkhk>*CJaJhkhkCJ\aJhkhkCJaJhkhk>*CJ\aJ {|%'2yhzp^pgd0@p^pgd0@^gd0@gd0@^gd0@ & F`gd0@ & F()*׸nZTJTAhuh}CJh}h}5CJ h}CJ'h(h;^0J5>*B*CJaJph#jMEh;^h#,CJUaJh;^CJaJjh(h;^CJUaJh(h;^CJaJh;^h;^5CJ h;^CJ h0@CJh(h0@CJaJ'h(h0@0J5>*B*CJaJphjh(h0@CJUaJ#jDh0@h0@CJUaJh0@CJaJ*+MNORSUVyz{~}wmwbSKhCJaJjh(hCJUaJh(hCJaJhh5CJ hCJ h}CJ+j6Gh}h#,5B*CJUph+jFh}h#,5B*CJUphhuh}CJ#huh}0J5>*B*CJph+jEh}h#,5B*CJUphh}5B*CJph%jhuh}5B*CJUph%'02y޿lZVPIB=P h0@h h0@5CJ h0@>*CJ h0@CJh0@#h7hti0J5>*B*CJph+jrHhtih#,5B*CJUphhti5B*CJph%jh7hti5B*CJUphhtihti5CJ htiCJ hCJhCJaJh(hCJaJ'h(h0J5>*B*CJaJphjh(hCJUaJ#jGhh#,CJUaJ| *%&'MNqrs ǾǢǾǾǢǾ{{u htiCJ hi{5CJhi{h/5CJ h/CJjIhZ )h0@CJUhh0@0J>*CJjIhZ )h0@CJUhh0@CJjhh0@CJU h0@5CJhth0@5CJhh0@CJh0@ h0@CJ h0@CJH*(z| ,_kl & F & F^`gd/ & F^gd/ & Fgd0@ ^`gd0@^gd0@p^pgd0@ ^`gd0@^gd0@*+,/023VWX[\^ klmvxy첖ymycM+jKhtih#,5B*CJUphhtihti5CJh/h/5CJaJh/h/CJaJhi{h/5CJaJ h0@CJ h/CJ+jBKhtih#,5B*CJUph htiCJ#h7hti0J5>*B*CJph+jJh/hti5B*CJUphhti5B*CJph%jh7hti5B*CJUph  _h)dmr|ннsib\U\U\ h|Cx5CJ h|CxCJ h|Cx>*CJh0@h0@5CJ+j!Mhh#,5B*CJUph#h7h0J5>*B*CJph+jLhh#,5B*CJUphh5B*CJph%jh7h5B*CJUph hCJhh5CJh?zh0@5CJ h0@CJhh0@5CJ htiCJ^_i*+K567ab| $IfgdH?gdgd & FT & F 8h^8`hgd hh^h`hgd & Fgd0@ & F^gd0@ & F`gd0@$56KLYZ[\¸waw+jQhZ )h5B* CJUphh|Cx0J5>*B* CJph+jQhZ )h5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh &6B* CJphh|Cx5B*CJ`OJQJphhn8[h hCJ h|Cx5CJ h|CxCJ jh|CxCJ!|ZMkd,N$$Ifl0d, \ 4 laytMkdM$$Ifl0d, \ 4 layt $IfgdH?"0ZMkdO$$Ifl0d, \ 4 layt $IfgdH?MkdN$$Ifl0d, \ 4 layt012CDEFZMkdO$$Ifl0d, \ 4 layt $IfgdH?MkdjO$$Ifl0d, \ 4 laytFGHIJKLYZQKI`^gdMkdP$$Ifl0d, \ 4 layt $IfgdH?Mkd>P$$Ifl0d, \ 4 laytYZ  aKQ;<=]^3^gdse ^`gdse^gdse & F@ ^@ `gdp & F^gdp ^`    -./9:<=Qкߨ򞒂vcTDjh|Cx5B* CJUphh|Cx0J5>*B* CJph%j+Sh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx5B* CJphh|CxB* CJph#hhh|Cx0J5>*B* CJph+jRhhh|Cx5B* CJUphhhh|Cx5B* CJph%jhhh|Cx5B* CJUphhhh|CxB* CJphQRSUVcnpqܘ|iZPh|CxB* CJphh|Cx0J5>*B* CJph%j|Th|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJph%jTh|Cx5B* CJUphh_}5B* CJphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jSh|Cx5B* CJUph 456wkaQE2Q%jUh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx5B* CJph#hhhh0J5>*B* CJph+j^Uhhh 5B* CJUph%jhhhh5B* CJUphhhhh5B* CJphhh5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jTh|Cx5B* CJUph6;<>?WXY_`abz{|ԮԤufSf%jWh|Cx5B* CJUphh|Cx0J5>*B* CJph%j6Wh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJph%jVh|Cx5B* CJUph%jXVh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph 3467VWXefhi﷧yfySy%jYh|Cx5B* CJUph%jYh|Cx5B* CJUphh|Cx0J5>*B* CJph%jXh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx0J5>*B* CJph%jXh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph9:;IJKLcdejklmnܤufSfIh|CxB* CJph%j[h|Cx5B* CJUphh|Cx0J5>*B* CJph%j$[h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJph%jZh|Cx5B* CJUphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jZh|Cx5B* CJUphn !"#DEFOPQvlh|CxB* CJph%j]h|Cx5B* CJUph%jo]h|Cx5B* CJUph%j\h|Cx5B* CJUph%j\h|Cx5B* CJUphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%j\h|Cx5B* CJUphh|Cx5B* CJph"QRopqwxyzꠍ~hV~A0 h &6h &65B* CJaJph)jh &6h &65B* CJUaJph#h &6h|Cx0J5>*B* CJph+j^h &6h|Cx5B* CJUphh &6h|Cx5B* CJph%jh &6h|Cx5B* CJUphh &6h|CxB* CJph'h~ih|Cx0J5>*B* CJaJph/ju^h~ih 5B* CJUaJph h~ih &65B* CJaJph)jh~ih &65B* CJUaJph3459:;<Ҿқr`J`>h|Cx5B* CJph+jo`h &6h|Cx5B* CJUph#h &6h|Cx0J5>*B* CJph+j_h &6h|Cx5B* CJUph%jh &6h|Cx5B* CJUphh &6h|Cx5B* CJph'h &6h|Cx0J5>*B* CJaJph'h &6h &60J5>*B* CJaJph)jh &6h &65B* CJUaJph/ji_h &6h 5B* CJUaJph<=]^xyGHab  d m z      @ I    !     2 3 4 U          b x       R      ( D ˾ hCJ hRCJ h|Cx< h|Cx5<hseh\ h|Cx5h|Cx h|CxCJH* jh|CxCJ hn8[CJ hn8[5CJ h|Cx5CJ h|Cx>*CJ h|CxCJA>  d   @    !      3 4 U  @ `^@ ``gdse ^`gdse^gdse^gdsep^pgdse^gdse       ` b x        Q R   & ^`gdse^`gdse^gdsep^pgdse ^`gdse ^`gdse& (    |   N  J a  +  & F7 pp^pgdCjR^gdse^gdse ^`gdse^gdseD  " $ ` b d v x z |   N    # J V W X } ~  ) T U z { | qjbhZ )hCJUh$h|CxCJh$h|Cx0J>*CJjUahZ )hCJUh$h$CJjh$h$CJU jh|CxCJ h|Cx5CJ h|Cx>*h|Cx0J5>*j`h|Cx5Ujh|Cx5U h|Cx5h|Cx h|CxCJ, p              * 0 2     ! - 2 A T [         ? A Q R k    ! " # ҵمzh]L0J5>*CJ"jbhZ )h5CJUjh|Cx5CJU h_pCJ h]LCJ h$CJh$h$5CJ jh|CxCJh$h|Cx5CJ h]L5CJ h|Cx5CJ h|CxCJjh$h$CJUh$h|Cx0J>*CJ0+      !   Q       |  * +  & F0 8^gdCjR & F/ 8^gdCjR^gdse & FQ pp^pgdCjR ^`gdse & F. pp^pgdCjR# 0 1                 & ' . U W \ ^   |    % ( + V y { | ƼƜ㖐~~xtnajh}6h}6CJU h}6CJh|Cx h_pCJ h|CxCJH*hshsCJaJ hsCJ h]LCJh]Lh|Cx0J5>*CJ"jch]Lh5CJUh]Lh|Cx5CJjh]Lh|Cx5CJU h|Cx5CJ h]L5CJ h|CxCJjh|Cx5CJUh|Cx0J5>*CJ&+ V    % & 5 {  I J     c      3 & F^ & F & F^gdse^gdse^gdse ^`gdse^gdse|        & 5 {    J i j k                       g |sjh|Cx5>*CJh|Cx5CJH*h\h\0J>*CJjeh\h9CJUh\h\CJjh\h\CJUh\h|CxCJh|Cx h|CxCJ h|Cx5CJ h}6CJh}6h}60J>*CJjh}6h}6CJUjdh}6h-ZCJUh}6h}6CJ(3 H g r s        % & O P         E gdpc & F^gdse & F^gdse & F & F^g q r |                " # & ) + , A B C L M P f g h                     ѻѻѻѻۇ h|Cx5CJ$jghZ )hCJUjKfhZ )hCJUjeh|CxCJUh|Cx0J>*CJjmeh|CxCJUjh|CxCJUh|Cx h|Cx5CJ h|Cx5CJ h|Cx6CJ h|CxCJ h_pCJ5           " ; D F Z [ \ ]            ҄rePr(jthh$hhzNB*CJUph̙h$hhs B*CJph̙"jh$hhs B*CJUph̙h$hhs CJ h$hh$h0J>*B*CJph(jgh$hh%&B*CJUphh$hh$hB*CJph"jh$hh$hB*CJUphh$hh$hCJ hs 5CJ hn8[5CJ h|Cx5h|Cx h|CxCJ h|Cx5CJE      " E F    '     > a ! ! ! & F^gdse  & F^gdse & F^gdse & F^`gdse        '      ' ! ! " " " " # # -# .# /# 2# 3# 5# M# # # # # # # # # # $ Ǻǭǂ{tn h|4hCJ h|Cx>*CJ h|Cx5CJ$ h_ CJh7h|Cx0J>*CJjKih7hb*CJUh7h7CJjh7h7CJU h_pCJ hn8[5CJ h|CxCJ h|Cx5CJh$hhs CJ"jh$hhs B*CJUph̙ h$hhs 0J>*B*CJph̙+! ! " " 4# 5# M# # # # # # # # $ $ % P% Q%  & F^`gd_ & F^gd|4h & F^gd|4h & F^gd_  & F & F^gdse & F^`gdse & F^gdse$ $ $ ($ $ $ $ $ $ $ $ $ $ $ $ % % % !% O% P% Q% ]% _% `% % % % ¬њ䑊ysf]MfjKjh_ hCJUh_ h_ CJjh_ h_ CJU h_ CJh{#h|Cx5CJ h|Cx5CJ h|4h5CJh|4hh|4hCJ#h&h&0J5>*B*CJph+jih&h&5B*CJUphh&h&5B*CJph%jh&h&5B*CJUph h&CJh|4hh|4h5CJ h|CxCJ h|4hCJ% % % % % % % & 0& 9& U& V& l& m& n& & & & & & & & & & & & g' h' i' r' {' ' ' ' ' ' ( ( ( "( )( *( J( ( ( ) !) ) ڜږږڜڏ h|Cx>*CJh|4hh|4hCJ h|4h5CJ h|4hCJ h_pCJh|Cx0J5>*jjh_ h5U h_ 5jh|Cx5U h|Cx5 h|Cx5CJh|Cx h|CxCJ h_ CJjh_ h_ CJUh_ h_ 0J>*CJ/Q% % % % U& V& & i' ' ' ' ( ( ( "( J( ( ( ( ( )  & F & F^gd_  & Fgd|4h  & F^gd_ & F^gd_  & F`gd_ gd_ `gd_ ) A) ) ) ** +* :* * * * * * * * + + 2+ W+ n+ +  & F^`gd_  & F^`gd_  & F^`gdxF & F^gdxF & F & F^gd_ & F^gd_ ) ) ) ) ) ) ) ) * * ** 9* * * * * * * * * * * * * + + + 1+ 2+ 7+ W+ + + + + , , J, S, h, i, , , , , , , , '- 0- 2- @- E- ühh|Cx5CJ h5CJh|CxCJmHnHu hxFCJ h|CxCJhh|CxCJaJ h5CJ h|Cx5CJ h|Cx>*CJ h|Cx5CJ$ h_ CJ h|Cx5CJ h_pCJ h|CxCJ jh|CxCJmHnHu4+ , J, |, , '- - . / f/ / / / / / -0 .0 l0 0 1 & F^gd+Z & F^gd+Z & F & Fp^p`gdxF & F^`gdxF & F^gdxF & F@ ^@ gd_ E- L- X- e- - - - - - - - . . . . . / / / / / 6/ C/ D/ F/ L/ f/ s/ / / / / / / / .0 V0 Y0 k0 l0 u0 x0 z0 0 0 i1 q1 r1 v1 1 1 Ǿꦟ㘎 hn8[CJ h|CxCJH*hh6CJ h5CJ h|Cx>*CJhpch|CxCJ h_ CJh_ h_pCJh_ h|CxCJh_ h_ CJ h_ 5CJ h_pCJ hCJ h|Cx5CJ h|CxCJhhB\5CJ hB\CJ21 N1 1 1 1 1 62 2 2 3 73 O3 3 3 3 B4 C4 v4 5 5 5 ^`gd+Z ^ gd+Z & F h  ^ gd+Z & F^gd+Z & F^`gd+Z & F^gd+Z1 1 1 2 2 3 3 3 3 3 4 4 B4 C4 v4 26 ;6 7 7 _7 h7 7 7 7 7 8 8 8 ,8 @8 B8 o8 {8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 +9 ;9 <9 H9 I9 L9 9 9 9 9 9 9 9 :: H: 䠳h+Zh+Z5CJH* h_p5CJ h+Z5CJ h+ZCJ h|Cx>*CJ h|Cx5CJ$ hCJhhCJ h5CJ h|Cx5CJ h_pCJ *h|Cx5CJ h|CxCJ?5 26 _7 7 7 7 7 7 7 7 +8 ,8 O8 8 8 8 8 ;9 <9 9 9 9  & F^`gd+Z & F^gd+Z & F^gd+Z & F & F^gd+Z & F^gd9 9 9 J: K: c: : : : ; V; ; ; ; ; ; ; Q< 7= 8= P= y= = = .> & F^gdxF & F & F^gd+Z & F^gd+Z & FH: K: c: : : #; ,; ; ; ; ; = = 7= 8= P= > -> > > > ? ? ? ? N? O? P? h? i? ? ? ? ? ? g@ h@ @ @ @ @ @ @ @ @ ƭthChh|Cx0J>*CJjlhChh&CJUhChhChCJjhChhChCJU hxF5CJh|Cx0J>*CJjkhZ )hCJUjh|CxCJU h|Cx6CJhpch|CxCJ hxFCJ h|Cx5>* h_pCJ h|Cx5CJ h|CxCJ,.> > > > > ? ? ? @ A A A AB B C RD D 'E (E JE KE  & F & Fgd+Z & F^gdxF & F^`gd+Z & F^gd+Z & F^gd+Z@ @ @ @ A A A A A #A 7A AA cA zA {A |A A A A A B B AB JB B B |C C C C D D RD ^D D D D D D D E E (E JE KE TE E E E E E ]F fF kF lF F F F G G ZG hG G G G G G H H -H JH XH I h|Cx6CJ hn8[CJhxFh|Cx5CJ h|Cx>*CJ hCJ hxFCJ hxF5CJ hDCJ h|Cx5CJ h|CxCJ h+ZCJHKE UE ]F F F F YG ZG iG G G G H H -H 0I 1I QI I I I J jJ kJ J  & F & F^`gdxF & F^gdxF & F^gdxFI *I 1I QI I I I I I I I J J kJ J J J J J {K K K K K K K K K L nL L L L M M M 3M 4M PM }M M M M M M JN VN gN pN N N 2O CO O O P P P P P P P P P IQ cQ R R -S 8S ȯh|Cx0J>*CJj mhZ )hCJUjh|CxCJU hDCJ h|CxCJ h|Cx>*CJ h|Cx6CJ hn8[CJ h|CxCJ h|Cx5CJEJ J J J J J K RK K K K K K K K K K K L mL nL L L L L M M 3M   & F & F^gdxF3M 4M PM |M }M M M M M M M JN N O ;P P Q IQ R R -S }S T T T & F^gdxF & F^`gdxF & F^gdxF & F8S }S S S S T T T T T T T T T T T U BU CU U U U U U V +V V W IW JW mW nW oW yW zW W W [X dX fX qX X X X X *Y 2Y 3Y aY bY qY rY yY {Y Y Z Z 8Z h|CxCJ h|Cx0J>*CJjmhZ )hCJUjh|CxCJUhDh|Cx5CJ h_}CJ hDCJ h|Cx>*CJ h|Cx5CJ$ h|CxCJH* h|Cx5CJ h|CxCJ9T T T T T T U V V +V V V V W [X X X X :Y aY bY qY rY jZ %[ & F^gd}6 & F^gdxF & F^gdxF & F8Z 9Z :Z DZ EZ jZ vZ Z Z %[ 1[ B[ L[ p[ [ [ [ [ [ [ [ t\ }\ \ \ \ ] ] ] )] ] ] ] ] ^ ^ "^ #^ D^ E^ F^ L^ پٸٲٲ٬٬َٛuihh|Cx0J>*CJjohh/FCJUhhCJjhhCJU hA5CJhChh|Cx>*CJ hChCJ hACJ hCJ hDCJ jh|CxCJmHnHu h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjnh|CxCJU)%[ t\ ] ] ] ^ :_ _ _ ` ` q` ` ` ` ` $a Ea Fa a a a  & F^gdxF & F^gdxF & F & F^gd & F^gdA & F%gdA & F^gd}6L^ M^ ^ ^ _ _ _ _ _ _ _ 3_ 4_ 5_ 8_ 9_ :_ A_ _ _ _ _ ` ` 1` 2` 3` =` >` E` [` \` e` g` p` ` ` ` ` ` ` ` 줝|||uupi h|Cx6h h|Cxh h|Cx6CJ h|Cx>*CJh|Cx0J5>*CJjph|Cx5CJU h|Cx5CJjh|Cx5CJU h|Cx5CJjRphh/FCJUhh|Cx0J>*CJjohh/FCJUhhCJ h|CxCJjhhCJU)` ` a #a ,a @a Da Fa Ga ha ia ja za {a a a a a a a a a a a a a a a a a b b b b !b %b &b 'b (b Hb Ib Jb Zb [b db eb b ʻѰʆѰjqh|Cx5CJUh|Cx h|Cx5CJh|Cx5>*CJ h|Cx>*CJh|Cx0J5>*CJj{qh|Cx5CJU h|Cx5CJjh|Cx5CJUhzhz6CJ hzCJ h|Cx6CJ h|CxCJ h|Cxh.a a a b &b 'b b b b b b b b b Sc xc c c d `d d d & F` & F^ & F^ & F & F^`gd: & Fgd:gdpc & F^gdxFb b b b b b b b b b b b (c Qc d d @d Od `d id d d d d e e _e ne |e e e e Bf Nf g 2g 4g Tg hg zg h h 'h (h (CJ hChCJ h|Cx6CJ h|Cx5CJ hx'CJh|Cx56CJh:h:h:5CJ h:CJh|Cx h|CxCJh|Cx0J5>*CJjh|Cx5CJUj{rh|Cx5CJU1d d e %e |e 4g 6g |g h 'h (h *CJh|Cx56CJ h:CJ hn8[5CJ hD6CJ h|Cx6CJ h|Cx5CJhChh|Cx>*CJ h|CxCJ h_}CJDOk `k tk k k k l l l 6m ,n -n n n n n n o o o ip jp p q q & Fp^p & F^ & F` & F^ & Fn n n n n n n n n n n n n oo yo zo o o o o o o p Gp Kp Lp Mp Np Vp jp ~p p p q q >q Kq Mq Tq q q r r pr r "s )s Rs ls ms s s s It Jt Zt h}6CJh}6h}66CJh}6h}65CJ h}65CJ hDCJ hn8[CJ h_}CJh|Cx56CJ hn8[5CJ h|Cx6CJ *h|Cx5CJh|Cx5>*CJ h|CxCJ h|Cx5CJ7q q -q Lq Mq Uq r r r !s "s *s Qs Rs s s t It Jt nt ot t t t ^gd}6 ^`gd}6 & F^ & F^ & F^gd}6 & FZt bt dt mt nt ot t t u u ru u u u u v v v 'v ov ~v v v v v w /w Gw Yw gw |w w w w x x Fx Lx Px Rx _x nx x x x x >y \y y y y y ۾۸۬ۦ۠ۋۋ۸h|Cx6>*CJ h|Cx>*CJh &6h|Cx56CJaJ h@CJ hhCJh|Cx5B* CJph hn8[CJ h{>CJhpch|CxCJ h|Cx5CJ( h|Cx5CJ h|CxCJh|Cx56CJh}6h}656>*CJh}656CJ3t u u 0u ru u u u u &v 'v nv ov ~v v v v v v Fw ~w w w x ^x & F^` & F`` & F^ & F^x _x nx x x x x x x =y >y \y y y y *z +z 9z :z Zz [z hz z C{ D{ n{ | p^p & F^ & F^ & Fy y y y y y y y y y z z z &z 'z (z )z +z 9z :z Zz [z gz iz tz D{ [{ m{ n{ { { | .| /| :| | | } } 1} 2} D} E} R} S} w} y} } } } ~ +~ ,~ .~ h &6h|Cx56CJaJ h &6CJ h|Cx6CJ h|Cx5CJhphp6CJhpchpCJ h|Cx>*CJhn8[0J>*CJjsh|CxCJUh|Cx0J>*CJjsh|CxCJUjh|CxCJU h|CxCJ5| | .| | | | | } } } 0} 1} 2} D} E} R} S} x} } } } } M~ N~ r~  & F & F^` & F` & F^.~ /~ 3~ 7~ D~ E~ K~ N~ `~ a~ r~ s~ ~ ~ ~ ~ ~ ~ ~      . W Y f u      ' ) E V W ׀ ؀ ـ 9 > ? F h|Cx0J>*CJjsh|CxCJUjh|CxCJU h &65CJ hn8[5CJ hDCJ hn8[CJh|Cx h|Cx6CJ h|Cx>*CJ h|Cx5CJ h|CxCJ>r~ s~ ~    w    ( ) W  $ % ^`^ & F^ & F^gdpc % . L M ? K M N ] ^ _ e t " t x Ʌ ݅ ޅ ߅    $ % & W n   ~ 㽶|v hhCJ jh|CxCJ h|CxCJH* h5('CJhhhh0J>*jmth UhhjhhhhU hhhh hh5CJ h|Cx>*CJh|h|CJ h|CJ h|Cx5h|Cx h|Cx5CJ h|CxCJ h|Cx>*CJ h|Cx5>*CJ .% M q  > ? N  ^ u ^` ^`gd|^ & Fv^v & F^` & FJ]J^ & FJ]J^` & FJp]J^p  & F^ " t ȅ Ʌ ' ) D z ʆ & և 3 O E ^ & Fhgd{> & Fhgdh & Fh ^`` ^` & Fgd| 2 3 F G N O Ո ؈   D E ~ ĉ ɉ ҉ ډ   O P Y zztph|Cx hL KCJ h_}CJ hvCJ hDCJ h|Cx5CJh{>h{>>*CJaJh{>CJaJ jh{>hhCJaJh{>hhCJaJh{>h{>CJaJ jh{>h|CxCJaJh{>h|CxCJaJ h{>h{> jh|CxCJ h|CxCJ hn8[CJ) ĉ ɉ  F | Њ  9 R j } Nj ݋  A  ^  & Fg^ ^`^ ^`Y e n u z {  0 7 I P Nj ы n p  K S    ] ^ _ ̨̳̾n,j@uhpchfgB*CJUaJph̙hpchseB*CJaJph̙&jhpchseB*CJUaJph̙hpchseCJaJhpchDCJaJhpch|Cx5>*CJaJhpch|CxCJaJ h|CxCJH* hDCJ h|Cx5CJ jh|CxCJ h|CxCJ hg4CJ$  ; < [ \ | } U V & Fv^v & Fgdg4^gdg4^p^pgdq: ^`p^pgdpc^gdpc_ e f g  : ; < = c d e n o " $ % L M N X ƻsmg]gM]Bhq:hq:0JCJjvhq:hQCJUjhq:CJU hq:CJ hDCJhq:h|Cx0J>*CJjvhq:hQCJUhq:hq:CJjhq:hq:CJU h|Cx6CJ h|CxCJh|Cx5>*CJhpch|CxCJaJhg4CJaJhpchseCJaJ&jhpchseB*CJUaJph̙$hpchse0J>*B*CJaJph̙X Y Z \ m V _ ` ɒ ̒ ? @ ^ _ ` ļ韘针{neUnjwh &6h CJUh &6h &6CJjh &6h &6CJU h &6CJ h &65CJh,h,5CJ h,CJ hn8[>*CJ h|Cx>*CJhg4h|CxCJaJhg4hg4CJaJhg4CJaJhg45CJaJhpch|Cx5CJaJ h|Cx5CJh|Cx5>*CJ h|CxCJ hq:CJjhq:CJU x Г ` a l ` a n 6 X Q |    & F%gdIc & F%gd^gdp^gd &6^gd &6^gdp & F` v w Г ` a l a m y Օ ݕ   5 I M N O X u v ʖ ˖ ̖ ֖ ז ýwn^wRwhIchIc0J>*CJj&xhIchIcCJUhIchIcCJjhIchIcCJU jhIcCJmHnHu jh|CxCJmHnHuh|CxCJmHnHu h?zCJ hIcCJ hCJ h|CxCJ h|Cx5CJh &6h &65CJ h7CJ h5CJ h &6CJjh &6h &6CJUh &6h &60J>*CJ ז ٖ ږ       Q b h i j k { |    ) = > ? @ ¼®¨¼Ȩ¼}o}e}h0 h0 0J>*jyh0 hjUjh0 h0 U h0 h0 h0 CJ h|Cx5CJ jh?zh?zCJ h CJ jh|CxCJmHnHu h?zCJ h|CxCJ hIcCJhIchIc0J>*CJjxhIchIcCJUjhIchIcCJUhIchIcCJ% Ø ԙ ՙ ; ~  ޚ ߚ   < k  & F%gd3D & F`gdpc & F & F^`gdp ^`gdp^gdp ^`gdp^gdp ՙ ڙ ۙ  К њ Қ ۚ ܚ ݚ ޚ ߚ      쭽򠕉zhzZzhpch|Cx0J>*CJaJ#jd{hpch|CxCJUaJjhpch|CxCJUaJhpch|Cx5CJaJhpch|CxCJaJh|Cxh|Cx0J>*CJjzhZ )hCJUjh|CxCJU h|CxCJ$ h|Cx5CJ$ h &65CJ hn8[CJh|CxCJmHnHu h|CxCJ h|Cx5CJ h0 h|Cx#  < [ i ӛ   & @ B R T V X Z [ r s t y z }  I J    ˟ ̟ }h%h%CJjh%h%CJUh%h%5CJ h%CJh|Cx5B* CJph jh|CxCJh3Dh3D5CJh|Cx0J>*CJj{h|CxCJUjh|CxCJU h|CxCJH* hDCJ h|CxCJ h|Cx5CJh|Cx, қ ӛ   ' D Z < & F^ & F` & F*gd3D h^`h & F` & F^ & F & F%gd3D n o Ӡ b ١ ڡ Q R b w Ģ Ţ Ƣ ^gdR,gdR, & F & F^` ^`^^ & F+gd3D & Fp^pgd% & F^    o ʠ ˠ ̠ Р Ѡ Ҡ Ӡ Ԡ   1 2 L M N ` a f ǽ}}pgWpKphmh3D0J>*CJj}hmhGrCJUhmhmCJjhmhmCJUh3Dh3DCJH* h3DCJ hmCJh3Dh3D0J>*j|h3DhGrUjh3Dh3DU h3Dh3Dh3Dh3D5CJ h%CJh%h%CJh%h%0J>*CJjh%h%CJUjB|h%hU# CJUf g ڡ R a k l ¢ â Ţ Ƣ Ǣ ޢ ߢ nbNn&j~hR,h|Cx5CJUaJhR,h|Cx5CJaJ jhR,h|Cx5CJUaJhR,h|CxCJaJhR,5CJ(aJ(hR,h|Cx5CJ(aJ( hR,h|Cx jh|CxCJmHnHu h|CxCJ h|Cx5CJ h3DCJh3Dh3D0J5>*CJ"jC~h3DhGr5CJUh3Dh3D5CJjh3Dh3D5CJU        0 1 2 5 6 8 9 U V W b c d e } ~  ӳǢǎ~Ǣj~VӢ&jhR,h|Cx5CJUaJ&j?hR,h|Cx5CJUaJhR,h|Cx0J5>*CJaJ&jhR,h|Cx5CJUaJ jhR,h|Cx5CJUaJ&jchR,h|Cx5CJUaJhR,h|Cx5CJaJhR,h|Cx5CJaJ jhR,h|Cx5CJUaJhR,h|Cx0J5>*CJaJ! d   _ ` n ' ( 8 n o z    & FgdZ^gd-z & F0^`0gdZ & F & F^ & F^gdpc^gdR, ã ģ ƣ ǣ    4 @ J ^ _ ` m ( 7 o p x z ξξ󦝦~wqwqj`jTh-zhZ5CJaJh8ehZ5CJ hZ5CJ h|CxCJ h|Cx5CJhq:ht CJaJhq:CJaJhq:hq:CJaJh|Cx5>*CJh|Cx&jhR,h|Cx5CJUaJhR,h|Cx0J5>*CJaJ jhR,h|Cx5CJUaJ&j%hR,h|Cx5CJUaJhR,h|Cx5CJaJ ĥ    Ϧ C D G H J M Q R Z [ \ ] ĽĶĶpdhxhx0J>*CJj1hZ )hCJUjhxhxCJUhxhxCJ hx5CJ hn8[CJ h8eCJ h|CxCJ hZ5CJ h|Cx5CJ hZ>*CJ hZCJh-zCJaJh-zh-z5CJaJh-zhZ5CJaJh-zh-zCJaJh-zhZCJaJ& D Q R ϧ Ч   ( Ш u - . Q  & F^gd8e p0^p`0gd8e & F 8  0^ `0gd & F^gd8e & Fp0^p`0gd8e & F0^`0gd8e Ч ק ا ٧      ( ) R S T i j h m ! , . R m ƪ Ӫ Ԫ ׻䱫{tmgc[ch $h|Cx5h|Cx h $CJ h|Cx6CJ h|Cx>*CJ hDCJh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|Cx5CJ h|CxCJhxh|Cx6CJhxhx0J>*CJjhZ )hCJUjhxhxCJUhxhxCJhxh|Cx5CJhxh|CxCJ"Ԫ   6 7 8 { ӫ    E F G Q [ p | ~ Ŭ Ƭ   ' ( 1     ) * ȴꞴ𗎈~x hCJhGzhGz5CJ hGzCJhs hs CJ h|Cx>*CJ h8eCJ *h|Cx5CJ h|Cx6CJ h|Cx5CJ h $CJ h $5CJh $h $CJaJh $h|CxCJaJh $h|Cx5CJaJ h|CxCJh|Cxh $h $5h $* 8 {  F G Q p Ƭ  (   & F`gdGz & Fgdpc & Fp0^p`0gd8e & F0^`0gd8egd $ ^`gd $^gd $ & F^gd8e  & F^gd8e* + O P Q T U V W X خ 첩ud[UNUDUjh|CxCJU h|Cx5CJ h|CxCJhs h|CxCJ hs hs 0J>*B*CJph̙(j'hs hzNB*CJUph̙hs hs B*CJph̙"jhs hs B*CJUph̙hs hs CJ hCJ#hh0J5>*B*CJph+jhhb*5B*CJUphh5B*CJph%jhh5B*CJUph   J ٯ گ ] I J k 1 3 & F^gd8e & F0^`0gd8e & Fخ ٮ ڮ   د ٯ ߯      ҽ|jaO"jhs hs B*CJUph̙hs hs CJ#hh0J5>*B*CJph+jwhhb*5B*CJUphhh5B*CJph%jhh5B*CJUphhhCJ hs 5CJ hn8[5CJ h|Cx>*CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU R S T Z [ \ ]  J k  4 d ֲ D E  + ˺˱}yncncncn] hyCJhpchpcCJaJhpch|CxCJaJh|Cxhpch|CxCJh|Cx5>*CJ h|Cxhh|Cx5>*CJ h|Cx6CJ h|CxCJ h|Cx5CJhs hs CJ hs hs 0J>*B*CJph̙"jhs hs B*CJUph̙(jhs hzNB*CJUph̙hs hs B*CJph̙#3 d ֲ E   + ޴ ߴ  & Fp0^p`0gd8e & F0^`0gd8e & F8^8gd8e & Fd gdQ & Fdgd}'  & F^gd8e & F  & F^gd8e & F^gd8e ߴ  Z [ \ ^ g i  ; I L N U u ն ֶ 4 5   r d o y ¹ Q R z { | 퍼"jhZ )h5CJUh|Cx0J5>*CJ"j߇hZ )h5CJUjh|Cx5CJU h|Cx6CJh|Cx hDCJ hD5CJ h|CxCJH* hn8[CJ h|Cx5CJ h|CxCJ h8eCJ7ߴ [   . ֶ 5   q r  & F8^8`gd8egdpc & F^`gd8e & F^gd8e & F8^8gd8e & Fp0^p`0gd8e & F0^`0gd8e ̸  Z D Ⱥ ? @ P Q  7 R  & Fgdv^gdv 0^`0 0^`0gd & F h^`hgd8e & Fc 8^gdCjR & F^`gd8e & F^gd8e| Ժ ׺   @ P Q \ o p r s Ż ƻ ǻ ջ U V X ] f g v x   5 6 ϱϤ㕤㕆}hvh|CxCJhvhvCJ hA;ZCJ hvCJhh|CxCJ hCJ hA;Z5CJhA;Zh|Cx5CJH*hvh|CxCJ aJ h|CxCJH* h|Cx5CJ h|Cx>*CJ hDCJ h|CxCJjh|Cx5CJUh|Cx0J5>*CJ1R } 3  a b {   & Fc`gdv`^p^pgdpc & Fp^pgdpc & F^gdpc 0^`0gdA;Z & F%gdA;Z^gdA;Z & Fgdv  " ( f i 3 7 8 <             1 3 : ; H I o ɻɫjh|CxCJU h|CxCJH* jh|CxCJ hvCJ hpcCJhA;Zh|CxCJH* hpc5CJ hn8[5CJ h|Cx5CJhA;ZhA;Z5CJ hA;ZCJ h CJ jh|CxCJ h|CxCJhA;Zh|Cx5CJ1 :  P $ % & u v : ! 5  & F0^`0gd8e^gdpc^gdpc & F^ & Fc`gdCjRo p q z { } ~ \ ] t u  # % & , / 5 6 7 ] ^ _ b r s v ֲֻ֫֝֋{rfhpch|Cx5CJaJhD0J>*CJjHhZ )hCJU hR,CJhth|Cx5CJ(aJ( h|Cx5CJ h":56CJ h|Cx6CJ jh|CxCJ hvCJ hn8[CJ hA;ZCJ jh|CxCJ h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU( : C _    ! 3 4 6 ? 7 @ \ m n q  p + . 9 ; G P W Y d f }   " + ѺѳѬѬѬѬџѳѓhth|Cx>*CJ$aJ$ hpcCJ hD6CJ h|Cx6CJ h|Cx>*CJ hTCJ hDCJ h+ CJ h|Cx5 h|CxCJ h|Cx5CJhpch3CJaJhpch|Cx5CJaJhpch|CxCJaJ: 7 n  M Z f H e f }    | & F^gd8e & F^ & F & F0^`0gd8e^gd8e| ! " +  Q R  7 ^ _  & F^`gd3 & F^`gd3 & F^gd3gdpc & F & F^gd8e    ҾvaP8a/jh3h|Cx5B* CJUaJph h3h|Cx5B* CJaJph)jh3h|Cx5B* CJUaJphhQ-h|CxB* CJaJph$hQ-h|Cx0J>*B* CJaJph,jhQ-h+B* CJUaJphhQ-hQ-B* CJaJph&jhQ-hQ-B* CJUaJphh8eh3B* CJaJphh|CxB* CJaJphh8eh|CxB* CJaJphh|Cx    7 8 9 O P Q R \ ] t u v ַ֑q]N7],jhQ-h+B* CJUaJphhQ-hQ-B* CJaJph&jhQ-hQ-B* CJUaJphh8eh|CxB* CJaJph h3h35B* CJaJphh|Cx5B* CJaJph/jh3h|Cx5B* CJUaJph h3h|Cx5B* CJaJphh35B* CJaJph)jh3h|Cx5B* CJUaJph'h3h|Cx0J5>*B* CJaJphv    $ % & 5 ʵxjRxj:x/jh3h|Cx5B* CJUaJph/j~h3h|Cx5B* CJUaJphh35B* CJaJph'h3h|Cx0J5>*B* CJaJph/jh3h|Cx5B* CJUaJph h3h|Cx5B* CJaJph)jh3h|Cx5B* CJUaJphhQ-h|CxB* CJaJph&jhQ-hQ-B* CJUaJph$hQ-h|Cx0J>*B* CJaJph5 6 7 8 R S T \ ] ^ _ v w ǶNJyhYH0/jh3h|Cx5B* CJUaJph h3h|Cx5B* CJaJphh8eh|CxB* CJaJph h3h35B* CJaJph hUh|Cx5B* CJaJph'hUh|Cx0J5>*B* CJaJph/jhUhj5B* CJUaJph hUhU5B* CJaJph)jhUhU5B* CJUaJphh35B* CJaJph)jh3h|Cx5B* CJUaJph_ v 6 7 E ^ M ' ( & F^gdU & F h^gdQ^gd3^gd3gdpc  & F^gd3 & F^`gd3 & F^gd3  ! ִ֎}lXI2X,jh8eh|CxB* CJUaJphh8eh|CxB* CJaJph&jh8eh|CxB* CJUaJph h8eh|CxB* CJaJhph h3h35B* CJaJphh|Cx5B* CJaJph/jvh3h|Cx5B* CJUaJph h3h|Cx5B* CJaJph h3h8e5B* CJaJph)jh3h|Cx5B* CJUaJph'h3h|Cx0J5>*B* CJaJph! , 4 5 6 7 E Q S ` a ^ g h Ʒ{riZPhZH}hZH}5CJjhZH}hZH}5CJUhbdhbdCJhQ-hQ-CJ hQ-5CJ hQ-CJ hbdCJ hbd5CJhbdh|Cx5CJ h|CxCJ h|Cx5CJ h|Cx6CJh|Cxh8eh|CxB* CJaJph&jh8eh|CxB* CJUaJph$h8ehD0J>*B* CJaJph$h8eh|Cx0J>*B* CJaJph + ( 4 : ; ߽ߤ|v|lf|_|TKhQ-h|CxCJhUfh|CxCJaJ h|Cx>*CJ hUCJhth|Cx5CJ hDCJ h|CxCJ h|Cx5CJhbdhbdCJ hQ-CJ hZH}CJ hbdCJ hbd5CJ"j:hZH}h/F5CJUhZH}hZH}5CJhZH}hbd5CJhZH}hbd0J5>*CJjhZH}hZH}5CJU"jhZH}h/F5CJU( ; _ p   & ' F ;  & Fs pp^pgdQgdpc & F0^`0gdU & F^`gdU & F@ 0^@ `0gdU & F^gdU & Ft pp^pgdQ & F^`gdU; _ p     4 C u     & ' ? E F n ùòââʢʕʑy h|Cx>*CJ hQ-CJhUfh|CxCJaJh|Cx hUCJ hU6CJ h|Cx6CJ jbh|CxCJ hZH}5CJhUh|Cx5CJ h|Cx5CJ h|CxCJhJ0hZH}6CJhJ0hR,6CJhJ0hR,CJhJ0hZH}5CJhJ0hZH}CJ,n o      # $ 1 2 ;     ` 瘝ztn hUfCJ h1MCJhfzh0J>*j-hfzh+UjhfzhU hfzh hCJ hJ0CJh|Cx5>*CJjh|CxCJUjhZ )hCJUh|Cx0J>*CJjhZ )hCJU h|CxCJjh|CxCJU(;  ` &    u ? }  & Fp^p`gdQ- & F@ ^@ gdQ- & F^`gdQ- & FgdU & F@ 0^@ `0gdU & F@ ^@ gdU & Fs pp^pgdQ ^ `  %    p s t u y z ˷˧ᗎqehUhU0J>*CJjhUhjCJUjhUhUCJUhUhUCJ hU5CJh|Cx0J>*CJjhZ )hCJUjh|CxCJUhZH}h|Cx5CJ h|CxCJhQ-hQ-CJ hQ-5CJ h|Cx5CJ h8eCJ hQ-CJ h1MCJ hyHCJ' ?   N o ~   4 6 D F X Y e v  tkhhCJjhhCJU hCJ hZH}CJ h|Cx6CJht:hth|Cx>*CJ$aJ$ htCJ ht5CJhQ-h|CxCJaJ h|Cx5CJ h|Cx>*CJhth|Cx5CJhQ-5CJaJhQ-hQ-CJaJhQ-hQ-5CJaJ h|CxCJ hQ-CJ*}  M N o ~    4 gdpc & F & Fp^pgdt & F^gdt ^`gdt & F^`gdt & F^gdt & FgdU & Fp^p`gdQ-4 6 F Y v - . J   , B C j  & F^`gdFvj  & F^gdFvj & F^gdFvj^gdFvj^gdFvjgdt:  , . J ^  , C j z  , B C P Q ^ b c d e ~ ƿʿʿʹʿʿʿʿƫoch|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphhB* CJ$phh|CxB* CJ$phhtB* CJ8OJQJphh|CxB* CJ8OJQJph hDCJ h|Cx5CJh|Cx h|CxCJ hCJhh0J>*CJjhhCJUj4hh"`nCJU$ A B C ^ _ . L ( _ - d ^gdW & F^gdWgdpc & F  & F^gdFvj & F^`gdFvj & F^gdFvj~     , - . ܷܕrfSrDrh|Cx0J5>*B* CJph%j8h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUphh|Cx5B* CJph+jNhh[wO5B* CJUphh5B* CJphh|CxB* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jٖh|Cx5B* CJUph. / I J K _ ` c d   ' ( ) yo]y"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph%jh|Cx5B* CJUph%jh|Cx5B* CJUph%j(h|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph ) ; < L M l m n r s w x  ɽɛɽɽɛvɽcɛɽɽ%jyh|Cx5B* CJUph"jh|CxB* CJUph%jh|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx0J>*B* CJph! ! & ' ( ) C D E ] ^ _ d g h ܤub%jWh|Cx5B* CJUphh|Cx0J>*B* CJph"jh|CxB* CJUphjh|CxB* CJUphh|CxB* CJph%juh|Cx5B* CJUphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUph       + - . N O P ǵuiYM:Y%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx5B* CJphhO#h|CxB* CJph hO#h|Cx0J>*B* CJph(jChO#h\xB* CJUphhO#hO#B* CJph"jhO#hO#B* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"jԞh|CxB* CJUphP U V Z d e     ʺʄqbPbBh|Cx0J>*B* CJph"jh|CxB* CJUphjh|CxB* CJUph%jh|Cx5B* CJUphh|CxB* phh|Cx0J5>*B* CJph%j9h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph     9 : ; A B C D K L g h i | } ˹˩{k_Lk%jrh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx0J>*B* CJphhn8[0J>*B* CJph K  W F    8 R & F^gdt^gdt ^gdt & F^gdW ^`gdW ^`gdW^gdW     8 9 : U V W X     - . 0 ԷԤԑ~k%j h|Cx5B* CJUph%jh|Cx5B* CJUph%jh|Cx5B* CJUph%jzh|Cx5B* CJUph%jh|Cx5B* CJUphh|CxB* CJphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx0J5>*B* CJph*0 : ; C D E F G n o p  ߼ϭߐϭϊ}ym\m jh7h75CJUaJh7h75CJaJh7h|Cxhpch|CxCJ h|CxCJ%j!h|Cx5B* CJUphhDB* CJphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphjh|Cx5B* CJUphh|Cx5B* CJphhn8[B* CJphh|CxB* CJph         # X c : O  ! ۿsjh|Cx0J>*CJjqh|CxCJUjh|CxCJU h|Cx5CJ h8z^CJ hn8[CJ h|Cx>*CJ hDCJ h|CxCJH* h|CxCJh|Cxh7h7h75CJaJh7h70J5>*CJaJ jh7h75CJUaJ&jh7h.5CJUaJ)R  1 a + U V < = p G & F^ & F & F^gdt & F^gdt Z 9 : O P k  V   * & F^gdt & F^gdt & F & F^ ! " F   1 r  & F 88^8gd H  & Fh^hgdpc & F & F^gdt^gdt & F^gdt & F^gdt   / B N   2 ;  , - B C D G H u ~  r  亂y hn8[CJhRh|Cx0J>*CJj_hRh|CxCJUhRh|CxCJjhRh|CxCJU hDCJ h|Cx5CJh|Cx5B* CJphh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cxh h|CxCJ h|Cx>*CJ h|Cx/   / 0 < r A B 2  u r gdpc & F & F^ & F` & F & Fh^hgdpc & F 88^8gd H  T W { } 3 7 9 Q   R S ^  V j l             ﰧh7h|Cx0J>*CJjȨh7h|CxCJUh7h|CxCJjh7h|CxCJUh|Cx5B* CJph h|Cx6CJ hCJ hn8[CJ hDCJ h|CxCJ h|Cx5CJ h|CxCJ h|Cx>*CJh|Cx6  ? | } 9  ^ _   & F^`gdGz & F^`gdGz ^`gdGz & F^gdGz & F  k l    [ \ |   c    =     ; [ gdpc & F^gdGz & F & F^gdGz & F^gd  ! \ |       / 0 1 : ;       ! 4 5 6 9 : ; =         " # $ 9 i   w zu h|CxH* h|Cx5h|CxB* CJphh|Cx5B* CJph h|Cx>*CJ h|CxB* ph hDCJjh|CxCJUh|Cx hn8[CJh|Cx0J>*CJj?h|CxCJUjh|CxCJU h|Cx5CJh|Cx5B* CJph h|CxCJ hGzCJ,[     O r       # $ 9 i  v  & F^ & F^  & F^ & F^` & Fgdpc  & F^gdGz & F^gdGz & F^gdGzv w        $ U ` i   & F^` & FL & FL ^` & F^ & Fp^p` @ ^@ `^gdpc & F^p^pw |       C D S T ` f   = > u     [ \ ' - ; U W սհՅ hf/CJhh|Cx0J>*CJjhhCJUhh|CxCJjhh|CxCJU h_}CJ hDCJ hCJ hn8[CJ h|CxCJ h|CxH* h|Cx5hpch|Cx5CJaJ h|Cx5CJh|CxhD4 d  6 ; V W u      & F^gdGz & F^gdGz & F^gdGz & F^` & F^ & F & F^ & F^`W u ~     w        B D W X Y Z            ` a  ·}wpga h4[OCJh4[Oh4[OCJ he5CJ ht}CJht}h|CxCJaJht}ht}0J>*CJaJ#jht}h$CJUaJjht}ht}CJUaJht}ht}CJaJ ht}CJ h|Cx5CJhGz h|CxH* h|Cx5h|Cx hn8[CJ h|CxCJ h|Cx5CJh|Cx5B* CJph" > a v w   B D     L }     & F^gdGz & F^gdGz & FgdGz & F^`gdGz ^`gdGzp^pgdGz^gdGz  & F^gdGz    - b    G H g     @ A P ^`gdGz h^`hgdGz & FgdGz & F^gdGz & F?gd4[O & F@gd4[O & F^gdGz & F^gde           G H Y e f             ! # 1 A N                ~x~ h|CxCJ h|Cx>*CJ hb>CJ hn8[5CJ hCJ h|Cx6CJ h|Cx5CJ h|CxCJ h4[OCJ heh4[O0J>*B*CJph(jwheh4[OB*CJUphheh4[OB*CJph"jheh4[OB*CJUphheh4[OCJ/P         5 B C f     V W d & F^gd4[O & F^gdGz & F ^`gdGz h^`hgdGz & F^gdGz & F^`gdGz      ; A C \   W X \ ] c d       ) 6 8 P U     V W      4 ; < > J [ \ whn8[B* CJphh|CxB* CJphh|Cx5B* CJphhn8[5B* CJphh|Cx h|Cx>*CJh|Cx56CJ hn8[CJ h|Cx6CJ h4[OCJh4[Oh4[O5CJ h4[O5CJ h|Cx5CJ hb>CJ hGzCJ h|CxCJh|Cx5B* CJph.d    ( ) 8       4 5 ^ % ;  & F^`gdGz  & F^gdGz^gdGz & F^gdGz & F^`gdGz & F^gdGz & F^gd4[O\ ^     0 1 D E a h          + 2 > @ H K M             +   \ h         F L m n jh~8h~8CJU hCJ hGzCJh|Cx5B*CJphhn8[5B* CJphh|Cx5B* CJph h|CxCJH* jh|CxCJmHnHu h|Cx5CJ hb>CJ h|CxCJh|CxB* CJph8; a  2         9 \        & F ^gdGz & F8^8gdGz^gdGz & F^gdGz & F^`gdGz & F^gdGz & Fp^pgdGzn        _ ` ! ! ! " " " " u# # # # $ $ $ -$ @$ D$ ;% <% G% & & <& I& C' L' u' ' ' ' ' ' ' ' ' ' ' ' ȻȻȻȻȵȻȬȨȡȗȊȡh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx>*CJh|Cxh|Cx5>*CJ hb>CJ hn8[CJ h|Cx5CJ h|CxCJh~8h|Cx0J>*CJjh~8h~8CJUjLhZ )hCJUh~8h~8CJ0 v ! 1! b! ! ! ! P" Q" " " # Z# [# t# u# # $ $ .$ ;% & F^gdGz^gdGz & F^gdGz & F ^gdGz;% <% H% & ;& <& J& & ' C' t' u' ' ' ' "( #( @( ) ) 2) ) * * "* & F^gdpc & F & F^gdGz & F^gdGzgdpc' ' ' ' ( #( @( ( ( ( ( ( ( ) ) ) ) 2) y) ) * !* * * + $+ -+ .+ S+ T+ f+ g+ }+ ~+ + + + + + + + + + Ĵͨtkh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx>*CJ h!CJ hn8[CJh|CxB* CJphhVb(h|Cx0J>*CJjhVb(h+<CJUhVb(hVb(CJjhVb(hVb(CJU hpcCJ h|CxCJ h|Cx6CJ h|Cx5CJh|Cx5B* CJph*"* w* * * * + + %+ + + + + + , , - - .. O. V. ^.  & F^gd! & F^gd! & F` & F^gd! & F & F^gdpc & F^gdGz+ + + + + + + + + + + + + + + + + , , , !, ., /, 1, 2, X, Y, Z, p, q, s, t, , , , , , , , , , , , , , , , , , , , , قhn8[0J>*CJj>h|CxCJUjŰh|CxCJUjHh|CxCJUjh|CxCJUj@h|CxCJUj׮h|CxCJUh|Cx0J>*CJjnh|CxCJU h|CxCJjh|CxCJU3, , , , - - - - - !- "- $- %- >- ?- @- F- G- H- I- K- L- e- f- g- m- n- o- p- r- s- - - - - - - - - - - - - - - - - - - - - - - . . h!CJjh|CxCJUjwh|CxCJUjh|CxCJUjh|CxCJUjh|CxCJUhn8[0J>*CJh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU6. . 1. 2. G. H. I. L. M. O. V. _. . . G/ H/ K/ m/ x/ y/ z/ / / \0 d0 0 0 W1 X1 [1 1 1 <2 D2 2 2 2 2 2 2 2 >3 t3 3 3 3 3 3 źy jh|CxCJmHnHu hG{CJ h|CxCJH* h|CJ hb>CJ hn8[5CJ h|Cx5CJh!h|Cx5>*CJhZshn8[CJaJhZsh|CxCJaJh|Cxh|Cx0J>*CJjSh|CxCJUjh|CxCJU h|CxCJ h!CJ/^. _. G/ H/ L/ M/ / / / / .0 \0 0 W1 X1 \1 ]1 1 1 1 1 & F^gd{> & F8h^8`hgd{> & F8^8gd{> & F h^gd{> & F^gd{> & F^gdGz1 <2 2 2 >3 t3 3 4 4 4 5 6 6 16 26 L6 ^gdGz & F^gdGz & F & Fgd{> & F^gd{> & F`gd{> & F^`gd{> & Fp^pgdG{ & FgdG{ & Fp^pgd{>3 3 3 4 4 4 4 4 4 4 4 5 5 5 6 6 6 *6 26 L6 e6 u6 6 6 6 6 6 6 7 7 7 7 y8 8 8 8 8 8 8 8 8 8 8 \9 e9 9 9 ; ; ֳֺ㊗{ hn8[CJh|Cx0J>*CJjh|CxCJUjh|CxCJU hb>CJh|Cx5B* CJph h|Cx>*CJh{>h{>5CJh{>h|CxCJh{>h{>CJ h{>CJ hn8[5CJ h|CxCJ h|Cx5CJ jh|Cx5CJmHnHu0L6 w6 6 6 6 7 )7 F7 v7 7 7 7 7 8 y8 [9 \9 g9 9 : *: N: O: r: 8h^8`hgdGz8^8gdGzp^pgdGz^gdGz & F pp^pgdGzr: ; r; s; ; ; ; ; )< *< |< }< < < < < < = = ^gdGz & F & F^gdGz & F^`gdGz & F^`gdpc & F^gdGz^gdGz & F pp^pgdGz; s; ; ; ; < < < < = = = 9= P= R= a= x= = = = = = > > 5> <> > > > > > > ? ? ? ? ? $? I? J? o? p? q? r? x? y? ? ? ? h|Cx0J>*CJh!0J>*CJj'hZ )hCJUjh|CxCJUhJ\h|Cx5CJ hn8[5CJ hCJ h\ CJ h|Cx6CJ hb>CJ h|CxCJH* hn8[CJ h!CJ h|Cx>*CJ h|Cx5CJ h|CxCJ0= 9= `= a= z= = = = > [> y> > ? ? %? {? ? ? ? ? ? *@  & F^`gdGz & F^gdGz ^`gdGz^gdGz ^`gdGz^gdGz? ? u@ @ @ @ @ @ A A MA PA RA A A B ;B DB B B C C C C C C "D :D HD wD D D D D D D D D D E E E qE sE E E E E E E :F CF 밪둛뛑 h{>5CJ hn8[5CJh{>h{>5CJ h{>CJh{>h|CxCJ hDCJh{>h{>CJ hb>CJ h|Cx>*CJ hn8[CJh|CxB* CJph h|Cx6CJ h|CxCJH* h|Cx5CJ h|CxCJ jh|CxCJmHnHu3*@ X@ t@ u@ @ A MA A ;B C C C PC C C C C C C !D "D ^gdGz & F^`gd! & F^gd! & F^`gdGz & F^gdGz & F^gdGz"D HD sE E RF F F F F G *G +G |G G G G G G HH H H & F^gd!gdpc & F^ & F`gd! & F & F^gdGz^gdD^gd{>^gdGzCF QF RF [F F F F F F F F F G G G G G G H H I #I $I ,I /I 0I JI KI LI TI UI VI WI uI vI wI zI {I I I I ۴۞ۗۍۀwۍjwۍjJh|CxCJUh|Cx0J>*CJj׵h|CxCJUjh|CxCJU h|Cx5CJh|Cx5B* CJ phh|CxB* CJphh|Cx5B* CJphhpch|CxCJ h|Cx>*CJ h|Cx h|Cx>*CJ h|CxCJhDhDCJhDhD5CJ hDCJ h{>CJ(H H I I #I $I .I /I VI }I I I I J 2J \J J J K  & Fhh^h`hgd! & Fhh^h`hgd! & F 88^8gd! & Fh^hgd! & F & F^gdpc & F^gd!I I I I I I I I I I I I I I I I J J J J J J J )J *J +J 0J 1J \J ]J |J }J ~J J J J K K %K &K 'K EK FK GK K жЩМИvp hSCJh|Cx5B* hphh|Cx5>*CJ h|Cx5CJ h|Cx5CJh|Cxjh|CxCJUj2h|CxCJUjh|CxCJUj8h|CxCJU h|CxCJhn8[0J>*CJh|Cx0J>*CJjh|CxCJUjŶh|CxCJU,K K &K 'K EK K K K M M M M M N N 9N UN VN N N N  & F^`gdGz & F8^8gdGz^gdGz  & F^gdGz & F^gdGz & F & Fh^hgd!K K K K K K nL sL uL {L ~L L L L L L L /M 0M 1M 7M 8M 9M M M M M M M M M N 9N VN N N N N N N IJxqhh|Cx56CJ hb>5CJ hn8[5CJ hGzhGz0J>*B*CJph̙(j,hGzhzNB*CJUph̙hGzhGzB*CJph̙"jhGzhGzB*CJUph̙ hGzCJ h|Cx5CJ h|CxCJh|Cx6B* CJph h|Cx6CJh|CxB* CJphh|Cx5B* CJph'N N O O +O {O }O O O O O P P P P P Q FQ GQ xQ Q Q ?R & Fp^pgdGz & F^`gdGz & F^`gdGz & F^gdGzN N N O O +O }O O O O P P GQ XQ R R R !R #R $R @R ZR [R _R `R gR jR nR oR xR yR R R R S S =S >S fS oS S S S S S \T iT T T T T T T T U U U U U 0U CU RU UU eU U U U U h|CxB* CJph hn8[CJ h!CJ h|Cx6CJhn8[5B* CJphh|Cxh|Cx56CJh|Cx5B* CJph h|Cx5CJ h|CxCJ hb>CJC?R @R ZR [R yR fS S S S T T jT }T T T T T T U U U V & F^gdN & F^gdN & F^gdGz & F^gd! & F^gdGz  & FU U U V #V xV V V V V V V V V W W W W W W W "W *W ,W 2W 3W 7W VW _W aW |W W W W W 5X CX NX OX `X nX X X X X X X X X 7Y AY CY WY Y Y Y Y )Z =Z >Z tZ Z Z Z Z Z Z Z Z h|Cx6CJh|Cx56CJ hb>5CJ hb>CJ h\ CJ h|Cx>*CJh|CxB* CJph h|CxCJH*h|Cx5B* CJph h|Cx5CJ h|CxCJDV wV xV V V 3W VW W NX OX PX X X Y Y (Z )Z >Z sZ tZ Z '[ ([  & F^`gdN^gdN ^`gdN & F^gdN & F^gdNZ [ [ [ [ [ %[ &[ ([ :[ ;[ ?[ [ [ .\ 0\ G\ H\ V\ Y\ g\ ] ] >] M] O] b] ] ] ] ] ] ^ ^ C^ L^ M^ ]^ `^ p^ ^ ^ ^ ^ ^ ^ ^ ^ _ _ _ _ _ _ _ _ κΩ h|CxCJ h|Cx5CJ h|Cx5CJ$ hJ\CJh|CxB* CJph h|Cx5CJ h|Cx5CJ hb>CJ h|Cx6CJh|Cx5B* CJphh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ7([ ;[ .\ /\ 0\ G\ H\ h\ ] ] ] A^ B^ ^ ^ ^ ^ ^ ~_ _ _ _ _ _ & F^gdN & F & F^gdJ\ & F^gdN_ _ _ _ ` ` ` .` ` +a `a a xooooo $Ifgd`kdl$$IflFd .t\+    4 layt|Bm $If  & F$If & F$If & F^gd|Bm _ ` ` ` ` !` "` #` *` +` ,` -` .` /` D` E` F` X` Y` [` \` v` w` x` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ` 缮ܜ܊缮xf#jhh|CxCJUaJ#j;hh|CxCJUaJ#jȻhh|CxCJUaJ#j_hh|CxCJUaJhhn8[0J>*CJaJhh|Cx0J>*CJaJ#jhh|CxCJUaJhh|CxCJaJjhh|CxCJUaJ h|CxCJh|Cx(` ` ` ` a a a )a *a +a ,a Ma Na Oa ^a _a `a aa za {a |a a a a a a a a a a a a a a a a a a 'b (b =b œ卉w卉#jhh|CxCJUaJh|Cx h|CxCJhhn8[0J>*CJaJ#j-hh|CxCJUaJ#jhh|CxCJUaJhh|Cx0J>*CJaJ#j;hh|CxCJUaJhh|CxCJaJjhh|CxCJUaJ(a a a a a $Ifgd  & F$If`kd$$IflFd .t\+    4 layt|Bma a a b 'b Db bb yb b $Ifgd  & F$If`kd$$IflFd .t\+    4 layt|Bm=b >b ?b Bb Cb b b b b b b b b b b b c c c c c c c c c c c c c c c c c c c ſũŚ}КſkY#jhh|CxCJUaJ#j`hh|CxCJUaJ#j[hhH0CJUaJhhCJaJjhhCJUaJ#jhh|CxCJUaJh|Cx h|CxCJhh|CxCJaJhh|Cx0J>*CJaJjhh|CxCJUaJ#j hh|CxCJUaJ"b b b b b c c .c ?c hc c c $Ifgd  & F$If`kdr$$IflFd .t\+    4 layt|Bm c c c c d ?d Vd $Ifgd  & F$If`kd$$IflFd .t\+    4 layt|Bmc c c d d d d )d *d +d =d >d Vd Wd ]d ^d wd xd yd d d d d d d d d d d d d d d d d d d d d d ɷɱɛɉwe#jhh|CxCJUaJ#j#hh|CxCJUaJ#jhh|CxCJUaJ#jGhh|CxCJUaJh|Cx h|CxCJ#jBhh|CxCJUaJhh|CxCJaJjhh|CxCJUaJhhn8[0J>*CJaJhh|Cx0J>*CJaJ'Vd Wd ]d d d d e e Te ce le ue ve $Ifgd  & F$If`kd$$IflFd .t\+    4 layt|Bm d e e e !e Ae Be Ce Re Se ve xe ye ze ~e e e e e e e e e e e f f 3f :f Gf Hf Yf f f f f f f tg zg {g g ׿|uooo h\ CJ h8,5CJh8,h8,CJ h8,CJh|Cx0J>*CJjh|CxCJUjh|CxCJU hn8[5CJ h|Cx5CJ h|CxCJ h|CxCJ#jhh|CxCJUaJhh|CxCJaJjhh|CxCJUaJhh|Cx0J>*CJaJ)ve we ye ze e Hf sg tg g g h (h )h vv & F^gd|Bm & F^`gd|Bm & F^gd|Bm`kd$$IflFd .t\+    4 layt|Bm g g )h 4h 5h Bh Kh Lh Ph hh wh h h h h ;i gi hi zi {i i i i i i i Qj Xj fj lj mj xj }j j j j j j j j k k (k @k k k k k l l l l l l l l l 򦠖ӏ hb>5CJh?h?6CJ h?CJh?5CJ\h?h|Cx5CJ h|CxCJH* hJ\CJ hb>CJ hn8[5CJ h|Cx5CJ h|Cx5h] h|Cx56hn8[h|Cx h|CxCJ h|Cx6CJ8)h Lh gi hi i Pj Qj ej fj xj 'k (k @k k k k k l l l l l ^gd|Bm^gd|Bm & F^gd|Bm & F^gd|Bmgdpc  ^gd|Bm^gd|Bml l l 'm nm om m m m 'n n n n o o no oo o o o o  & F@ ^@ `gd|Bm & F@ ^@ `gd|Bm & F^`gd|Bm & F & F^gd|Bm & F^`gd|Bml l l l l m m m $m %m &m 'm (m om m m m m m m m m m m m 'n ,n -n .n n n n n n o &o @o Uo oo uo vo o ɴ֣蝗vlvhNhn8[5CJhNh|Cx5CJ hBfCJ hn8[5CJhNh|Cx>*CJ h|BmCJ h|CxCJ h|Bmh|Bm0J>*B*CJph̙(jh|BmhfgB*CJUph̙h|Bmh|BmB*CJph̙"jh|Bmh|BmB*CJUph̙h|Bmh|BmCJ h|Bm5CJ h|Cx5CJ)o o o o o o o o o o o o o o o o o Hp Ip cp jp kp vp p p p p Aq Nq q q q r r r *r Zr ^r jr lr nr pr rr r r r ¸±¤ž±±±‘‹‘±{±t h|Bm5CJ h|BmCJh8,h|Cx5CJ hb>CJ h8,CJ hn8[5CJ hn8[CJ hJ\CJ hb>5CJ h|Cx5CJhNh|Cx>*CJ h|CxCJhNh|Cx0J>*CJjVhNh~CJUhNhNCJjhNhNCJU hNCJ-o o bp cp vp p p p q \r ^r rr r r r s s s t t Mt \t ]t st t .u  & F^`gd|Bm & F^gd|Bm & F^gd|Bmr s s t @t Lt Mt \t st t t 7u 8u Ju Ku Xu Yu iu ju qu ru }u ~u u u u u u u u v !v "v >v ?v Bv Cv fv gv hv v v v v v v v v v ƱУƎУ}jh|CxCJU h|Cx>*CJ(jhhZ )hB*CJUphh|Cx0J>*B*CJph(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph h|Cx5CJ( h?5CJ$ hn8[CJ h|Cx5CJ h|CxCJ0.u /u 7u u u u u u u u u v v v v w w w 4x x y Ty y & Fp^pgd|Bm & F^gd|Bm & F^ & F & F^`gd|Bm & F^gd|Bmv v v w w ow pw qw rw w w w w w w 4x 5x x x x x y y Ty ]y _y `y by oy py qy |y y y y y y z z *z +z 2z CJh|CxB* CJphh|Cx5B* CJphh|Cx5CJH* h|BmCJ h|Cx5CJ jh|CxCJmHnHu jh|CxCJmHnHu h|CxCJh|Cx0J>*CJjh|CxCJUj h|CxCJU1y z z +z z z ,{ { { 5| Z| [| m| 8} 9} P} j} *~ ~  & F! 8^gd|Bm h^`hgd|Bm & F 8^gd|Bm & F^gd|Bm & F^gd|Bm^gd|Bm| 4| 5| =| ?| @| A| C| D| F| H| I| [| l| m| | | | | | | 9} P} T} _} } } ~ ~ ~ '~ (~ ?~ @~ U~ V~ W~ X~ ~o~dh|Cx0J5>*CJj+h|Cx5CJUjh|Cx5CJUh|Cx0J>*B*CJph(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph hb>CJh|Cx6B* CJphh|Cx5B* CJphh|Cx5CJH* h|Cx5CJ h|CxCJ h;CJ%X~ Z~ [~ ~ ~       ) Q Z € ˀ ր $ ) * / V \ h p q  / 0 1 ŹůůŒyd(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUphh|CxB*CJph h|Cx6CJh|Cx6B* CJphh|CxB* CJphhb>5B* CJphh|Cx5B* CJphh|Cx5CJH* h|Cx5CJ h|CxCJjh|Cx5CJUh|Cx0J5>*CJH*'~ ~   )  ˀ $ g h q  ; > 7  & F pp^pgd H  & F^gd|Bm & F^gd|Bm & F^gd|Bm & F^`gd|Bm1 8 9 : ; W e ɂ ׂ  > G 7 @ B D E M R \ ҄ m w x ҅ U V W ɾhd=hgCJaJ hgCJ hb>5CJ hJ\5CJ jh|CxCJmHnHu h|CxCJ h|Cx5CJhb>h|Cxh|Cx5B* CJphh|CxB*CJphjh|CxB*CJUphh|Cx0J>*B*CJph. l m " # H I ~  & F^`gd|Bm & F^gd|Bm & F^ & Fgdpc^gd|Bm^gd|Bm & F 8^gd|Bm & F^gd|BmW X ! " # H V Y Q ^ ~ 6 7 C D L ъ ڊ  * 쫥zzzzh|Cx5B* CJph hJ\CJ h|Cx>*CJh|Cx h|Cx6CJ h|Cx5CJ h|CxCJhd=hgCJaJ$hd=hg0J>*B*CJaJph̙,j3hghgB*CJUaJph̙hgB*CJaJph̙&jhd=hgB*CJUaJph̙0 6 7 N > ? Z [ m M N p ͌ X Y e   & F^gdBf & F & F^`gd|Bm & F^gd|Bm & F^gd|Bm* > ? L X Z [ m  & ' A B C K L N p ͌ ٌ < @ Y e h s {   ? @ M N O  # E G P d e ƽơڑhFXhFXCJ hFXCJhFXh|Cx5CJ hb>CJhUh|Cx0J>*CJj hUhs>LCJUhUhUCJjhUhUCJU h|Cx5CJh|Cx5B* CJph hb>>*CJ h|Cx>*CJ h|CxCJ h|CxCJ3 e g ɏ ʏ ޏ - . I  x , G H ? & F^gdJ\ & F` & F & F^`gd|Bm & F^gd|Bm & F^gd|Bme g h v w ɏ ʏ ޏ ߏ    * + . I | } ɼՑՑՊռzne^ h|Cx6CJh|Cx5>*CJhBfhn8[0J>*CJjhBfh|CxCJU h|Cx5CJ$ hn8[CJhBfh|Cx0J>*CJj}hBfh|CxCJUhBfh|CxCJjhBfh|CxCJUh|Cx5B* CJph h|CxCJ hLCJ hL5CJhFXhFX5CJ hFXCJ hFX5CJ# ϐ א ܐ ݐ ސ     ‘ Ñ đ , 6 V d i o Ē ʒ ̒ ے % ' 0 @ G H I J \ k  ٓ ړ 1 2 4 ; h|Cx5B* CJph hn8[CJ hJ\5CJhJ\h|Cx5CJ hJ\CJ hb>CJ h|Cx>*CJ h|Cx6CJ hn8[5CJ h|CxCJ h|Cx5CJC? @ ] Ĕ G H ՘ ֘ ܙ ݙ   %  & Fgdpc & F^gdJ\ & F^gd|Bm & F^gd|Bm ” Ô Ĕ Ҕ u  A B g Ľ؏wgXw jhJ\h|Cx5CJaJhJ\h|CxCJaJmHnHuhJ\h|CxCJH*aJhJ\h|Cx5CJaJhJ\h|CxCJaJh/h/0J>*jah/h Ujh/h/U h/h/ h/CJ hn8[5CJ h|Cx5CJ h|CxCJh|Cx5B* CJphh|CxB* CJphh|Cx6B* CJph!   G H X Y Z Ԙ ՘ ֘  9 < L a } ݙ ) 5 l m t u    q ѿ乯䣗~w~ hJ\>*CJ h|Cx>*CJ hb>CJh|Cx6B* CJphhn8[5B* CJphh|Cx5B* CJphh|CxB* CJph hJ\CJ h|Cx0J>*j4h|CxUjh|CxUh|Cx h|Cx5CJ h|CxCJhJ\h|CxCJaJhJ\hJ\CJaJ.q s ě ś ϛ ԛ ՛ ֛ כ 6 T q y Ü ǜ ̜ Ҝ Ԝ ۜ ܜ    & ( ) 4 5 ; = hA h\18CJ^JaJhA h\18CJaJhA h|CxCJaJh*z5B* CJph h*zCJh|CxB* CJphh|Cx5B* CJph hn8[CJ hJ\5CJ h|Cx5CJ hb>CJ hn8[5CJ h|Cx5CJ h|CxCJ hJ\CJ2 ϛ 5 6 V ǜ  % & 4 5 = P  & F^gd|Bm & F^gd|Bm & F & F^`gd|Bm & F^gd|Bm Q ] _ s ß ğ ٟ ڟ Ϡ Р   j y z { | P Ľ落{k_落hLuh|Cx0J>*CJj hLuh&CJUhLuhLuCJjhLuhLuCJU h|Cx5CJhn8[5B* CJphh|Cx5B* CJph h|Cx>*CJ hBfCJ h|Cx6CJ h|Cx5CJ h*zCJh|CxB*CJphh|Cx5B*CJphh|CxB* ph h|CxCJhA h|CxCJaJ%P Q _ ß ğ ٟ ڟ G  i j , O P b  C & F^gd|Bm & F & F^gd|BmP _ ` b C L ˣ ; ? Ϥ Ф פ ؤ ܤ , 5 b j l u  ) + @ B b c Ǧ զ J M §   9 : ⺶hpch|CxCJ h|CxCJH*h|Cx h|Cx5CJ$ hn8[CJ h*zCJ hn8[5CJ h|Cx5>* h|Cx5CJ h|CxCJhn8[5B* CJphh|Cx5B* CJph> ʣ ˣ ; Ϥ Ф ߤ , k l u f ֦ & F^  & F & F & F^gd|Bm & F^gd|Bm & F^`gd|Bm֦ צ D E X l m ̧   9 : D F > ? * ,    & F@ ^@ `gd & F^gd & F & F^ & F^: A D F G b c d s t v w Ш Ѩ Ҩ ި ߨ  ðϡϗ{hY{{FY{{%jh|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphhBf5CJ8OJQJh|Cx5CJ8OJQJ       5 6 7 < = ? @ Y Z [ b c d   H J L j l p ܤuf\I%j`h|Cx5B* CJUphh@CB* CJphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJph%jh|Cx5B* CJUphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUphp r t v ֪ ت ܪ ު    2 4 H J & ( , . ̹ت̗ت̄تqتgWjh|Cx5B* CJUphh|CxB* CJph%j\h|Cx5B* CJUph%jh|Cx5B* CJUph%j`h|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh@CB* CJphh@Ch@CB* CJph. h j l ¬ Ĭ " $ & . D F ѶzmZK<h@C0J5>*B* CJphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh@Ch@CB* CJphh*z0J5>*B* CJph%j`h|Cx5B* CJUphjh|Cx5B* CJUphh@CB* CJphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jh|Cx5B* CJUphh|Cx5B* CJphF J L    * B D H J Į Ʈ ʮ ̮    ³~kaWh|CxB* CJphh|CxB* CJph%jh|Cx5B* CJUph%jPh|Cx5B* CJUph%jh|Cx5B* CJUphh*z0J5>*B* CJphh@C0J5>*B* CJphh|Cx0J5>*B* CJph%jDh|Cx5B* CJUphjh|Cx5B* CJUphh|Cx5B* CJph"  : < > L N P R T ﷭ucQ?Q3h|Cx5B* CJph#h@Chn8[0J5>*B* CJph#h@Ch|Cx0J5>*B* CJph#h@Ch@C0J5>*B* CJph+jh@Ch|Cx5B* CJUphh@Ch|Cx5B* CJph%jh@Ch|Cx5B* CJUphh@CB* CJphh|CxB* CJphh|Cx0J5>*B* CJph%jDh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph   " $ d f h а Ұ ԰ 0 2 4 ^ ` b 㵥pcP%jh|Cx5B* CJUphh@Ch@CB* CJph%j.h|Cx5B* CJUphh@C0J5>*B* CJph%jh@C5B* CJUphjh@C5B* CJUphh@C5B* CJphh|Cx0J5>*B* CJph%j(h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphb d f h ر ڱ ܱ     ! " ˸שˇשtשj`Pjh|Cx5B* CJUphh|CxB* CJphh|CxB* CJph%jh|Cx5B* CJUph%jh|Cx5B* CJUphhn8[0J5>*B* CJphh|Cx0J5>*B* CJph%j"h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh@Ch@CB* CJphh@C5B* CJph ! " # $ . / > ? K Q U s ׳  & F ^gd H & F ^gd H & F^gdBf & F^gdBf & F & F^gd & F@ ^@ `gd & F@ ^@ gd" B C D S T V W y z { ѸzgzTzJh|CxB* CJph%jh|Cx5B* CJUph%jih|Cx5B* CJUphh|Cx0J5>*B* CJph%jh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jgh|Cx5B* CJUphh|Cx5B* CJph   ! " # $ - . / > ? K s t ﵩzmdTmHm?mhTBh|CxCJhTBh|Cx0J>*CJjhTBh-ZCJUhTBhBCJjhTBhBCJU h|Cxhh|Cx h|Cx>*CJ h|CxCJ h|CxCJ h|Cx5CJ h5B*CJphh|Cx5B*CJphh|Cx5B* CJphh0J5>*B* CJph%jch5B* CJUphh5B* CJphjh5B* CJUph ʳ ˳ ̳ ճ ֳ        % &  )  6 C / 0 F G H L M % ſũrih|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ hCJhpchBCJhBh|Cx5CJ h|CxCJj4hTBh-ZCJU hTBCJhTBh|CxCJhTBh|Cx0J>*CJjhTBhBCJUjhTBh-ZCJUhTBhBCJ%׳   % &   ) ŵ 5 6 C } % Q  & Fgd8^8gd[^^^gd & F & F ^gd H%    \ ^      g r s t κ Ϻ   , R ^ a b ʻ ϻ ӻ        2 3 ɼϳhTBhTB0J>*CJjChTBh5NCJUhTBhTBCJjhTBhTBCJU hTBCJ hTB5CJ h|Cx5CJ h[CJ h>!CJ hCJ h|CxCJh[h[6CJ5Q    e g t Ϻ  R S b ʻ ˻ ӻ  b  & Fgd @ `^@ ``gd @ ^@ ` ^`gd^ & Fgd3 4 Z [ \ _ ` a b e f m n 쬥uiSuAu; hBCJ#hh|Cx0J5>*B*CJph+johTBh5N5B*CJUphhTB5B*CJph%jhh|Cx5B*CJUphhh|CxCJ h|CxCJ h*z5CJ h|Cx5CJ hTB5CJhTBhTBCJ#hTBhTB0J5>*B*CJph+jhTBh5N5B*CJUphhTBhTB5B*CJph%jhTBhTB5B*CJUph  & . / a { | ~  ׽   1 2 3 {qaqjhZ )hCJUjh|CxCJU h*zCJ h*z5CJhb-0hb-0CJ hb-05CJ h|Cx5CJh|Cx hy;CJ h|CxCJ hCJ hBCJ hBhB0J>*B*CJph̙(j hBhfgB*CJUph̙hBhBB*CJph̙"jhBhBB*CJUph̙$ / | ~ ֽ ׽ q Ծ H J  & F pp^pgdQ & F ^gdQ^gdBf & FJ`gdpc^gdy; h^`hgd3 G H J K L 8 D F J H J  9 d g ۺ̬ۣ~xq~xxhxb h*zCJh3h3CJ h|Cx5CJ hCJhhCJhh|CxCJ h3CJ hBCJ h|Cx>*CJhpch|CxCJhMh|Cx0J>*CJaJ#jhMh|CxCJUaJjhMh|CxCJUaJhMh|CxCJaJ h|CxCJjh|CxCJUh|Cx0J>*CJ&J = > N % t < = J  & F^`gdBf  & F^gdBf & F ^gdBf^gdBf & F^gdBf & F ^gdQ = > N \   % & < = I J U    ' D L N ` {  & ' ( ) * J K L U V X { } hBfCJ hCJh|Cx0J>*CJjh|CxCJUjh|CxCJU hHoCJ jh|Cxh|Cx h3CJh3h35CJ h|CxCJH* h|Cx>*CJ h|Cx5CJ h|CxCJ hCJ9    X { } 3 4 P 5  & F^`gd} & F^gd}^ & F ^`gdBf^gdBf & F^`gdBf & F^gdBf & F^gdBf 4 > P V [ 6 > ? @ } + ýЭwjahHohHoCJjhHohHoCJUh}h|Cx5CJhh}6CJh}h}5CJ h_}CJ jh}h}CJ h}CJ h}5CJhhCJ hJjnCJ hCJ h5CJ h|Cx5CJ hm5CJ hBfCJ h|Cx>*CJhpch|CxCJ h|CxCJ h*zCJ$5 } P    ? ( { ^gdBf & F^ & F^ & F^gd} ^`gd}^ & F^`gd} & F^gd}+ , - < = P T V a   ) 0 9 D b j СƏzzztnzzh h_}CJ hPCJ hCJ h|Cx5CJh}h|Cx0J5>*CJ"jh}h=)i5CJUjh}h}5CJUh}h|Cx5CJ h*zCJ h}CJh}h}5CJ h|CxCJhHoh|Cx0J>*CJjhHohHoCJUjhHoh|CxCJU&  j  ( P Q   + / e  # % 3 I q  = ? J ' ( 1 2 { ? 쮥Ӯӥ hfCJhW1hf5CJhPhPCJ hP5CJhPheu5CJheuh|Cx5CJheuh|Cx>*CJ hPCJ h_}CJ h|Cx5CJ hn8[CJ heuCJ h|CxCJ h|CxCJH*: K L c 2    & F^`gdBfgdpc & F^gdBf & F^gdBf & F gd^^gdBf^gdBf ^`gdBf? B V _ K L V W c 2 D 4  0   * W X n o p q    ៛ hQ70J>*j hC+UjhQ7UhQ7 hQ75CJ h|Cx>*CJ h|Cx6CJh|Cx56CJ hmCJh|Cxh^h^CJ hm5CJh^h^5CJ h|Cx5CJ hW1CJ h^CJ h|CxCJ hfCJ2 W X   x v G @ C   9 ^`^ & FY` & F^^ & F^gdpc & F    y v G P Z    C D E P Q @ L C L  9 m n d { 7 F Ͻhh|Cx>*CJaJh|Cx5>*CJ hn8[5CJ hn8[CJ h|Cx6CJ h|Cx0J>*jhUjh|CxUh jh|Cxh|Cx h|Cx5 h|Cx5CJ h|CxCJ h|Cx5CJ 8 " c d { # 6 7 G H |  b  & F^`gdBf & Fp0^p`0gdBf^gdpc & F & F` & F^` & F^ & F^ ^`F G H T { |    * b h t 9 : 9 ý򮤒ɂypic huICJ hn8[5CJh|Cx5>*CJ jh|CxCJ huI5CJh|Cx0J>*CJ"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph hn8[CJ h|CxCJ h|Cx5CJhpch|CxCJaJhpchCJaJhpch5CJaJ hCJ h|Cx>*CJ& # $ =  x   ; c d  & F^gdBf  & F^gdBf & F^gdpcgdpc & F^gdBf & F^gdBf & F # $ <    F I V _ x - . ; c d   ( ) * < = > ? h|Cx0J>*CJj5h|CxCJUjh|CxCJU hz 5CJ h|CxCJH*hBfh|CxCJhh|Cx>*CJ h|Cxh h|Cx>*CJhn8[h h|Cx5CJh|Cx h|CxCJ huICJ h?CJ6d ?  2 u v L m    gdpc & F^gdBf & F^gdBf & F^gdpc & F  " 2 ; = > e f g s t u v L X m s t u v  $ ݸtke hzCJhzh|CxCJhzhz0J>*CJjhzh~CJUjhzhzCJUhzhzCJ hz5CJ h|Cx5CJh|Cxhz h|Cx0J>*CJjhz h-ZCJUhz hz CJjhz hz CJUhz h|Cx5CJ h|CxCJ h_}CJ'     = > ? L M O P q r s     ԴԴԴ~ԴlԴhh|Cx"jh|CxB* CJUph"jh|CxB* CJUph"jh|CxB* CJUph"jh|CxB* CJUphh|Cx0J>*B* CJph"jh|CxB* CJUphjh|CxB* CJUphh|CxB* CJph h|CxCJ h|Cx5CJ hzCJ(   ^ \  F | D E ^ _ r 7$8$H$^7$8$@&H$ & FR ^gdCjR & FR p@ @ ^@ gdCjR & FR pp^pgdCjR & FR ^gdCjR & F^gdBfgdpc & F`gd \ ^ F Z  E ^   8 9   X Y  % & < =     - . 0 1 r s 򪔪򪔪h|Cx5CJH* hpcCJ h|CxCJH* h|Cx5CJ hCJhih|CxCJhih|Cx0J>*CJj{hZ )hCJUhihiCJjhihiCJU h|CxCJ h|Cx>*CJ:r ]  > ? T 7$8$H$ p7$8$H$^pgdpc7$8$H$^`gdpc & F^ 7$8$H$^ 7$8$H$^7$8$H$^`   0 1 ? Z [ i hEkd$$Ifl0(#4 la.EkdL$$Ifl0(#4 la. $7$8$H$If hEkdx$$Ifl0(#4 la. $7$8$H$IfEkd$$Ifl0(#4 la.   G d hEkd@$$Ifl0(#4 la. $7$8$H$IfEkd$$Ifl0(#4 la.d e f o p q hbXJ7$8$H$^` 7$8$H$^7$8$H$Ekd$$Ifl0(#4 la. $7$8$H$IfEkd$$Ifl0(#4 la. ! " .   ) A s  + , o & F  7$8$H$^7$8$H$^` 7$8$H$^ & F^ + , R S  " V W ^ _ } - . : ; Q T v y   =   I J Y [ \ t u v | }  h|Cx0J>*CJjlh|CxCJUjh|CxCJU h|Cx5CJh|Cx h|Cx5CJ h"VrCJ h|Cx>*CJ h*zCJ hCJ hn8[CJ jh|CxCJ h|CxCJH* h|CxCJH* h|CxCJ9 >    I J " # = > k 7$8$H$`7$8$H$7$8$@&H$  & F^ & F^ & F^ & F & F  & FZ & F`    ! # = > ? W X Y ʠ~wjaQjjZh h PCJUh h CJjh h CJU h|Cx>*CJ h|Cx5CJjh|CxCJUh*z0J>*B* CJphh|Cx0J>*B* CJph"jVh|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJUY _ ` a b         3 4 9 ; F m   C D S T ] _ i o       " & ŵΩΚΓΓΏ~wmg~~~aΓ h-CJ h(rCJh(rh(r5CJ h(r5CJh-h|Cx5CJ h-5CJh|Cx h|Cx5CJh(rh|Cx5B*CJphhpch|Cx>*CJaJjh h PCJUh h CJ h|CxCJh h|CxCJjh h CJUhn8[0J>*CJh h|Cx0J>*CJ&    3 4   C T   "   C    R & F^`07$8$H$^`0gdpc7$8$H$ 7$8$H$^ 7$8$H$` & F@&`&       C O      S W Y `        P Q ~         " # . : < = R S T W X r s ͼݩݜ|h|Cx0J>*CJj@h|CxCJUjh|CxCJUh(rh(rB* CJph jh(rh(rCJ hn8[5CJ h|Cx6CJh(rh|Cx>*CJh(rh|Cx5CJ h*zCJ h(rCJh(rh(r5CJ hn8[CJ h|Cx5CJ h|CxCJ0R S     + j } ~   . - ^`gdBf & F@&^gdBf7$8$H$^`gdBf & F^gdBf & F@&^gdBf 7$8$H$^gdBf 7$8$H$` 7$8$H$^7$8$H$s   , - : H J V W X Y m[U h(rCJ#h9-h9-0J5>*B*CJph+jh9-h#,5B*CJUphh9-h9-5B*CJph%jh9-h9-5B*CJUphh9-h9-CJ h9-5CJh(rh|Cx5CJh9-h|CxCJh"h|Cx hn8[5 h|Cx5h|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ - H T E x   D 7$8$H$^`gdBf p7$8$H$^pgdBf & F 87$8$H$^gd H & F 87$8$H$^gd H7$8$H$^`gdBf 7$8$H$^gdBf & F 87$8$H$^gd H [ d h H Q T U u v w z {  x y ܻͭܛ͍~tb~"jGhZ )h5CJUhu$hu$5CJjhu$hu$5CJUh(rh(r0J5>*CJ"jzhZ )h5CJUh(rh|Cx0J5>*CJ"jhZ )h5CJUjh(rh(r5CJUh(rh(r5CJ h(rCJ h"CJ h|CxCJ h|Cx5CJ!              ! 1 < D E                   ɿxr h- CJ hn8[5CJ h*zCJ hzCJ h,CJh,h|Cx5CJ h|Cx5CJh$gh|Cx>*CJ hu$CJ h|CxCJH* h|CxCJhu$h|Cx5CJjhu$hu$5CJUhu$h|Cx0J>*CJH*hu$h|Cx0J>*CJhu$h|Cx0J5>*CJ,D      6 J >    U   {7$8$@&H$^gdpc7$8$@&H$^`gdBf7$8$@&H$^gdBf 7$8$H$^gdBf 7$8$H$^gdBf p7$8$H$^pgdBf & F 87$8$H$^gd H & F   7$8$H$^ gd H        6 J V > G c p                   ̷wqeZh$gh$gCJaJh}$ch|Cx5CJaJ h}$cCJh}$ch|Cx0J>*CJH*h}$ch|Cx0J>*CJjhZ )hCJUh}$ch}$cCJjh}$ch}$cCJUh[.h|Cx5CJh}$ch*zCJaJh}$ch}$cCJaJh}$ch}$c5CJaJh}$ch|Cx5CJ h|Cx5CJ h- CJ h|CxCJ    ? @ A R S T U Y [ g k             m p     ޲~skse^eWQe h$gCJ h|Cx5CJ h|CxCJH* h|CxCJh*zCJaJh}$ch|CxCJaJh}$ch}$c6CJaJh}$ch}$cCJaJh}$ch}$c5CJaJh}$cCJaJh}$c5CJaJh}$ch|Cx5CJaJh}$ch$g0J>*CJaJ#jh}$ch$gCJUaJh}$ch$gCJaJjh}$ch$gCJUaJh$gCJaJ     ! B =     s   { & F p@ @ 7$8$H$^@ gd H @ 7$8$H$^@ gdBf & F pp7$8$H$^pgd H7$8$@&H$^`gdBf7$8$@&H$^gdBf7$8$@&H$^gdBf 7$8$H$^gdBf 7$8$H$^gdBf    ! - 0 A D j m         B F Q c j q {               = A D j n      2 = s                T k m    hn8[CJ h|CxCJH* h|Cx6CJ h|Cx5CJ h(rCJh$gh$g5CJ h$g5CJ h*zCJ h|CxCJ h$gCJI T `  , P      .    ' 7$8$H$^gdCa7$8$H$^`7$8$@&H$ 7$8$H$` 7$8$H$^gdBf & F pp7$8$H$^pgd H & F p@ @ 7$8$H$^@ gd H  , /          , . 7 8 9 i j l m r s }            @ B W     . 򽱽ءاujh|CxCJUh% h% 6CJ h% CJ hn8[CJh% hh6CJH* hCaCJh% hh6CJh% hCa6CJH*h% hCa6CJ hn8[5CJhCah|Cx5CJ hhCJ h|Cx5>* hCJ h|Cx5CJ h|CxCJ h|Cx>*CJ+' X    M z  ! ! !! k! ! ! 7$8$@&H$^`gdF>7$8$@&H$`gdF>7$8$@&H$ 7$8$H$^ 7$8$H$`7$8$H$^`gdh7$8$H$^`7$8$H$^`gd% . / 0 K L M f    ! ! ! !! "! h|CxCJ hn8[CJhhCJ jh% h% CJhh5CJ h% CJ hF>CJ hF>5CJ hCJ h5CJhh|Cx5CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjHh|CxCJU0! ! H" W" " " " " # # .$ e$ $ $ % & F8^8` & F `gd H & F^` 7$8$@&H$^ 7$8$H$^ 7$8$H$` & F^`7$8$H$^`gd & F^`gdy# z# {# # # # # # # # # .$ 7$ R$ ]$ e$ i$ $ $ % ,% % % % % % % & ' ' ' ' ' ' ' ( ( ( ( ( ( ( ( ( ( ( ( )) ǽǶǰǰݧݧ{h]h]CJ h]5CJh% h]5CJ h]CJ jh]h]CJh% h% CJ hF>CJ h|CxCJH*h|Cx h*zCJ h|CxCJ h|Cx5CJh% h|CxCJ h% 5CJh% h% 5CJ jh% h% CJ h% CJ/ % ,% ]% % % & ' ' ( ( ) ) ) * * * 7$8$@&H$` 87$8$@&H$^8 & F7$8$@&H$ & F^ & F^ & FgdF> & FgdF> 7$8$H$^ & F^ & Fh^`h & F `gd H)) *) 3) ) ) ) ) p* r* * * * * * * + + &+ (+ + + j, n, , , , - - f- j- . . . . . M. `. g. l. o. . . . . . . . . Y/ t/ շ۱۫۫۫۞۫۫} h|Cx5hih|Cx5B*CJphhih|CxB*CJphhihiB*CJph hiCJ hCJhF>h|Cx5CJ h|CxCJH* h|CxCJH* hn8[CJ hF>CJ h|CxCJ h|Cx5CJ h]CJh]h]CJh]h% CJ1* * + (, j, - - - - . M. . . X/ Y/ t/ / 7$8$@&H$^`^ & F7$8$H$gdi & F7$8$H$gdi 7$8$H$`7$8$H$ ^`gdF> 7$8$H$^7$8$H$^`t/ x/ / / T0 Z0 0 0 1 1 2 2 2 2 3 3 3 3 03 93 :3 ;3 <3 G3 T3 ^3 3 3 3 3 3 4 4 ,4 -4 .4 E4 P4 ]4 ^4 a4 4 4 5 5 5 5 &5 )5 *5 򺴫촥~ h}$cCJH*h}$ch}$cCJH*h}$ch|Cx5CJ h}$cCJ h*zCJ h"VrCJh h CJ h CJh h|CxCJh h|Cx5CJ hn8[5CJh}$ch|CxCJH* h|Cx5CJ h|CxCJH* hn8[CJ h|CxCJ h|Cx5CJ1/ T0 1 1 1 3 3 3 3 /3 03 I3 -4 .4 a4 5 /5 5 6 6 (6 Z6 [6 y6 & F^gd & F^ & F- & F & F^ 7$8$@&H$^*5 /5 75 I5 J5 b5 e5 5 5 5 5 5 5 6 6 '6 N6 Y6 [6 a6 b6 d6 o6 6 7 7 7 7 7 7 77 87 97 C7 D7 [7 7 7 7 7 !8 #8 G8 H8 g8 s8 8 휬{whBh|Cxhpch|Cx5CJaJ h*zCJh}$ch}$c0JCJjhZ )hCJUjh}$cCJUh}$ch}$cCJh}$ch}$c5CJ h+ CJ hn8[5CJh}$ch|Cx5CJ hn8[CJ h|CxCJH* h}$cCJ h|Cx5CJ h|CxCJ.y6 7 7 7 "8 #8 G8 H8 g8 8 n9 |: : 8; ; ; < = = = > > #> ^gdBf & F^gdBf & F h^gdQ^gdpc & F & F^8 8 n9 p9 s9 9 9 9 9 9 9 9 9 : : R: T: {: |: : : : : : ; ; g< h< < < < = = = = > > #> $> 7> :> H> J> K> M> N> > > > > > > 򳩳h|Cx5B* CJphh|Cx5CJH* h|Cx6CJhg:h|Cx>*CJ hg:h|Cxh|Cx h|CxCJH* hn8[CJ h*zCJ jhBhBCJ h}$cCJ hBCJh|Cx5CJH* h|CxCJ h|Cx5CJ3#> $> I> > > ? T? U? z? ? ? @ @ @ @ A A )A *A 5A 6A A A A & F^gdoS & F & F^ & F^` & F^gdpc> > > ? ? U? i? l? y? z? {? }? ? ? ? ? ? ? ? @ @ @ @ @ @ @ !@ ^@ u@ @ @ @ @ @ @ @ @ @ @ @ A (A )A *A 5A vA wA A A 㟬㏉{ h|CxCJH* h|Cx>*CJ h|CxCJ h|Cx5CJ h|Cx0J>*CJjh|CxCJUjh|CxCJUh|CxB*CJphh|Cx5B*CJphh|Cx5CJH* h|Cx6CJ h|Cx5CJ h|CxCJh|Cx5B* CJphh|CxB* CJph0A A A B _B B B B B (C )C >C C aD D D 8E 9E E  & Fp^p`gdoS & F^gdg: & Fp^pgdoS & Fp^pgd`i< & Fp`^p``gdoS & F^gdoSA A A B B 8B 9B :B FB IB ^B _B `B aB B B B B B B B B B C C )C =C >C ?C VC YC C C C C C C 8D GD aD eD D E 9E CE E E E F F 3F 4F 5F HF JF KF jF Ƽ՟jh|CxCJU hbXCJ hP(5CJ h*zCJh;B* CJphh|CxB* CJph h;CJh`i<h`i<CJ h|Cx5CJ h|CxCJH*h`i<h|Cx5CJ h`i<5CJ h`i<CJ h|CxCJ8E E E 4F 5F F F +G G G H 'H H H I I & F^gdoS & F h^gdQ ^`gdoS^gd`i< & F^`gdoS & Fp`^p``gd`i< & F^gdoS & F^`gdoSjF kF lF F F F F G G H H H H I I I "I #I 1I LI TI J J @J \J K K 8K L L L &L ,L L L /M 8M M M M M M M M N N QN RN hN uN ~N N N N N !O "O KO aO ٺٶͯ٨ٕٛٯٕٕٕ hn8[CJjh|CxCJU h*z5CJ h|Cx6CJh|Cx h_}CJ h`i<CJ h|Cx5CJh|Cx5B*CJph h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU:I #I LI @J K K 8K K L L &L L /M M :N uN JO KO aO O O ^gdoS ^`gdoS^gdoS & F^gdoS & F^gdoSgdg: & F- pp^pgdCjRaO bO fO O O O O O O O O O O O O O O O VP `P bP xP zP |P ~P P P P P P P 4Q 6Q NQ PQ pQ Q Q R RR TR jR lR R R R T (T CT PT mT zT T T T T U "U QU \U U h|Cxh h*z5CJ h|Cx>*CJ h$CJ h|CxCJH* jh|CxCJh|Cxh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ h*zCJ h|Cx6CJ h|CxCJ*CJh|Cx0J>*CJjhh|CxCJU h|CxCJjh|CxCJU0W W W W W W W W W W W X X +X .X X X X X X X X X Y Y 5Y 7Y gY pY rY sY }Y Y Y Y =Z >Z sZ Z Z Z Z Z Z Z Z Z Z Z پٴ٪پٴҡ҄ hn8[5CJ jhmhmCJhmhm5CJhmhmCJh) h|Cx>*CJh) h|Cx5CJ hmCJ h|CxCJH* h*z5CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU04W W W +X X X Y gY sY >Z Z Z Z Z [ [ [ 1\ 2\ & F^gdoS & F, 8^gdQ & F8h^8`hgdoS & F^gdoS & F8^8gdoS8^8gdoS & F ^gdoSZ Z Z Z [ [ [ [ 2\ 8\ 9\ D\ N\ [\ \ \ ] 3] H] h] u] ] ] ] ] ^ ^ ^ ^ ^ ^ ^ !^ $^ (^ )^ 2^ <^ T^ U^ _^ ^ ſ~~tjthn8[B* CJphh|CxB* CJph h|Cx6CJh[h[0J>*CJaJ#jhh[h[CJUaJjh[h[CJUaJh[h[CJaJ h[CJ hg:CJ h_}CJ hn8[5CJ hn8[CJ h|CxCJ h|Cx5CJh) h|Cx56CJh) 56CJ)2\ D\ \ \ \ ^ ^ 3^ ^ ^ ^ _ X_ _ _ _ _ ` a ca a a ^`gdoS^gdq gdg: & F^gdg: & F^gdoS & F^gdoS^ ^ ^ ^ ^ ^ X_ a_ _ _ _ _ _ _ _ _ _ _ _ _ _ ` ` ;` I` l` ` ` ` ` ` ` ` ` ` ` ` ` ` ` ѳtejhJhq 5CJUhJh|Cx0J5>*CJhJh|Cx0J>*CJhJhq 0J>*CJj?hJhCJUhJhq CJjhJhq CJUhJh|Cx5CJ hq 5CJ hq CJhq h|CxCJ hn8[5CJh|Cx h|Cx6CJ h|CxCJ h|Cx5CJ'` ` ca fa a a a a a a a a b )b b b b b b c c c c c c 0d Td Vd d d d f f f 2f f f Dg Fg hg g g g h 0h |h h h h h h h h h 8i Dj Ej ]j _j h|Cx5B* CJphhY3h|CxCJ h*zCJ jh|CxCJ jhY3hY3CJ hJCJhq hq 5CJhq hq CJ hq CJ hY3CJ h|Cx5CJ h|CxCJhJh|CxCJ:a )b c c /d 0d Ud Vd d d f 8g g h zh |h h h h 8i & Fp^pgdoS & F^`gdoS & F^gdoS & F^gdoS^gdoS^gdJ & Fgdq  & FgdJ8i Dj Ej j j j k k l l l Lm n n %o o o Up Vp p p  & F@ `^@ ``gdoS & F pp^pgdQ^gdoS & Fp^pgdoS & F^gdoS & F^gdoS_j `j xj yj zj j j j j j j j j j j j k k k k 1k dk xk k k k k k k k k k k k k k k k k k k k ¸¯©£©©©ҖyrihThTCJ hT5CJh)_h|Cx5CJh)_h)_5CJh)_h)_CJ h)_5CJ h)_CJ h\ CJ h)aVCJh)aVh*zCJh)aVh)aVCJH*h)aVh)aVCJ hn8[5CJ h|Cx5CJh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU)k k k k l l (l *l +l Gl Hl Il Sl Tl l l l l l l m m !m -m Am Km Lm Um Wm pm m m m m m m n n n n Ĵͨ񛔡yrl hh{CJ h|Cx>*CJ hn8[CJ hM{CJ *h|Cx5CJ hTCJ h)aV5CJ h)aVCJ h|Cx5CJhTh)_0J>*CJj)hThCJUhThTCJjhThTCJU h)_5CJ h)_CJh)_h)_5CJ h|CxCJhTh|CxCJ'n n >n ?n @n Zn [n an n n n n n n n n n n n n o o o o $o %o .o 0o >o No o o o o o o o o p p ǮǨ~ǨǨtj~dǒǮǮ h*zCJhV6h{d5CJhh{h{d5CJhV6h|Cx5CJhV6hV6CJH* hV6CJh{dh{dCJ h{d5CJ h{dCJ h|Cx5CJ jhM{hM{CJ hM{CJ h|CxCJhh{h|Cx0J>*CJjhh{h;~%CJUhh{hh{CJjhh{hh{CJU'p p p 4p Vp ]p `p gp p p p p p p p p p p p p q q q q q r 6r Ur r r r r r r r r r r r r r r r r r r r s öÙ}j(hhah;~%5Uhhahha0J5>*j^hhah;~%5Ujhhahha5Uhhahha5B*phhhahha5hhah|CxCJ h|Cx>*CJh|Cx6>*CJ hh{5CJ h_}5CJ h|CxCJ h|Cx5CJ/p p q q q 5r 6r Ur r r r r r #s dd$If[$\$ & F^`gdoS & F^gdoS & F^gdoS s s s !s "s #s Os Qs Us Vs \s ]s `s as ~s s s s s s s s s s s s s s s s s s s s s s s s s s t t t t t t t t t t t t t (t |t }t t øøøøøøøøøøøøôøøøøøøøøë hn8[CJ h|CxCJ h|Cx5CJ h|CxCJhhahhaCJhhahhahhaB*ph hhahhahhahha5B*phhhahha0J5>*jhhahha5Ujhhah;~%5U8#s $s Qs Vs ]s as `SSSS dd$If[$\$kd$$Ifl\4xD T8044 laytoSas bs s s s s `SSSS dd$If[$\$kdx$$Ifl\4xD T8044 laytoSs s s s s s `SSSS dd$If[$\$kdF$$Ifl\4xD T8044 laytoSs s s s s s `SSSS dd$If[$\$kd$$Ifl\4xD T8044 laytoSs s t t t t `SSSS dd$If[$\$kd$$Ifl\4xD T8044 laytoSt t t t (t )t dt t `TOOOCC & F^gd & F & F^gdoSkd$$Ifl\4xD T8044 laytoSt t t t t t t t t t t u .u /u Du Eu Fu Lu Mu Su Tu _u u u u u u u v v fv v v v v v v v v v +w ,w 쳺򣜣숁xoh]h) CJh]h]CJ h]5CJhqhq5CJh) h) 5CJ h) >*CJ h) CJhFh) 5CJ hq6CJ hFCJh|Cx0J>*CJj~ h|CxCJUjh|CxCJU jhqhqCJ hqCJ h|CxCJ h|Cx5CJ)t t t t Tu u ,w :x x z )z z { 3{ `{ { { | | | A} B} ^gd?<^gd^gd & F pp^pgdQ & F^gd & F^gd,w 8w Jw Kw ^w _w `w qw rw w w w w w w w w w w w w w w w w w w w w %x 'x *x 9x :x Cx xx {x ~x x x x x x x x x y "y %y Vy ɿɿ~ hCJhFhFCJH* h|CxCJ h|Cx5CJhqhF5CJj hFCJUjP hFCJUhqhq6CJ hqCJhF0J>*CJj hFCJUjhFCJU hFCJhFhF5CJ1Vy Wy ]y `y y z z 'z (z )z .z /z 3z 4z 8z z z z z z z { { { { ${ 3{ D{ J{ _{ `{ i{ { { { { { { | .| 6| | | | | } ײh|Cx5B* CJphjh|Cx5B* CJUph h|Cx>*CJ h|Cx6CJ h5CJhqhqCJhqh|Cx5CJ h*zCJhqhq6>*CJhqhq5CJ hqCJ h|Cx5CJ h,CJ h|CxCJ hCJ-} } } -} .} 1} ?} A} B} c} d} } } } } ~ ~ .~ F~ G~ H~ ~ ~ ~ ÷vvvncTcBT#j h[hSCJUaJjh[h?<CJUaJh[h?<CJaJh[CJaJ jh?<hXOCJaJh?<hXOCJaJh?<hCJaJh?<hXO5CJaJh?<h~8CJaJ h|CxCJh|Cx6B* CJphh|CxB* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%j. h|Cx5B* CJUphB} c} d} } } } } ~  M N a b s c  F  Մ ^`gdff^gdff & F & Fugd?<^gd?<~ ~ ~ ~   M N a b c { | } ̾|dP|A7h|CxB*CJphjh|CxB*CJUph'hyhy0J5>*B*CJaJph/j hyhy5B*CJUaJph hyhy5B*CJaJph)jhyhy5B*CJUaJph h|CxCJ+h~8h|Cx56B*CJ`OJQJaJ`ph hXOCJh[CJaJh?<hXOCJaJh[h?<CJaJjh[h?<CJUaJh[h?<0J>*CJaJ ŀ ƀ ǀ ʀ ˀ ̀ ̀ ΀ ߹{gVAV)jhyh@5B*CJUaJph hyh@5B*CJaJph'hyh|Cx0J5>*B*CJaJph/jb hyh|Cx5B*CJUaJph hyh|Cx5B*CJaJph)jhyh|Cx5B*CJUaJphh|CxB*phhy0J5>*B*CJphh|Cx0J5>*B*CJphjh|CxB*CJUph"j h|CxB*CJUph      ( ) + , H I J Ҿҭo[G//jhyh|Cx5B*CJUaJph'hyh|Cx0J5>*B*CJaJph'hyhZ90J5>*B*CJaJph/jJhyh|Cx5B*CJUaJph)jhyh|Cx5B*CJUaJph hyh|Cx5B*CJaJph hyh@5B*CJaJph'hyh@0J5>*B*CJaJph)jhyh@5B*CJUaJph/j hyh{5B*CJUaJphJ K T U W X t u v w ށ ߁ ±±±s[s±C/j6hyh|Cx5B*CJUaJph/jhyh^-5B*CJUaJph hyhZ95B*CJaJph)jhyhZ95B*CJUaJph/j6hyh|Cx5B*CJUaJph hyh|Cx5B*CJaJph)jhyh|Cx5B*CJUaJph'hyh|Cx0J5>*B*CJaJph'hyhZ90J5>*B*CJaJph     # $ & ' < = > A B D E c d e f ڮښq\qD\/jhyh~85B*CJUaJph)jhyh~85B*CJUaJph hyh~85B*CJaJph/j<hyh|Cx5B*CJUaJph'hyh|Cx0J5>*B*CJaJph'hyhZ90J5>*B*CJaJph/jhyh|Cx5B*CJUaJph)jhyh|Cx5B*CJUaJph hyh|Cx5B*CJaJphf q r s t Ă ł Ƃ ŵxlYJ4Y+jhZ )h5B*CJUphhYh|Cx5B*CJph%jhYh|Cx5B*CJUphhy5B*CJphhy0J5>*B*CJphh|Cx0J5>*B*CJph%j h|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hyh|Cx5B*CJaJph)jhyh~85B*CJUaJph'hyh~80J5>*B*CJaJphƂ ɂ ʂ ̂ ͂   & ' ( 1 2 4 5 U V W Z [ c d ˵˟ڍwg[Hg%jh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph+jhZ )h5B*CJUph#hYh*z0J5>*B*CJph+jhZ )h5B*CJUph+jLhZ )h5B*CJUphhYh|Cx5B*CJph%jhYh|Cx5B*CJUph#hYh|Cx0J5>*B*CJph ƒ ؃ ك ڃ      < = > D E F G h i j } ~  ԮԘԂl+jhZ )h5B*CJUph+jhZ )h5B*CJUph+jhZ )h5B*CJUph%jh|Cx5B*CJUph%jh|Cx5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx0J5>*B*CJph( Ԅ ք      * + 2 3 F G H [ \ ] ^ qePe(jyhZ )hB* CJUphh|Cx0JB* CJph(jhZ )hB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJh|CxB*CJphh|CxB*phh|CxB*CJphh|Cx5B*CJphh|Cx0J5>*B*CJphjh|Cx5B*CJUph%jSh|Cx5B*CJUphՄ ք ]    p   Y Z  & F^ & Fp^pgdff & F ^gdff & F ^gdff & F & F^gdBf & F h88^8gdBf …   1 3 4 Z [ \ m n p s u     ǽͳ͇͇tkY"jhffh|CxB* CJUphh2rh5CJ aJ hffh|Cx5CJ aJ h|Cx5CJh|Cx5CJH* h|Cx0J>*jh|CxUjh|CxUh|Cx h|Cx5hBfh|Cx56hffh|Cx>*CJ h|CxCJ h|CxCJh|Cx0JB* CJphjh|CxB* CJUph"jh|CxB* CJUph ; < = M N O P Q R ̇ ه Z c   ˺˴~wwwjaQjjh=h_1CJUh=h=CJjh=h=CJU h|Cx5CJ h_}CJhgihgi0J>*jhgihZUjhgihgiU hgihgi hgiCJ h|CxCJ hffh|Cx0J>*B* CJph"jhffh|CxB* CJUph(jvhffh|CxB* CJUphhffh|CxB* CJph e ҉ މ `  ; < & !   3  & F& 8^gdQ & F ^gdoS & F & F^gdoS & F^gdoS & Fegdg: & F` & F^ Љ щ ҉ ۉ މ  ` k 7 E T c  < L M N { | } & /  ! B ώ Ў ùÖùÖz h|CxCJH*(j.hZ )hB*CJUphh|Cx0J>*B*CJph(jyhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph h*z5CJ h|Cx5CJ h|CxCJjh=h=CJUh=h|Cx0J>*CJ0Ў      " ) 2 3 4   O P b c { | } ) * + ~ue~j^ hZ )hCJUhwEhwECJjhwEhwECJUh!h!5CJ h!CJh|Cx0J>*CJh!0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJh|Cxhn3h|Cx5CJ aJ hyCJhmfhyhs;hyhy5 hy5 h|CxCJ% O P b c  f ؒ f U w ] ^  & Fgd & F 8^gdQ & F^gdoS & F^gdoSgdg: & F & Fgdg: & F& 8^gdQ+ ; < = z   ! " ' ( F G ] e f j ؒ  ) 1 f v T U Ѯכה׎Ѯׇ~th`Y hhhCJaJhh5CJaJh0h05CJh!h0CJ h05CJ h0CJ h!CJH*h!h!CJH*h!h!CJ h!5CJ hCJ h*zCJ h|CxCJhshs5CJ hsCJ h!CJhwEh!CJjhwEhwECJUhwEh!0J>*CJ"U q      v w  򙐀tnga[Qajh|CxCJU h!CJ h|CxCJ h|Cx5CJ hsCJh0h00J>*CJj!h0h{CJUh0h0CJjh0h0CJUh0h05CJh0h!CJh)J^h!0J5>*CJ"j3!h)J^h{5CJUh)J^h)J^5CJjh)J^h)J^5CJU h0CJ h!5CJ    ! " # $ % & J K L P R Z [ \ ^ j k l ޖ p t U Y i u ~ ʽִʭ~rʭʭʭʭʭk h*z5CJhh|Cx0J>*CJj#hh|CxCJUhh|CxCJjhh|CxCJUhh!CJ h|Cx5CJh*z0J>*CJj"h|CxCJU h|CxCJ h!CJh!0J>*CJh|Cx0J>*CJjh|CxCJUj!"h|CxCJU) ޖ p U r ՚ ֚ 9 ԛ  Y 7$8$H$^`gdoS p7$8$H$^pgdoS7$8$H$^`gdoS 7$8$H$^gdoS & F^gdoS 7$8$H$^gdoS & F^gdoS ݘ ޘ ߘ A B r s * + , 2 3 4 ֚ ˛ ̛ ߛ ٿٹٳٳnٿ hoShoS0J>*B*CJph̙(j$hoShfgB*CJUph̙hoShoSB*CJph̙"jhoShoSB*CJUph̙ hoSCJ h*zCJ hn8[CJj$h|CxCJU h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUj#h|CxCJU+ $ 4   3 > 6 ?  A D l u ' 3 c d y У ѣ ң ۣ ľrfhh0J>*CJjo%hhCJUhhCJjhhCJUhhmf5CJhh5CJ hCJhh5h hL7CJhL7hL75CJ jh|CxCJmHnHu hoSCJhoSh|Cx5CJ h*zCJ h|CxCJ h|Cx5CJ(Y ̝  6  ܟ l à  7$8$H$^gdoS @ 7$8$H$^@ gdoS7$8$H$^`gdoS7$8$H$^`gdoS 7$8$H$^gdoS p7$8$H$^pgdoS & ' 4 c d y ޣ ߣ f 7 ^gdoS  & F^gdoSgdg: & F' 8^gdQ  & F^gdoS  & F^gdoS & F^gdoS & F^gdoS7$8$H$^`gdoSۣ ܣ ޣ ߣ       ] ^ _ c d e f 7 @ B C f g h ոȬ쥚|uuuk[kj4'hZ )hCJUjhCJU h5CJ hhhh0J>*j]&hBUhL7jhhU hhh!h0J>*CJj%h!hCJUjh!hCJUh!hCJh!h5CJh hCJjhhCJU!h o p z { 1 : Z [ h j k Ŧ Ʀ Ǧ Ѧ Ҧ զ ֦       @ A B L ļıļğĕȈȕrjc*h|Cx5Uh|Cx0J5>*j)h|Cx5Ujh|Cx5Uj;)h|CxU h|Cx0J>*j(h|CxUjh|CxUh|Cx h|Cx5 h5hj'hZ )hCJU hCJjhCJUh0J>*CJ, 0 Z [ Ԧ զ  Y    > ? K xMkd,$$Ifl0T! 4 laytoS $Ifgdg:p^pgdoS`gdoS & F^gdoS  ^gdoS L M Y Z Ч ѧ ӧ ԧ    > ? a b | } ڨ ۨ 8 = > C ̪ Ϫ X Z h k L N S 񽷽hg:h|CxCJH*aJhg:h|CxCJaJhg:h|Cx5CJaJ h|CxCJh|Cxj,h|Cx5Uj+h|Cx5Uh|Cx0J5>*j*h|Cx5U h|Cx5jh|Cx5U:K a b j | } YMkdo-$$Ifl0T! 4 laytoSMkd-$$Ifl0T! 4 laytoS $If Ĩ ڨ YMkdC.$$Ifl0T! 4 laytoS $IfMkd-$$Ifl0T! 4 laytoSڨ ۨ F YMkd/$$Ifl0T! 4 laytoS $IfMkd.$$Ifl0T! 4 laytoSF G ^ j k u YMkd/$$Ifl0T! 4 laytoS $IfMkd/$$Ifl0T! 4 laytoS 8 L D  I  @ ^@ gdg: & Ffgdg: & Fggdg:^gdg:gdg:MkdU0$$Ifl0T! 4 laytoSS V ? B D G   M Y _ ` u ߱ F G    襉~hg:h*zCJaJhg:h|CxCJaJmHnHuhg:h6CJaJ% jhg:h|CxCJaJmHnHuhg:hCJaJhg:h*z5CJaJ jhg:h|CxCJaJhg:hoSCJaJhg:h|CxCJaJhg:h|Cx5CJaJ/ n M G t u ߱ 4  ^ _ w  7 ߴ  & Figdg:^gdg: & Fjgdg:p^pgdg:  _ w / 6 7 C ߴ ܵ ݵ ޵  " # , i { ȷ    i   9 Ĺėymbhg:hCJaJhg:h5CJaJ% jhg:h|CxCJaJmHnHuhg:h*zCJaJhg:h|Cx0J5>*CJaJ#j0hg:h<CJUaJhg:hCJaJjhg:hCJUaJhg:h(CJaJhg:h|Cx5CJaJhg:h|CxCJaJhg:hn8[CJaJ& # i    } M h i  z Ժ   ! " 4  & Fhgdg:^gdg:p^pgdg:9 :   ! " 4   H L h ʼ < >     u } о ھ ޾ 2 G 纲盐yyky jhh|CxCJaJhh|CxCJaJhh|Cx>*CJaJhg:hg:CJaJhg:h|Cx5CJaJhg:h_}CJaJhg:CJaJhrCJaJhg:h|Cx>*CJaJh|Cxhh|Cx5>*CJaJ hg:h|Cxhg:h|CxCJaJ jhg:h|CxCJaJ*4 k ػ  ̼  1 2 G  , V ^`gdoS & F^gdoS^gdoSp^pgdoS & Fkgdg:      + , 5 7 U V b z ø|qiaZJjhTBhTBB*Uph hTBhTBhTBCJaJhCJaJhhCJaJh5CJaJhh5CJaJhhuCJaJhuCJaJhhu5CJaJhCJaJhhCJaJhhh0J>*j@1hh<UjhhU hh h5CJh|CxCJaJ       = 7 8 g h & ' - . ԾԳԾynbnbnbnbnbnbnZhCJaJhhCJH*aJhhCJaJhh5CJaJhhCJaJhuCJaJhCJaJ$j2hTBh5NB*UphhTBhTBB*ph hTBhTBhTBhTB0J>*B*phjhTBhTBB*Uph$j2hTBh5NB*UphhTBB*ph .   x y * + I & F^gd & F^`gd & F^gd & F & F^gdn3 & F^gdoS^gdoS. 7    : ; < A B E F k l m v w x y ) I Z оxrkbrrrh}h}CJ h}5CJ h|CxCJj3h|Cx5CJUh|Cx0J5>*CJji3h|Cx5CJU h|Cx5CJjh|Cx5CJUh|CxB* CJphh/;h|Cx5CJ$aJ$ hCJ huCJhuhu5CJhuCJaJhuhuCJaJhuhu5CJaJ$Z [   % ; C      ! @ дݫ톘{i{"j5hZ )h5CJUh|Cx0J5>*CJ"j4hZ )h5CJUjh|Cx5CJU hR05CJhR0h|CxCJhR0hR00J>*CJjs4hR0hwTCJUjhR0hR0CJUhR0hR0CJ h*z5CJ h|Cx5CJ h|CxCJ h*zCJ'@ A B I J K L ^ _ d e f u   , 6 7 : O V w 4 5 6 ^ _ ` k l m ~ ~ ɾӷӢӢӢtӢnӢ h> CJ"j7hZ )h5CJUh;sth;st5CJ h>CJ h}CJ h_}CJ h|CxCJh;sth;stCJ h;stCJ h;st5CJh}h|CxCJ$aJ$h|CxB* CJph h|Cx5CJh|Cx0J5>*CJjh|Cx5CJUj6h|Cx5CJU+ K L ^ _ f 7 O 4 5 m [ k & F^` & F^ & F^^ & Fgd;st & Fgd;st & F & F^gd~    1 2 3 B C l o r   T U v w x { |  ' 5 6 7 H I ھ䐢h|Cxh|Cx0J5>*CJ"jI8hZ )h5CJUjh|Cx5CJUhqhq5CJ hqCJ htCJh|Cx0J>*CJj7h|CxCJUjh|CxCJU h|Cx5CJ hVfCJ h|CxCJ jh|CxCJ2 S T V  = z p r   < & F` & F^` & F & F & F^ & F^^gdt & F^`I V b   = @    F J z  N r |   3 4 5 8 9 < D  æ㏙ hq5CJhqhq5CJ hqCJ h|Cx6CJh|Cx0J5>*CJ"j9hZ )h5CJUjh|Cx5CJU hn8[CJ hn8[5CJ h|CxCJH* h|Cx5CJ hBCJhBhB5CJ h|CxCJ1  `  3 4 B ) ^gdq & Fp0^p`0 & Fp`^p`` & F^ & F` ^` & F^`gdq & F^         4 B ) - < b      C b c ʽʲʏ}k"jM;hZ )h5CJU"j:hZ )h5CJU hqCJhqh|Cx5CJhqhqCJaJhqCJaJhqh|CxCJaJ h|Cx6CJ h_}CJ h|CxCJ h|Cx5CJh|Cx0J5>*CJjh|Cx5CJU"j9hZ )h5CJU) C D  x    g h } ~  & F`gdfMgdoS & F & F^`gdg: ^` & F^ & F^ & F` x   Y ^ g h | } ~         zpajhfMB* CJUphhfMB* CJphhfM5B* CJph hfM5CJj<hfMCJUhfM0J>*CJj <hfMCJUjhfMCJU hfMCJhfMhfM5CJaJh}h|Cx5CJ$aJ$h}h|CxCJ$aJ$ hoSCJ h|Cx5CJh|Cx h|CxCJ h*zCJ& > ? @ M N P Q q r s z { }  vk\Rh;sthfM5CJjh;sthfM5CJUhfM0J5>*CJ"j>hZ )h5CJUjhfM5CJU hfMCJ hfM5CJhhfMB* CJph(j=hZ )hB* CJUphhfM0J>*B* CJphjhfMB* CJUph(j=hZ )hB* CJUphhfMB* CJph  D E S  j 4 c  & F- `gdCjR & F^`gd;st & F^gdR2 & FgdR2 & F^ & F`^gdfM & F^gdfM      A B C O P h i  % E Q S T ߽߃qha[Qh{h{5CJ h|CxCJ h|Cx5CJh%;hfMCJ"j@hZ )h5CJUh;sthfM5CJhfM0J5>*CJ"j0@hZ )h5CJU hfM5CJjhfM5CJU hfMCJh;sth*z0J5>*CJh;sthfM0J5>*CJjh;sthfM5CJU"jc?hZ )h5CJUT X ` a h p q " # j k |   w d ﵫxr h*zCJh|Cx5CJH* h|Cx5CJ h|Cx>*CJhg:h;stCJ jh|CxCJhR2h|Cx5CJh;sth|Cx5CJh;sth{5CJ hn8[CJhR2hR25CJh{hR25CJ hR2CJ h{CJh{h{5CJ h|CxCJh{h|Cx5CJ, d j  / A v $ V q  & FW^ 8h^8`h^ ^`` & F` & F^ & F^`d g j s t u v      # % & J K L ߺxfVjBhZ )hCJU#h;sth;st0J5>*B*CJph+jCBh;sth;st5B*CJUphh;sth;st5B*CJph%jh;sth;st5B*CJUphh;sth|Cx5CJh;sth;st0J>*CJjAh;sth0tCJUh;sth;stCJjh;sth;stCJU h;stCJ h|CxCJ h|Cx5CJ!L S T \ ]      / 2 A D # ԥ柘xohb hzICJ hzI5CJh|Cx0J>*CJjDh$h0tCJU h$CJjh|CxCJU h|Cx5CJ h|CxCJj4DhZ )hCJU h;stCJh;st0J>*CJjqChZ )hCJUh;sth;stCJh;sth|CxCJjh;sth;stCJUh;sth|Cx0J>*CJ%# $ 1  & ( 3 ] g  ' 5 8 L   ꇀqjhBQhBQ5CJU h|CxCJH* h|CxCJH* h*zCJ hj~CJ hn8[5CJ hBQCJhBQhBQCJ hBQ5CJhBQh|CxCJ hzICJ hzI5CJ h9iFCJ h9iF>*CJ h|CxCJh9iFh|Cx5CJ h|CxCJ h|Cx5CJhzIhzICJ,   ( ] 8  & FX & F`gd9iF^gd9iF h^h`gd9iF8^8^ & FW  =  ~ueY~SIh9iFh9iF5CJ h9iFCJhp hp 0J>*CJjFhZ )hCJUhp hj~CJhp hj~0J>*CJjFhZ )hCJUhp hp CJjhp hp CJUhp hj~5CJ hj~CJ h|CxCJhBQh*z0J5>*CJjhBQhBQ5CJU"jXEhZ )h5CJUhBQhBQ5CJ T U } ~      - 6 L M U  * H wpgT%jhoho5B*CJUphhohoCJ ho5CJh|Cx5>*CJh|CxB* CJph hn8[CJ hzICJ h|CxCJ h|Cx5CJh9iFhj~CJ h*zCJ hj~CJhj~hj~CJ hj~5CJ h9iFCJh9iFh9iF0J>*CJjGhZ )hCJUjh9iFh9iFCJUh9iFh9iFCJ  M * . A ! 2 w x y ~ $If ^`gdoS8^8gdoS^gdoS & F^gdoS & F^ & F`^ & F^gd9iF A  " $ 3 5 x y ˹˰|l`|YRYYYNh|Cx h|Cx5CJ h|CxCJH*h$h$0J>*CJjIh$h0tCJUh$h$CJjh$h$CJU h|CxCJ h$CJhg:h|CxCJh|Cx5>*CJhohoCJ#hoho0J5>*B*CJph%jhoho5B*CJUph+jtHhhq5B*CJUphh5B*CJphy | ~   1 2 I J K E _ s t   ' V W X ` h i # ( 9 : # w ¹𹝔 h-HCJh$h|CxCJ h$CJ h|CxCJH* hn8[CJh$5>*CJh|Cx5>*CJhg:h|CxCJ hzICJhzIh|CxCJhzIhzICJ h_}CJ h|Cx5CJ h|CxCJh|Cx h|Cx>*8~ KkdI$$Iflr B8804 laXytoS$If KkdJ$$Iflr B8804 laXytoS$If       # * KkdjK$$Iflr B8804 laXytoS$If* 0 1 2 9 = C H I KkdIL$$Iflr B8804 laXytoS$IfI J K QE5,8^8gdoS & Fh^`hgdoS & F^gdoSkd(M$$Iflr B8804 laXytoS C E t  W X i " # : { ^gdoS  ^gdoS8^8gdoS & FgdzI^gdoS ^`gdoS h^`hgdoS # 5 C  i j $If^gdBf^gdoS^gdoS  ! ` h i j   ˺xkWxGh h%;0J5>*B* ph3'jROhZ )h5B* Uph3h h%;5B* ph3!jh h%;5B* Uph3h h%;0J5>*B* ph'jNhZ )h5B* Uphh h%;5B* ph!jh h%;5B* Uphh h%;>*h h%;5>* h|Cx>*CJh|Cx h[7CJ h-HCJ hn8[CJ h|CxCJ % 1 h $IfskdN$$Ifl\4 d(#ppT4 laytBf  % 1 2 [ \ ] f g i j ɼɘڍڂxgZFg'j3RhZ )h5B* Uph3fh h%;5B* ph3f!jh h%;5B* Uph3fh h%;0J>*jrQhUjh h%;Uh h 0J5>*B* ph3f'jPhZ )h5B* Uph3fh h 5B* ph3f!jh h 5B* Uph3f h h%;h h%;5B* ph3!jh h%;5B* Uph3h i   $IfskdP$$Ifl\4 d(#ppT4 laytBf       , - U V W b c d e ѽѶxdTxGjh h%;5Uh h%;0J5>*B* ph3'j&UhZ )h5B* Uph3h h%;5B* ph3!jh h%;5B* Uph3h h%;0J>*jYThUjh h%;U h h%;'jShZ )h5B* Uph3fh h%;5B* ph3f!jh h%;5B* Uph3fh h%;0J5>*B* ph3f  , d $IfskdS$$Ifl\4 d(#ppT4 laytBf  ! Y $IfskdU$$Ifl\4 d(#ppT4 laytBf     ! " G H I Q R X Y s u v ǼDZǣǖ~rmfVrmjYhZ )h5U h h h 5h h 0J5>*j XhZ )h5Uh h 5jh h 5Uh h h%;0J>*j>WhUjh h%;U h h%;h h%;0J5>*jh h%;5UjwVhZ )h5Uh h%;5!Y Z g h q r $IfskdX$$Ifl\4 d(#ppT4 laytBfr s t u | $Ifgd0t$IfskdXY$$Ifl\4 d(#ppT4 laytBf      F I J o p q y z ǹxh\WxP h;sth h 5h h 0J5>*j]hZ )h5Uh h 5jh h 5Uh h 5>*h%;h;stCJaJh;st5>*CJaJh 5>*CJaJh%;h 5>*CJaJh%;h h%;0J>*j[hUjh h%;U h h%; h h hg:h  $IfskdZ$$Ifl\4 d(#ppT4 laytBf $Ifskd/[$$Ifl\4 d(#ppT4 laytBf     / > G H ttkkkkkk $Ifgd0t  !$Ifgd0t^gdBfskdz\$$Ifl\4 d(#ppT4 laytBf H I $Ifgd0tskd]$$Ifl\4 V(#Tpb4 laytBf    " $ p v z |          >  hp CJ h$CJ hn8[CJ hGdCJ h CJ h*zCJH* h|CxCJH* h*zCJ h|CxCJ h|Cx5CJ h;sth h;st h{6 h;sth{h h{5 h;sth;st h 6h h{4 $Ifgd0tskd_^$$Ifl\4 V(#Tpb4 laytBf $Ifgd0tskd^$$Ifl\4 V(#Tpb4 laytBf 4Mkd!`$$Ifl04 VT4 laytBf $Ifgd0tskd_$$Ifl\4 V(#Tpb4 laytBf   ! P $If^gdBf^gdoSMkd`$$Ifl04 VT4 laytBf $Ifgd0tP Q g { | ]Mkd_a$$Ifl04- (4 laytBf$IfMkd`$$Ifl04- (4 laytBf r ]Mkd3b$$Ifl04- (4 laytBf$IfMkda$$Ifl04- (4 laytBfr t ` b t  ]Mkdc$$Ifl04- (4 laytBf$IfMkdb$$Ifl04- (4 laytBf       Q a p q         4 5 6 B C E G H J ` q      9 : s t         / 1 L U q ҹ褞ҹ҂ h;stCJjoh|CxCJUh"h|CxCJ h"CJ h;st6CJ h|CxCJH* h|Cx6CJh|Cx0J>*CJj=ihZ )hCJUjh|CxCJU hGdCJ h*zCJ h|CxCJ h CJ jh h CJ3       ]Mkdc$$Ifl04- (4 laytBf$IfMkdqc$$Ifl04- (4 laytBf       ]Mkdd$$Ifl04- (4 laytBf$IfMkdEd$$Ifl04- (4 laytBf  5 F G Q b ]Mkde$$Ifl04- (4 laytBf$IfMkde$$Ifl04- (4 laytBfb c p y z   ]MkdWf$$Ifl04- (4 laytBf$IfMkde$$Ifl04- (4 laytBf       ]Mkd+g$$Ifl04- (4 laytBf$IfMkdf$$Ifl04- (4 laytBf       ]Mkdg$$Ifl04- (4 laytBf$IfMkdg$$Ifl04- (4 laytBf     G  ]Mkdh$$Ifl04- (4 laytBf$IfMkdih$$Ifl04- (4 laytBf       ]Mkdvj$$Ifl04- (4 laytBf$IfMkd j$$Ifl04- (4 laytBf       ]MkdJk$$Ifl04- (4 laytBf$IfMkdj$$Ifl04- (4 laytBf     + , ]Mkdl$$Ifl04- (4 laytBf$IfMkdk$$Ifl04- (4 laytBf, - 3 4 5 9 ` ]Mkdl$$Ifl04- (4 laytBf$IfMkdl$$Ifl04- (4 laytBf` a e f g k l ]Mkdm$$Ifl04- (4 laytBf$IfMkd\m$$Ifl04- (4 laytBfl m q r s   ]Mkdn$$Ifl04- (4 laytBf$IfMkd0n$$Ifl04- (4 laytBfq        ) G H R k l ~        6 ʼʴʨʴʝzszzf]h[7h[7CJjh[7h[7CJU h[75CJ h9CJ h[7CJh[7h[75CJ h|Cx>*CJ hR0CJhR0h|CxCJaJhR0hR0CJ\aJhR0CJaJhR0hR0>*CJ\aJhR0hR0CJaJhR05CJaJhR0hR05CJaJh|CxB* CJph h|CxCJ h CJ!       ]QE & F^gdR0 & F^gdBfMkdo$$Ifl04- (4 laytBf$IfMkd|o$$Ifl04- (4 laytBf   G H        ! H I = q r & F^gd & F^gd & F^gd[7 & F^gdR0^gdR0    # 7 = J X { + 7 8 I \ ^ _ + , - : ; r ýɶìÜýìÆ}h[7h|CxCJjqh|CxCJUh|Cx0J>*CJjphZ )hCJUjh|CxCJU h5CJ h*zCJ h|CxCJ h|Cx5CJ h[7CJh[7h[70J>*CJjh[7h[7CJUjPph[7hCJU0 ] d f g ƿ~xk[kOkx~h-Hh-H0J>*CJjsh-HhCJUjh-Hh-HCJU h-HCJ h|CxCJhg>h-H0J>*CJjrhg>hCJUhg>hg>CJjhg>h-HCJUh-Hh-HCJ h-H5CJ h|Cx5CJh[7h|Cx0J>*CJj rh[7hCJUh[7h|CxCJjh[7h|CxCJU \ ] " # i           & F^`gdz & F & F^`gd & F^gd & F^gd # 1 3 4 [ \ ] ` f g h                5 6 7 : ; <     |nhzh|Cx0J5>*CJ"juhzh5CJUjhzh|Cx5CJUj#uhZ )hCJU hzCJhzh|Cx5CJh|Cxh[70J>*CJh|Cx0J>*CJjXthZ )hCJUjh|CxCJU h|Cx5CJ h|CxCJ hCJ+              ! H I J V W X Y Z         - :     ߹ߓߓ{ߓic\ h|Cx5CJ hCJ"jxhzh5CJU hzCJ"jwhzh5CJUhzh|Cx5CJh|Cx0J>*CJjfwh|CxCJU h|CxCJjh|CxCJUhzh*z0J5>*CJhzh|Cx0J5>*CJjhzh|Cx5CJU"jvhzh5CJU$         , - u v              & F & F^`gdz & F@ ^@ `gdz & F^gd             - . N O P S T b c h i v             B E    颴v"jzhzh5CJU hCJ h*zCJhzh|Cx0J5>*CJ"jyhzh5CJUjhzh|Cx5CJUh|Cx0J>*CJjgyh|CxCJUjh|CxCJU hzCJhzh|Cx5CJ h|Cx5CJ h|CxCJ)                 : ; < > C D P Q         3 : ǡujj^W hz6CJhzh|Cx0J>*CJhz0J5>*CJj)|hzhgCJUhzhzCJjhzhzCJU hzCJ hz5CJhzh*z5CJh|Cx5>*CJ hQDxCJ h|CxCJhzh|Cx5CJhzh|Cx0J5>*CJjhzh|Cx5CJU"j`{hzh5CJU"  / g h   { |   Y Z   4 5 o p    & Fgdz & F^`gdz & F^`gdz & F^`gdz & F^gdz & F^gd: < C h q r }     |       r              " $             " ~   ɽɷɷɭ~ hCJh|Cx5>*CJ h2rhCJh2rhh2rh5CJhg:h2rhCJ h2rh>*CJh2rhh2rh>*CJ h*zCJ hCJ h\CJ h|CxCJhzh|CxCJhzh|Cx6CJ h|Cx5CJhzhz5CJ hz5CJ hzCJ1          " # K     = ] ^    $ & F^gd & F^gd2rh & FU 88^8gdQ & Fgdz                       8 9 : F G I J g h i t u w x   ѻᰩ~wlwaj~h|CxUj3~h|CxU h|Cx0J>*j}h|CxUjh|CxUh55h\0J>*j=}h55h?rU h55h55jh55h55Uh|Cx0J>*CJj|h|CxCJUjh|CxCJU hQDxCJh|Cxh|Cx5>*CJ hzCJ h|CxCJ hn8[CJ&$ %         Y ! I! y! ! 7# P# # \$ I% % % %  & FgdQDx & F^gdg> & F & F^gd                            ; < = M N O P Q n o p s t v w           ŻŮj7hUjlhUjh|CxUh|Cx0J>*CJjrh|CxCJUjh|CxCJU h|CxCJj h|CxUjh|CxUj'h|CxUh|Cx h|Cx0J>*jh|CxU4      ' ( ) = > ? _ `                         ! " $ % K L M V W Y Z { | } jfh|CxCJUjhUjօhUjhUjPhUjhUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJh|Cxjh|CxU h|Cx0J>*3} ! ! ! ! 2! 3! 4! G! H! I! J! e! f! g! w! x! ! ! ! ! ! ! ! ! ! ! ! ! ! ! " " 0" jhZ )hCJUjӉhZ )hCJUj^h|CxCJUjh|CxCJUjph|CxCJUjh|CxCJUh|Cx h|CxCJjh|CxCJUh|Cx0J>*CJ10" 1" 2" <" =" ?" @" e" f" g" o" p" r" s" " " " " " " " " " " " " " " " " " # # # # ,# -# .# 5# 6# 7# O# c# d# # # ֶ֦֖ֆրsjh|CxCJU hX'CJj>hZ )hCJUjwhZ )hCJUjhZ )hCJUjhZ )hCJUj,hZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJUjahZ )hCJU-# # # # # # # # # # # # # $ $ $ &$ '$ \$ ]$ $ $ $ $ $ $ $ $ $ $ $ $ $ $ % % % % #% $% %% (% )% H% b% c% y% z% {% % % % 渰永jh|CxCJUjh|CxUh\ h|Cx0J>*j=hUjh|CxUh|Cxjh|CxCJUj=h|CxCJUj~hZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJU3% % % % % % B' E' b' k' m' n' ( ( ( ( ) 1) J) K) t) u) v) ) ) ) ) * %* &* '* 5* 6* 7* 8* X* ڼڬڔڍ{rerjh55h55CJUh55h55CJh555B* CJph h|CxCJ h|Cx5CJhQDxh|Cx5B* CJphh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|CxCJH* hQDxCJ h_}5CJ h|CxCJhQDx5B* CJphh|Cx5B* CJph h|Cx5CJ#% % (& o& b' n' ' r( ( ( ) ) 1) ) ) ) * * &* '* f* * & F^gdg> & F^gdg> & F^gdQDx & F & FgdQDx & F^gdQDx & F`gdQDxX* Y* Z* c* d* e* f* * * * + + + + + &+ b+ c+ q+ }+ + + + + + + + + + + , ', (, ), 5, ľxxhXjƖhZ )hCJUjhZ )hCJU h|Cx5CJh|Cx5B* CJph hQDxCJhg>h|Cx5CJh|Cx0J>*CJj:hZ )hCJUjh|CxCJU h|CxCJh55h|CxCJh55h55CJh55h550J>*CJjh55h55CJUjh55h?rCJU"* * * + + b+ c+ q+ + + , , - . . u/ v/ / / / / B0 0 0 1 }1 Z2 & F^gdg> & F^gdg>5, 6, >, ?, e, f, g, |, }, , , , - - - =- >- ?- H- I- K- L- t- u- v- - - - - . . *. +. ,. 5. 6. 7. ;. =. B. D. E. F. p. q. r. . . . . . jhZ )hCJU h|CxCJH* hCJjhZ )hCJUjhZ )hCJUjZhZ )hCJU h|Cx5CJh|Cx0J>*CJjhZ )hCJU h|CxCJjh|CxCJU2. . . . . v/ / / / / / 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 (1 }1 ƺ֣֪֖֝tk[tOthVIhVI0J>*CJjOhVIhwCJUhVIhVICJjhVIhVICJU hVICJ hthCJhthhthCJ hth5CJ hn8[CJ h|Cx5CJ hqCJh|CxB* CJphh|Cx5B* CJph hCJhh5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU}1 1 [2 g2 h2 2 2 2 +3 ,3 D3 |3 }3 3 3 3 3 3 3 3 3 3 3 3 3 4 !4 "4 %4 &4 (4 N4 j4 k4 |4 ~4 4 4 򹦗o򿹦chV5B*CJph#hVhV0J5>*B*CJph+jhVhV5B*CJUphhVhV5B*CJph%jhVhV5B*CJUph hVCJ hgJrCJh|CxB* CJphh|Cx5B* CJphhthhth5CJ hthCJ hth5CJ h|CxCJ h|Cx5CJ%Z2 [2 h2 2 +3 ,3 ;3 |3 }3 3 4 ^5 5 5 5 5 5 27 ~7 8 9 9 : 7$8$H$^gdg> & F^gdg> & F^`gdg> & Fp^pgdg> & F^gdg>4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 5 5 5 *5 +5 ,5 95 :5 <5 =5 E5 G5 \5 ^5 g5 5 5 5 ־֬־vmg`` h|Cx5CJ h_}CJh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|CxCJ+jhVhV5B*CJUphhV5B*CJph hgJrCJ hVCJ#hVhV0J5>*B*CJph%jhVhV5B*CJUph+j]hVhV5B*CJUph"5 5 5 5 5 5 6 r6 s6 6 6 6 6 6 6 6 '7 (7 )7 /7 07 17 27 67 C7 I7 X7 }7 ~7 7 8 8 8 8 8 8 8 8 8 8 8 8 ɼɖulh|Cx0J>*CJjGhZ )hCJUjh|CxCJU h|Cx>*CJ h=h=0J>*B*CJph̙(jph=hfgB*CJUph̙h=h=B*CJph̙"jh=h=B*CJUph̙ h_}CJ h=CJ h|CxCJ h|Cx5CJh|Cx5B* CJph)8 8 8 9 9 9 #9 t9 u9 9 9 9 9 9 9 9 9 9 9 9 9 : : ; -; .; /; D; E; F; M; N; Q; ]; ^; ; ; ; ; ; ٸ٬ٟ٬وoj΢hZ )hCJUhhCJjhhCJUh|CxB* CJphjeh|CxCJUh|Cx5B* CJphjh|CxCJUj{h|CxCJU h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjh|CxCJU': ; ; P; Q; ^; ; < = P= = = )> > > > > '? ? @ I@ @ A A A B  & F^gdg> & F^gdg> & F^gdg>; ; ; ; < < 8< 9< ;< d< e< f< r< t< y< z< < < < < < < < = = = = = "= $= %= '= 6= 7= G= S= t= u= v= Ƿק͞׎ׇׇׇׇׇ͞yׇsg jhrhrCJ hrCJ hg>5CJ h_}5CJ h|Cx5CJj7hZ )hCJUh|Cx0J>*CJjhhZ )hCJUjhZ )hCJU hCJjh|CxCJU h|CxCJhh|CxCJjhhCJUhh|Cx0J>*CJ&v= w= = = = = = = = = = = = = > > > !> "> '> (> )> 2> h> i> > > > > > > > > > ? 䞕ypicWh|Cx5B* CJph h~8CJ h|Cx5CJhh|CxCJhh|Cx0J>*CJjghZ )hCJUhhCJjhh|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU *h|CxCJ *hn8[5CJ *h|Cx5CJ h|CxCJ h|Cx5CJ hrCJhrhrCJ" ? &? '? D? X? ? ? ? ? ? ? @ @ A A AA FA A A A A A A B B >B TB VB WB {B |B }B B B B B B B B B B B B B B B B B B ɹɹɹzj̨hZ )hCJUjhZ )hCJUh|Cx0J>*CJj2hZ )hCJU hCJjh|CxCJU h_}CJ h|CxCJh~8h~8CJ *h~8h~85CJ *h~8h~8CJ h|Cx5CJh~8h|Cx5CJ0B >B ;C D D D &E E E E QF F G uH pI 6J eJ J *K +K @K mK K $ & F^a$gdg>^gdg> & F^gdg> & F^gdg>B C ;C DC C C C C C C C D D D D E E E #E $E &E 2E E E E E E E F F QF ]F F F F F G G G 򧞎xkxj9h|CxCJUjh|CxCJUhh|Cx0J>*CJjhhZ )hCJUhh|CxCJjhh|CxCJUh|Cx5B* CJphh~8h|Cx0J>*CJjhZ )hCJUh~8h|CxCJjh~8h|CxCJU h|CxCJ h|Cx5CJ&G G G G G H H NH UH uH xH I I ^I oI pI I I I 6J ?J J J J J J J J +K @K K K L L L L L L ǣ攊ugh|Cx0J>*B*CJph(jyhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUphh|Cx0J5>*CJ"jhZ )h5CJU h5CJjh|Cx5CJU hg>CJ h_}CJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ%K L L 9L xL L L !M zM N N O O eO O O bP pP P ZQ R bR p^pgdg>^gdg>^gdg> & F^gdg> & F^gdg> & F 8^gdg>L 9L CL DL hL iL jL vL wL xL L L L L M !M -M _M aM zM M M M M M M M M N !N #N &N 'N 4N 6N :N ;N EN FN NN N N N N N N N O +O ,O ިޑjh|Cx5B* CJUphjhh[wOCJU hn8[5CJjhZ )hCJU hg>CJ h|Cx5CJh|Cx0J>*CJj"hZ )hCJU hCJjh|CxCJU h|CxCJh|Cx5B* CJph1,O SO TO UO bO cO eO O O bP nP pP wP P P ZQ gQ R "R WR aR bR xR R R S S S S S S S T T ,T -T .T ηÞ}sa}"jðhZ )h5CJUhh5CJjhh5CJU"jhZ )h5CJUjh|Cx5CJU h|Cx5CJ h|CxCJh|Cx5B* CJphh|Cx0J5>*CJjh|Cx5B* CJUph+j%hZ )h5B* CJUphh5B* CJph$bR R S T oT U iU uU U &V W W W -W cW dW W W W W AX X & F^gdg> & F^gdg> ^`gdg>^gdg> & F p@ @ ^@ gdg>^gdg>.T 8T 9T oT pT T T T T T T T U U U U U U $U iU rU uU vU U U U U U U U U U U U &V 'V ʸѭݣ}}kѭe^} h|CxCJH* hg>CJ"j&hZ )h5CJU h|Cx5CJh|Cx0J>*CJjYhZ )hCJU hCJjh|CxCJUh|Cx0J5>*CJ"jhZ )h5CJU h5CJjh|Cx5CJU h|CxCJjhh5CJUhh|Cx0J5>*CJ#'V NV OV PV ZV [V \V yV zV V V V V V V V V V V W W sW ~W W W W W W W W W W W Կ|ppj`Sjh|CxCJUjh|CxCJU hrCJh|Cx5B* CJph h\ 5CJ hg>CJh|Cx0J5>*CJ"jhZ )h5CJU h5CJjh|Cx5CJU h|CxCJ h|Cx5CJhh|Cx0J5>*CJjhh5CJU"jhZ )h5CJUhh5CJ W W W W W X X AX MX X X X X X X VY WY {Y Y /Z 0Z XZ YZ ZZ [Z Z Z Z Z Z Z Z Z ulZ"jhh|CxB*CJUphhh|CxCJ(j϶hZ )hB*CJUphhh|Cx0J>*CJ jhh|Cx0J>*CJUjhZ )hCJUhhCJjhhCJU hn8[CJ h|Cx5CJ h_}CJ h|CxCJ hrCJh|Cx0J>*CJjh|CxCJU Z Z Z Z Z Z Z Z Z Z Z Z [ [ [ ![ "[ ([ 0[ :[ ;[ [[ \[ ][ d[ e[ g[ h[ [ ˺˱{uo_{RIhx#3hx#3CJjhx#3hx#3CJUjhZ )hCJU hCJ h>CJh|Cx0J>*CJjAhZ )hCJU hUCJjh|CxCJU h|CxCJ h|Cx5CJhh|CxCJ hh|Cx0J>*B*CJph"jhh|CxB*CJUph(jhZ )hB*CJUphhh|CxB*CJphX Z Z [ \ \ ] H] J] o] ] ] ] ] ^ _^ ^ ^ ^ ^ _  & F^`gdn3 & F^gdn3 & F & F^gdg>^gdg>^gdg> & F^gdg>[ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ \ \ \ %\ &\ (\ )\ Q\ R\ S\ V\ b\ c\ \ \ \ \ ] ɽɫн}m}d[}h_}0J>*CJh|Cx0J>*CJj&hZ )hCJUjh|CxCJU"j[hZ )h5CJU hR5CJh|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJU h|Cx5CJ h|CxCJhx#3h|Cx0J>*CJjhx#3hx#3CJUjŹhZ )hCJU#] '] 4] =] H] I] J] o] ] ] ] ] ] ] ] ] ] ^ ^ `^ o^ q^ |^ ~^ ^ ^ ^ _ _ 0_ 1_ x_ _ _ _ ` ` ` )` +` 6` 8` A` D` O` P` ` ` ;a Ra Ta ha a a a a -b @b Kb Lb b b ˮ hn3CJ h_}5CJ h8z^CJh|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJUh|Cx5>*CJh|Cx5B* CJph h_}CJ h|CxCJ h|Cx5CJ=_ _ &_ x_ 7` 8` P` x` ` ` ` a Sa Ta a ,b -b Lb Rc Sc c c d Fd d d d  & F & F^gdn3 & F^gdn3b c c Sc fc hc ic c c c c c c c c c c c c c c c c c d d *d 2d Dd Ed d d d d e e e "e |vp`jLhZ )hCJU hrCJ h_}CJ hn8[5CJ h|Cx5CJh;ah|CxCJh;ah|Cx0J>*CJjh;ahzNCJUh;ah;aCJjh;ah;aCJUh|Cx0J>*CJjhZ )hCJUjh|CxCJUhX'h|Cx5CJaJ hn3CJ h|CxCJ%"e #e 3e Ue Ve We ce qe e e e e e e e e Zf [f tf uf vf f f f f f f f f f f f f f f g g g /g 0g [g \g g ѪzjPhZ )hCJUjhZ )hCJUjhZ )hCJU h|Cx>*CJh|Cx0J>*CJj hZ )hCJU h|Cx5CJ hX'CJhX'h|Cx5CJaJhX'hX'5CJaJ h|CxCJjh|CxCJU*d 2e 3e Ve We e e e e e f /f Lf Yf Zf [f tf uf f [g g h Yh Di ti ui i  & F & F^gdn3g g g g g g g g g g g g h h 2h 3h 4h 7h 8h Bh Mh Yh Zh zh {h |h h h h h h h h h h h h i i i i i Di Ei ii ְֶ֠֐րjhZ )hCJUj'hZ )hCJUjjhZ )hCJU h_}CJjhZ )hCJUjhZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJUj hZ )hCJU,ii ji ki ri si ui i i i i i i i i i i i i j 0j *CJjfhh|CxCJUhh|CxCJjhh|CxCJU hn8[CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJUjhZ )hCJU"i j j j j j k k k k k 'm ;n #o Ko lo o o o (p p Aq tq q & F^gdBf & F@ ^@ gdQ & F^gdBf & F & F^gdn3k k 8k 9k :k Hk Ik Lk Mk gk hk ik qk rk uk vk k k k k k k k k k k k k ﾆ|mcQm"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|CxB* CJphh_}0J5>*B* CJph+jhZ )h5B* CJUph%jWh|Cx5B* CJUphh|Cx0J5>*B* CJph+jhZ )h5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphk k k k k k k k k k k k l l l l l !l "l =l >l ?l Fl Gl Il Jl al bl cl ٵ٢}k^H+jQhQh|Cx5B* CJUphhQh|Cx5B* ph#hQh|Cx0J5>*B* CJph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph"jgh|CxB* CJUph"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUphh|Cx0J>*B* CJphcl nl ol ql rl l l l l l l l l l l l l l l l l l l l l l m m m %m &m 'm (m >m ?m @m Dm ˵˟ˉs]+jhQh|Cx5B* CJUph+j3hQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jAhQh|Cx5B* CJUph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph$Dm Em Gm Hm cm dm em nm om qm rm m m m m m m m m m m m m m m m m m n n n n &n 'n (n 9n :n ݟ݉s]+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph+j!hQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph$:n ;n *B* CJph+jhQh|Cx5B* CJUph%jhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUphhQh|Cx5B* CJphn n n n n n n o o o !o "o #o $o >o ?o @o Ho Io Ko Lo co do eo jo ֵֵֵ}gU}}?U+jdhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph+jphQh|Cx5B* CJUphhQh|Cx5B* CJph#hQh|Cx0J5>*B* CJph%jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUphjo ko lo mo o o o o o o o o o o o o o o o o o o o o o p p p ݟ݉tcKt/j4hQh|Cx5B* CJ UaJ ph hQh|Cx5B* CJ aJ ph)jhQh|Cx5B* CJ UaJ ph+jhQh|Cx5B* CJUph+jJhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph p &p 'p (p )p Hp Ip Jp bp cp kp lp op |p p p p p p p p p Ų{l]G{8hQh M5B* CJph+j&hQh|Cx5B* CJUphhQh_}5B* CJphhQhn8[5B* CJph#hQh|Cx0J5>*B* CJph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph hQh|Cx5B* CJ aJ ph)jhQh|Cx5B* CJ UaJ ph'hQh|Cx0J5>*B* CJ aJ php p p p p p p p p q q q q q q q 9q :q ;q ?q @q Aq Bq bq ݪn_L_%jhQh|Cx5B* CJUphhQh|Cx5B* CJph"jhQhyI\5CJUhQh M0J5>*CJ"jhQhyI\5CJUhQh?5CJjhQh?5CJUhQh?0J5>*CJ+jhQhyI\5B* CJUphhQh?5B* CJph%jhQh?5B* CJUphbq cq dq rq sq tq uq q q q q q q q q q q q q q q q q q q q q q q q ֵֵֵֵֵsֵֵ]K#hQhn8[0J5>*B* CJph+jhQh|Cx5B* CJUph+j{hQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph#hQh|Cx0J5>*B* CJph%jhQh|Cx5B* CJUph+j hQh|Cx5B* CJUphq q q q r r r !r "r $r &r Er Fr Gr Tr Ur Vr Wr tr ur vr r r r r r r r r r r r r r r ݟ݉sa#hQhn8[0J5>*B* CJph+jhQh|Cx5B* CJUph+j7hQh|Cx5B* CJUph+jhQh|Cx5B* CJUph#hQh|Cx0J5>*B* CJph+jShQh|Cx5B* CJUphhQh|Cx5B* CJph%jhQh|Cx5B* CJUph"q $r r s s s s s s s t t t t u Av Bv & F^gdn3 & Fp^pgdn3^gdn3 & F^gdn3^gdn3^gdn3 & F & F^gdBfgdg: & F^`gdQ & F^gdBfr r r s s s s (s )s *s 0s 1s 4s 5s Ks Ls Ms Ys Zs \s ]s rs ss ts ws xs zs {s s s s s s s s s ֵֵֵֵֵֵsֵֵ]ֵֵ+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUph+jhQh|Cx5B* CJUphhQh|Cx5B* CJph#hQh|Cx0J5>*B* CJph%jhQh|Cx5B* CJUph+j#hQh|Cx5B* CJUph#s s s s s s s s s s s t t t t t t u u ,u 4u Hu Ku Pu Vu uu yu u u u v 7v \v ]v ^v w w w fw jw sw tw uw ֵ~wqwqk h $SCJ hyCJ hy5CJh|Cx h_}CJ h|Cx5CJ h|Cx>*CJ h|CxCJh|CxB* phh|Cx5B* ph hQh|CxhQh|Cx5B* CJph#hQh|Cx0J5>*B* CJph%jhQh|Cx5B* CJUph+jxhQh|Cx5B* CJUph*Bv ]v w w w tw w w w x x &x x x x x x x %y cy dy  & Fgdn3^gdn3 & F^`gd-& & F^`gdy & F^gdy & F^gdn3uw vw w w w w w w w w x %x &x Nx Ox kx lx x x x x x x x x x x x x x x y y 񾷰xib\S jh|CxCJ hn8[CJ h-&5CJh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hn3CJ hy5CJ h|Cx5CJ h|CxCJh|Cx0J>*B*CJph(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph y 5y 6y dy ly my ny oy y y y y y y y y y y y y y y z z >z ?z z z z z z z z z z z z { { { { C{ D{ o{ p{ { { { { { { { { { v| y| {| Ե h/CJ h_}CJ hCJ hn8[CJ h $SCJ h|Cx>*CJ h_}0J>*j7hUh|Cxjh|CxU h|Cx5 h-&CJ h|CxCJ  jh|CxCJ h|CxCJ8dy y y y y y z .z qz z z z z z z { ={ _{ { { { { { { { |  & F^^^gd $S & F & F| | +| D| M| e| | $} O} X} } } } <~ =~ ~ ~ ~ ~    & F`^``gdj? & F^`gdj? & F^`gdj? & F ^`gd $S^gd $S{| || | | | | | | | | | | | | | | | | | | | | | | | | | | } 򻵨ulfVljhO|hH0CJU hO|CJhO|h|CxCJhO|h|Cx0J>*CJEHhO|h|Cx0J>*CJjyhO|hH0CJUhO|hO|CJjhO|hO|CJU h|CxCJ h/CJhj?hj?0J>*CJhj?h/0J>*CJjhj?hCJUhj?hj?CJjhj?hj?CJU} } } "} #} } } } } } } !~ #~ ;~ <~ =~ K~ N~ a~ n~ r~ t~ y~ {~ ~ ~ ~ ~ ~ ~ ~   2 3 4 5 6 оз~ufjh/h/5CJUh/h|CxCJ h|Cx>*CJ jhj?hj?CJhj?hj?CJH* hj?CJ hZCJ hqCJhj?hj?5CJ hq5CJh|Cx h_}CJh|CxCJEH h|CxCJhO|h|Cx0J>*CJjhO|hO|CJUjUhO|hH0CJU% 2 3 ~  F Ӏ Հ ڀ ? A L ߁ 3 4 E ^`gd=p^pgd=^gd= & F` & F^`gd?k  & F6 U V W Z [                F Q Ӏ Հ ؀ A D E L ԽԽԊxq h|Cx6CJ h|Cx>*CJh|Cx h|Cx5CJ h|CxCJ"j\h/h5CJUh/h_}CJ"jh/h5CJUh/h|CxCJh/h|Cx0J5>*CJjh/h/5CJU"jh/h5CJUh/h/5CJ( ܁ ݁ 4 : ; > ? C w ɂ ҂ ~ Ѓ у Ӄ ԃ ރ ߃ ; J R ^ _ j k t u  ( ] ^ %   0 1 2 t h=CJ h|Cx>*CJh|Cx5>*CJh|CxB*CJphh\ h\ CJH* h\ CJh= h|Cx>*h|Cx h_}CJ h|Cx5CJ hn8[CJ h|CxCJ jh|CxCJ*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|Cx>*CJh|Cx5>*CJ h|Cx5CJ jh|CxCJh|CxCJEHhWh|Cx0J>*jh#,UhWjhWhWUh|Cx h|CxCJh $Sh|Cx>*CJ!    ) _ n o  ] ^ v w I J & F^gdj% & F^ & F^ Ջ ' )   ! ] ^ v w  Ǎ ȍ ɍ э ҍ ڍ ۍ ܍ ĽķıĞėĽĽċ|qh]ċh|Cx0J5>*CJh|Cx0J>*CJh_}0J5>*CJj-h|Cx5CJUjh|Cx5CJU h|Cx>*CJhGhG5CJhj%hj%CJ hj%CJ hGCJ h|Cx5CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jhZ )h5B*CJUph$      J K ` a b e f ׎    # $ - . 9 F Ï ҏ   9 uih-&5B*CJphjh|Cx5B*CJUph hn8[CJh|Cx0J>*CJjxh|CxCJUjh|CxCJU h|Cx>*CJjh|Cx5CJU h|CxCJhn8[0J5>*CJh|Cx0J5>*CJjh|Cx5CJUjh|Cx5CJU h|Cx5CJ' ֎ ׎ 8 9 F  Ï ԏ i j w  & F^ & F^` & F^` & F^` & F^ & F9 : ; > ? A B a b c f g j t ~       @ F O V ^ ` a v ̒ ͒ ܒ ٸěĕĎěććěě~~ěxoěh|Cx5>*CJ h_}CJh|Cx56CJ h|Cx6CJ h|Cx>*CJ hn8[CJ h|Cx5CJ+jh-&hb*5B*CJUphh-&5B*CJph h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jh-&hb*5B*CJUph+  _ ` v ̒ ͒ ے 1 2 \ 1 2 e g  & F^gdn3 & F^` & F^ & F & F^gdn3 2 E 3 F g n o v  # + 3 N U p ٕ \ q r | – ˖ ̖ ז    & ' < g m n o p | q r | } ǘ ̘ ƺj%h|CxCJUjh|CxCJUh|Cxh|Cx5B* CJphhmf5B* CJph h|Cx5CJ$ h|Cx6CJ hn8[5CJ h_}CJ h|Cx5CJ h|CxCJ hn8[CJ>  o p ؕ ٕ [ \ }   & ' < q r  & F^gdn3 & F & F^gdn3 & F^`gdn3 & F^gdn3r . / y z ۙ ܙ 9 : L M   \  & F 4`gdn3 & Fgdn3 & F & F^`gdn3 & F^gdn3   / ? @ H I P z ܙ : K L M Ě  " % . / 0 \ j ڜ = l Ɲ ǝ Ş ͞ F T h i Ѵjh|CxCJU h_}CJ jh|CxCJh|Cx h>CJh?k hn3CJhn3h|Cx>*CJh|CxB* CJph h|Cx>*CJ hn8[5CJ h|Cx5CJ h|CxCJh|Cx0J>*CJjh|CxCJU7\ x ٜ ڜ < = d F  & F^`gdn3  & F^gdn3 & F^gdn3 & F^gdn3 & F@ `^@ ``gdn3 & F`gdn3 & Fgdn3 & F^`gdn3  " r    - ? X     ' Y Z ܤ ݤ ޤ  ݻ֩ݕ݉wlh|Cx0J5>*CJ"j hZ )h5CJUjh|Cx5CJUhqHhqHCJH*hqHh|Cx5CJ hqHCJ *h/h/5CJ *h/h|Cx5CJ hn8[CJ *h|Cx5CJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJhn8[0J>*CJ* r  ? b ʦ ˦ צ  P è  & F^`gdn3 & F^gdn3 & Fgd?k ^gdn3 & F pp^pgdQ & F- pp^pgdCjR & F^gdn3  a b o p I ˦ Ԧ    P Y s t M ƪ E X ī ϫ  4 ͽֱ h_}CJ h?CJ jh|CxCJ hn8[CJ h_}5CJ h|Cx5CJ hPCJhVIhVI0J>*CJjhZ )hCJUhVIhVICJjhVIhVICJU hVICJ hqHCJ h|CxCJhqHh|Cx6CJ3è  3 |  D E X   <  ! K & F^gdn3 & F   ^ gd ^`gdn3 & F^gdn3 & Fp^pgdn3 & F^`gdn3    0 @ [ d     < = > S T W ` j p q } ί ԯ W ` w İ Ͱ # % & < V k } h/hIhKCJ hIhKCJhn3h|Cx6CJhn3hn36CJ hn3CJ h_}CJ h_}5CJ h|Cx6CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ *h|CxCJ h|CxCJ8K ϭ  [   W  W v w  ó  ' o ^`gdn3 & F^gdn3 & F^gdn3 & Fp^pgdn3 & F^gdn3 & F^`gdn3 z | Ȳ ɲ   ó ̳ ޳  $ ' 4 H I x y ۵    몤뒅p_ h-&h|Cx0J>*B*CJph(j{h-&hB*CJUphh-&h|CxB*CJph"jh-&h|CxB*CJUph h|CxCJ h|Cx5CJ$ h_}CJ jh|CxCJmHnHuh|Cx0J>*CJjh|CxCJUjh|CxCJU h>CJ h|CxCJ h|Cx5CJ hn8[5CJ%o ڵ ۵   9 Y t u " 6 7 H ߷ M & F^^ & F & F^^gdn3   t " 7 H   . / 0 A B Q ]  ( * - 2 6 ? B I J K T [ R } ۻ u ڶک͗͐ hn35CJh|Cx56CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h_}CJ h|Cx6CJ h|Cx5CJ hYCJ h|CxCJ h|Cx>*CJh^h|CxCJ h|Cx>*CJh-&h|CxCJ8 Q  J K [  Q R } ڻ ۻ ` & F & F^ & F^` & Fp^p ^`^ & F^ / t u ܼ | }    A  & F^`gdn3p^pgdn3 & Fp^pgdn3 & F^gdn3^gdn3 & F^gd2? & F^gdn3^gdn3 & F`^    % R T U n o p y z { | ߽  $ 5 6 ξ     # A J ǿ Ϳ v H Q T U    . ͽֱ敖 h+ZCJh|Cx hn8[5CJ h|Cx>*CJ h_}CJ hn8[CJ h|Cx5CJh/h/0J>*CJjh/hCJUh/h/CJjh/h/CJU h/CJ h2?CJ h|CxCJh1h|Cx5CJ4 u v H T  .  & F p^pgd/ & FN pp^pgdCjR & FO pp^pgdCjR^gd/^gd/ & F & F^gdn3 & F^gdn3 & F^`gdn3. D \ c i j k    4 / 9 a e 4 @  ? T c d y Ծh|CxB* CJphjh|CxB* CJUph h/CJ h2?CJh+Zh+Z5CJ *h|Cx>*CJ h+ZCJh|Cx0J>*CJjh|CxCJUjh|CxCJU jh|CxCJmHnHu h_}CJ h|CxCJ h|Cx5CJ,  / ? r s y z ^gdjgd^ & F p^pgd/^gd/ & F^gd/ & F^gd/ & F p^pgd/y z { ~  A K L W q r s x y z & ' ( M N O j  C ` { ~ yofh>h>CJh>h>5CJh>h|Cx5CJ h>CJh|CxCJmHnHu jh|CxCJmHnHuh|Cx h|Cx>*CJ h-&5CJ h|Cx5CJ h_}CJ h|CxCJh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"jwh|CxB* CJUph( i j { ~ Z  h n o  & F^`gdj & F^`gdj ^`gdjp^pgdj & Fp^pgdj^gdj^gdj & F^gdj , 6 Z c e {      x  1 9 E Q o ~  ۱۔ۍvmh|Cx0J>*CJjh|CxCJUjh|CxCJU h;f5CJ hn8[5CJ hB='CJ h|CxCJH*hB='hB='CJ hB='5CJh/h>5CJh>CJmHnHu jh|CxCJmHnHu h|Cx5CJh>h>56CJ h>CJ h/CJ h|CxCJ*          * , B C D E g u  ƻ~x~xnx~gx h*CJ h*CJaJ#jhYh+CJUaJjhYhYCJUaJhYhYCJaJ hY5CJh|Cx0J>*CJjeh|CxCJUjh|CxCJU hjCJ h|Cx5CJ h|CxCJ(  s   + , g  Z ^gd* & F & FgdCJ h|Cx5CJ h|CxCJ9 M N i "   ? m ' (  & F & F` ^gdCjR & F^gd*^gd* & F^gd*^gd*p^pgd* ' ( N A I Q g h [ d f p r } w | P _ a m q |  P a ʷ° hn8[CJ h|Cx>*CJ h|Cx0J>*j2h|CxUjh|CxUh|Cx h|Cx>*CJ h>CJ h|Cx5CJ h|Cx5CJ$h^h|CxCJ h|CxCJ h|CxCJH*<( P Q g h [ f P a  P * ^gd* & F- pp^pgdCjR & F^gd* & F^`gd* & F^gd*gd^ & F & F^gd?^gd?  ( ) * 3   M N Y Z - 8 ﯣ~wpw h?5CJ h|Cx5CJh|Cx0J5>*B*CJph+j hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h>CJh|Cx h*h* jh|CxCJ h*CJh*h*5CJ h?CJ h|CxCJh*h|Cx5CJ,* X ) ) , - 9 ^gd* & F & Fgd* & F^gd* & Fgd* & F^gd* & Fgd* 4 8    9 : ; _ ` a j k l m    & ' , - m"jhZ )h5CJU"j:hZ )h5CJU"juhZ )h5CJUh|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJUh^hCJ h|Cx>*CJ jh|CxCJ h|Cx5CJ h|CxCJ h|CxCJ h|Cx>*CJ * 4   9 : l ; = R S F & Fp^pgd9 & F^`gd9 & F^gd9gd^ & F^gd & F^gd- S T U ` a      & ' ( * = R ɲ}scsZsTT hCJh|Cx0J>*CJjDhZ )hCJUjh|CxCJUh|Cxh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|Cx>*CJ h|CxCJh|Cx0J5>*CJjh|Cx5CJU"jhZ )h5CJU h|Cx5CJR S T x y z E G S U [ { | } {u{k{[kRk{h|Cx0J>*CJjhZ )hCJUjh|CxCJU h>CJ h|CxCJ h"CJhh0J>*CJjhhM6CJUjhhCJUhhCJ hCJhh0J5>*CJ"j hX_fhM65CJUhh5CJjhh5CJU h5CJF G T U z | $ % ? @   b H  & F^`gd9 & F^`gd9 & F^gd9  " $ % ? @ Q S \   I J K _ ` 츯jhZ )hCJUjhZ )hCJUj hZ )hCJUhh|CxCJhh|Cx>*CJ h|Cx5CJh|Cx0J>*CJjDhZ )hCJUjh|CxCJU h|CxCJ hCJ h>*CJ- , l Q 8^8gd9 & F ^gdQ^gd9^gd9 & F^gd9  & F^gd9 & F^gd9 & F^`gd9 ! " # * + , - Y Z [ j k  !  W X } δīΛĒΆ΀΀zslbzbzbh*h|Cx5CJ h*5CJ h|Cx5CJ h*CJ h>CJh|Cx5B* CJphh>0J>*CJj3hZ )hCJUh|Cx0J>*CJjnhZ )hCJUjh|CxCJU h|CxCJ hn8[h h|Cxh h|Cx5hh^h|CxCJ h|Cx>*CJh"hCJaJ& W X W X p q U V 9 : & F^gd*  & F^gd*^gd* & F@ `^@ ``gd* & F & F^gd* & Fp^pgd98^8gd9 & F ^gdQ}  < E X p q r   U b   8 9 > ĺĶ|wrkk h|Cx5CJ h4Y5 h>5h h|Cx0J5>*jsh hU# 5Uh h 5jh h 5Uh> h|Cx5h|Cxh*h*>*CJ h*CJh*h|Cx5CJ h>CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ*: # $ ( ) C X  # $ , V W  & F^`gd* & F^gd*^gd*  & F^gd* & F & F`gd* & F@ ^@ gd* & F^gd* # $ ' ( ) @ A  # $ , V W a b h i ͽ؄xobYIjhZOeh:fCJUhZOehZOeCJjhZOehZOeCJUh*5>*CJh*h|Cx5>*CJh|Cx5>*CJh|Cx0J5>*B*hph*jhZ )h5B*Uhphh|Cx5B*hphjh|Cx5B*Uhph h|Cxh hn8[CJh^h|CxCJ h|Cx>*CJh>5>*CJh^h^CJ h|CxCJW b   a q  {    I T ^gd* & F pp^pgd H & F^gd*  & F^gd*^gd*gd^ & Fgd* & F gdQ & Fhh^h`hgd*     a m o p   q z    ˡvhb hn8[CJh|Cx0J>*B* CJph"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|Cx5 h|Cx0J>*jAh|CxUjh|CxUh|Cx hI5CJ h|Cx5CJ h^h|Cx h|CxCJH* h|CxCJhZOeh|Cx0J>*CJjhZOehZOeCJU%  ) * + . / {          - . / G H I R   3 4 b g        $ % & ︱{{nehn8[0J>*CJjh|CxCJU jh|CxCJh|Cx0J>*CJjHh|CxCJUjh|CxCJU h|Cx>*CJ hzCJ h|Cx5CJ h|CxCJh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph'T   " b 6  n    , R S  m ! & Fp^pgd*^gd* & F^gd*^gd* & F^gd* p^p`gd*p^pgd*& ' 6 C g v   ( ) K L M Z [ n               * + S Z [ e } ~ ﯦ|uoi hv CJ h_MVCJ hn8[5CJh]"h|Cx0J>*CJH*h]"h|Cx0J>*CJjh]"hb*CJUh]"h]"CJjh]"h]"CJUh*h|CxCJh|Cx0J>*CJjJh|CxCJU h|Cx>*CJ hzCJ h|Cx5CJ h|CxCJjh|CxCJU&        ? H ! * v w x y  ַϰochv 0J>*B*ph$j hv h%&B*Uphhv hv B*phjhv hv B*Uph hv hv hv CJ h|CxCJ h|Cx5CJh_MVh_MV0J>*j h_MVhPU h_MVh_MVjh_MVh_MVU h_MV0J>*j6hPUh_MVjh_MVU&  D 1 s   +    K    n o  s t  ^gd* & F^`gd* & F^gd* & F^gd* & Fp^pgd* #   < = > A B D M O m   1 4 s |  + 2       K W   o       s t  Ϲ۪}wsh|Cx hn8[CJh|CxB* CJphh|Cx5B* CJph hzCJh[7h|Cx5CJ *h|CxCJh|Cx0J5>*B*CJph+j hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|CxCJH* h|CxCJ h|Cx5CJ- i j |    0 p      a      & F^gd*^gd*^ & F ^`gd*  & F^gd* & F^gd*  !^gd*^gd* i j z     8 C                       9 I a i k r t |    ' w z    & ( , d ʴʴ hn8[5CJ hzCJj h|CxCJUhz0J>*CJhn8[0J>*CJh|Cx0J>*CJj& h|CxCJUjh|CxCJU h|Cx5CJ h|Cx>*CJ h|CxCJ h|Cx>*CJ h|Cx5CJh|Cx h|CxCJ4d k         , / l t u ~       }          2 3 E F [ c h o       ﵯh/wh/w5CJ h/wCJh/wh|CxCJh/wh/wCJh7Th|Cx5CJ h7TCJ h7T5CJ hzCJ hz5CJh|CxB* CJphh|Cx5B* CJphh7Th|CxCJ h|Cx5CJ h|CxCJh/wh|Cx5CJ-  , u   }    ! ! 1" " " a# 1$ $ $ % % % ^gd* & F^gd* & Fp^pgd* & F^`gd* & F^gd*         ? V     ; O ! ! )! 5! U! V! a! b! ! ! ! ! ! ! ! ! 񽴫|l|`|h/wh|Cx0J>*CJju h/whs>LCJUjh/wh/wCJU hCJ h/wCJ h|Cx5CJ h|CxCJh/wh|CxCJh/wh/wCJh% h/wCJh% h/w5CJh% h|Cx0J5>*CJ"j h% hs>L5CJUh% h% 5CJjh% h% 5CJU%! ! ! ! ! ! ! ! 0" 1" <" \" i" j" " " " " " " " " " " " " " C# D# Y# Z# [# ^# _# a# i# # # 1$ :$ $ $ % % % % :& <& N& Z& }& ~& ůů hn8[CJ h|CxCJH*h|Cx5B* CJph hzCJj} h|CxCJUh|Cx0J>*CJj h|CxCJUjh|CxCJU hn8[6CJ h|Cx6CJ h|Cx5CJh/wh/wCJ h/w5CJ h|CxCJ h/wCJ3% N& & b' ' ' ( * + W+ , , - 5- - - . / / #/ & F`gds9 & F & F^gd* & Fp^pgd*  & Fp^pgd* & F^`gd* & F^gd*~& & & & & L' V' b' f' ' ' ' ' ' ' ' ( H( L( W( u( v( ( ( ( J) P) _) c) m) u) ) ) ) ) ) ) ) * * * qh h|Cx0J5>*CJ"j h hs>L5CJUh h 5CJjh h 5CJUh% h|Cx>*CJ h% CJh% h% >*CJ h|Cx>*hCAh|Cx h|Cx5 h|Cx5CJ h/w5CJ h/wCJh/wh/w5CJ hzCJ h|CxCJ(* * 9* :* ;* K* L* N* Q* W* k* s* u* v* * * * * * + + + "+ ++ 8+ W+ \+ ]+ t+ u+ + {uo`Vh h 5CJjh h 5CJU h CJ hzCJh2ph|Cx0J>*CJjBh2phs>LCJUh2ph2pCJjh2ph2pCJU h% 5CJ h|Cx5CJ h% CJ h|CxCJh% h|Cx0J5>*CJ"jshZ )h5CJUh% h% 5CJjh% h% 5CJU+ + + + + , +, f, h, , , , , , , - - - - - - 3- 5- =- x- z- - - - - - ˾˾ˮ}qf[OfhCAhCA5CJaJhCAhCACJaJhCAh|CxCJaJhCAh|Cx5CJaJh|Cx0J5>*B*CJph+j2hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hCACJ h|Cx5CJ h|CxCJh h|Cx0J5>*CJjh h 5CJU"jh hs>L5CJU- . . >. I. . . / !/ #/ $/ )/ u/ v/ / / / R0 a0 1 1 21 31 41 A1 B1 1 1 72 K2 2 2 2 2 2 2 *3 +3 ,3 13 23 33 43 =3 >3 3 3 "4 Ǩ󤜤|h|CxB* CJphhn8[ h|Cx0J>*jh|CxUjh|CxUh|Cxh|Cx0J>*CJjhZ )hCJU hHCJjh|CxCJU h|Cx>*CJ hn8[CJh^h|CxCJ h\ CJ hzCJ h|Cx5CJ h|CxCJ/#/ $/ / / / / / / / 0 0 /0 Q0 R0 b0 c0 1 1 Y1 ~1 1 1 1  & F^`gds9 & F^gds9 & Fp^pgds9 & F^gds9 & F`1 1 62 72 K2 2 2 2 2 2 43 53 I3 3 3 74 {4 |4 %5 ^`gds9^gds9  ^gds9^gds9gd^  & F^gds9 & F & F^`gds9 & F^gds9"4 64 74 {4 |4 4 4 4 4 4 4 4 4 4 4 5 5 5 "5 #5 $5 %5 6 6 *6 +6 ^6 g6 6 6 6 6 K7 L7 U7 V7 m7 7 7 7 7 7 '8 38 c8 ɺɺɺɺ~~xx~~ h+"CJ h|Cx5CJ jh|CxCJ+j>h9h5B*CJUph+jh9h5B*CJUphh9h|Cx5B*CJph%jh9h|Cx5B*CJUphh9h|Cx5CJh|CxB* CJph h|CxCJh|Cx h|Cx5,%5 u5 5 \6 j6 6 -7 U7 V7 m7 7 '8 ~9 9 9 : : ; h; i;  & Fgds9 & F^gds9  !^gds9 & FP pp^pgdCjRp^pgds9^gds9 ^`gds9c8 g8 u8 }8 8 8 8 8 `9 b9 ~9 9 9 9 9 9 9 9 : ": #: %: (: 1: 2: ?: A: K: R: T: [: \: ]: ^: : : : : : : : : : : ͻﮞqh9h90J>*B*ph$jh9hB*Uphh9h|CxB*phjh9h|CxB*Uph h9h|Cx h/CJ hs9CJ *h/hs95CJh/hs95CJ h|Cx5CJ h|CxCJH*ht:h|Cx5CJ h|CxCJh/h|Cx5CJ+: : ; ; (; h; i; }; ; ; ; ; < *< >< D< F< \< ^< `< r< v< < < < < < < <= '> d> e> n> p> q> > > > /? 0? :? F? r? q@ @ žŵŵˢ{hGh$5CJ h+"CJ ht:5CJh$h$5CJ h$CJht:h|Cx5CJh$h/CJh/h/CJ h/5CJ h/CJ ht:CJht:ht:5CJ hs95CJ h|Cx5CJ hs9CJ h|CxCJh/h|Cx>*CJ,i; ; e> q> > 0? ? ? q@ @ ,A -A IA A B B /B 0B WB {B B & F`  & F & F^gds9 & F8^8gds9 & F ^gdQ & F^gds9 & F`gds9@ @ @ @ -A IA A A B /B 0B F ?F gF ޻޵޻ޱުޱޖh|CxB*CJphjh|CxB*CJUph h|Cx5 h|Cx>*CJh|Cx hzCJ hn8[CJ h|CxCJH* h|Cx5CJh|CxOJQJ h|Cx5CJ h|CxCJ h$CJhGh$5CJhGh$5CJH*2B B B B B B 3C DC kC tC C C C C C C C D OD PD D D D D 7E 8E & F^` & F` & F & F^8E QE RE \E E E E F F ,F -F uF vF F G G G 9H H H H I & F^gd| & F^gd|gd^ & F^gd|^gd| & FgF hF iF rF sF vF F F F F F F F G G GG HG nG oG pG sG tG G G G G G G G G H H ȵȯȥȕsdȯ^Qjh+TMh+TMCJU hzCJh|Cx0J5>*B*CJph+j?hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|CxB* CJph hn8[CJh|Cx5B* CJph h|Cx5CJ h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(jhZ )hB*CJUph H H H H +H ,H 6H 7H 9H ?H HH PH H H KI NI ZI [I }I I I I J ]J ^J _J pJ qJ rJ J J J K K L L L ڼ|ulb\b h|CJh|h|Cx5CJh|Cx6>*CJ h|Cx>*CJ hQhQhQhQhQCJaJhQhQ5CJaJhQh|CxCJaJ hn8[CJ hzCJ h|Cx5CJ h|CxCJh+TMhn8[0J>*CJh+TMh|Cx0J>*CJjh+TMh+TMCJUjh+TMhRfCJUh+TMh+TMCJ$I I J ]J ^J _J qJ rJ J J K #K oK K L pL L L ^`gd| & F^gd| & F^`gd| & F^gd|^gd| & Fgd^^gdQ^gdQL L DL pL yL L L L L L M M lM ~M AN ON PN QN rN sN tN wN xN N N /O 0O GO HO IO NO OO `O oO O O /Q Q Q Q R R R R S ÷Ò{rh|Cx0J>*CJjh|CxCJUjh|CxCJUh|Cx0J5>*B*CJph+jKhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx5B* CJph h|Cx5CJh|Cxh|h|Cx5CJ h|CJ h|CxCJ,L L L M jM kM M ?N @N |N N O _O `O O O O O /Q Q Q Q BR R & F^gd| & F^gd|^gd| & F^ & F`gd|R R R R %S iS jS S S S T 2U W W W EX X X X X X X  & F^gd| & F^`gd| & F^gd\c^gd| & F^gd|S #S kS xS S S S S S S S S S S S S S T T T T T T T 2U >U V ZW nW W W W W W W X X X X X X X X X Z Z Z 򻱻򧡻򏈁{ hH{CJ hn8[5h h|Cx5h h|Cxh hn8[5CJ hmfCJ h\cCJh h\c5CJh h 5CJ h CJhuhu0J>*jUhuhUjhuhuU huhu hu5CJ h|CxCJ h|Cx5CJ.Z Z Z [ ([ ,[ \ \ \ %\ &\ E\ W\ [\ \\ u\ \ \ \ \ \ \ \ i] u] w] ] ] ] ] ] ] ] ] ǽ򟙏~ub%jh@'Fh@'F5B*CJUphh@'Fh@'FCJ h@'F5CJh) hH{5CJh) h|Cx5CJ h) CJhH{h) CJ jh|CxCJmHnHu h|CxCJH*hH{h|Cx5CJhH{h|CxCJhH{hH{CJ hn8[CJ hH{CJ h|Cx5CJ hzCJ h|CxCJ h|Cx6CJ!X \ D\ E\ [\ \ ] i] @^ ^ '_ _ _ _ ` N` ~` ` a Ma Oa ^gd| & F^gdH{ & Fp^pgd|p^pgdH{ & F^`gd| & F^gd| & F^gd|] ] ] ] ] ] ] ] ] ] ] @^ D^ /_ S_ p_ ~_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ ` ` ` ` ` ` ` ` ` a a a ȶȭvmh|h|CxCJh|h|Cx5CJ hH{5CJhH{hH{CJ h|Cx5CJ h|CxCJh) h|Cx5CJ hH{CJh@'Fh@'FCJ#h@'Fh@'F0J5>*B*CJph%jh@'Fh@'F5B*CJUph+j0h@'Fhb*5B*CJUphh@'Fh@'F5B*CJph*a Oa aa a a a a )b ?b Ab Pb b b b c 4c Cc Hc Jc [c ]c ^c c c c c c c c d d Td ]d d d d d "e .e ze e e e e e e e e e f f g g g ˻ԯh|CxCJmHnHu jh|CxCJmHnHu hzCJ jh|CxCJh!gh|Cx0J>*CJjh!ghCJUh!gh|CxCJjh!gh|CxCJU hz5CJh|Cx h|Cx6CJ h|Cx5CJ h|CxCJ5Oa qa a a a 'b (b Qb b b b c c 4c c c c d Td ^ & F & F^gd|^gd| & Fp^pgd|gds & F^`gd| & F^gd| & F^`gd|Td "e ze e e f f g g (h h i i i i i i j =j j j j ^gd!g & Fp^p`gd!g & F^gd!g & F^ & F@ `^@ `` & F^^g g g g g g g g g h h h (h 1h h h i i i i i i i j j j j j j j k 7k 9k Sk \k ck yk zk k k k k k k l "l ϶ϭ|v hFbCJh%tha5ZCJ h%tCJ h7}NCJ h4nCJ hMq(CJ h=CJh%thz5CJh%thzCJh!ghb5CJ hbCJhhbCJ hb5CJ hz5CJ h|Cx>*CJ hn8[5CJ h!g5CJ h|CxCJ h|Cx5CJ-j j j j j 8k 9k k Hl l l l l (m Em n n #n Yn @ ^@ gd!g p^p`gd!g & Fgd!g ^`gdbgdb & Fgdz^gd= ^`gdb^gdb^"l #l &l ,l Bl Gl Hl bl wl |l l l l l l l l l l m m m m m (m Em Qm n n n "n #n $n ľ}wwqwk\jhh5CJU hCJ h!gCJ h|CxCJh|Cx0J5>*CJ"jhZ )h5CJU h|Cx5CJjh|Cx5CJU hz5CJhbhb6CJ hbCJ h9 CJ hLBPCJ h]FCJ h CJh%th9 CJh%thzCJ hjtCJ hFbCJ h#CJ $n Kn Ln Mn Wn Xn bn n n n n n o 9o Ro oo ro o o o o o o o o o o o p p zszjd^Th%thz+5CJ hz+CJ hpCJhphoCJ h# 5CJ hp5CJ h'lCJh'lhCXy6CJ hCXyCJ he)CJ hsuCJhsuhsuCJ ho5CJ hoCJ h|Cx5CJ hCJhh0J5>*CJjhh5CJU"j_heh"`n5CJUhh5CJYn bn n n n o o o 'p p p p p +q q q q r r & F^gd & F` & F^@ ^@ gdp^gdp@ ^@ gdf p^p`gdo & Fgd!g p^p`gd!g p !p 'p ,p 3p 5p p p p p p p p p p +q 5q q q r r Ur ^r r r r r r r r r r s s s s Gs Js ys ľľľľľľ|pi hG5CJ *hhG6CJhgh|CxCJ$aJ$hgh|Cx5CJ$aJ$ hu5CJ huCJhuhu5CJ jh|CxCJmHnHu h!gCJ h|CxCJ h|Cx5CJ hpCJ h-$CJ hvKCJh]Fh(95CJh]FhvK5CJ hz+CJh%thz+CJ&r r r r r s s s s s u v 8w w w w y ty y xz  & F^`gd| & F^gd|^gd|^gd| & F & F` & F^`gd & F`gduys ~s s s s s s s s s s t t Jt Zt \t ^t ,u 8u u u v v 8w Aw w w w w w w :x Yx x x y y ty y y y xz z z z z z z z z -{ ?{ B{ O{ X{ Y{ { | | | | | »ִ֭ϭ֟ h|Cx5CJ h|5CJ hz5CJ *h|CxCJ hn8[6CJ h|Cx6CJ hzCJ h|Cx5CJ h|CxCJ hGCJ hG5CJ h&WbCJ hCJhgh5CJ=xz yz z z z ,{ B{ { { | | | u| | | | | } B}  & F^`gd| & F^gd| & F pp^pgdQ & F` & F & F^`gd| & F^gd|^gd|| | } B} } } } } } } } } } ~ ~ ~ ~ P~ Q~ R~ W~ X~ Y~ \~ e~ h~ i~ j~ k~ ~~ ~ ~ ~ S \ ^ i k Ų{ukuauuhojhojCJH*hojhoj5CJ hojCJ#hh0J5>*B*CJph+j*hh<5B*CJUphhh5B*CJph%jhh5B*CJUph hCJ hmBCJhqh|CxCJ h|Cx5CJhqh|Cx5 h|CxCJ hqCJhqh|Cx5CJ%B} } } } ~ S e ـ   . y z   N  & F^gd| & F^gd| & F^gd| & F pp^pgdQ & F^`gd|k p r x e n ؀  - z       > ? @ K L M N Z E O ˃ ك    L N ۄ ҵũh-h-CJjh-h-CJU h|CxCJH* hn8[CJh#$h#$0J>*CJjh#$hCJUjh#$h#$CJUh#$h#$CJ h#$5CJ h|Cx5CJ$h|Cx h|Cx5CJ h|CxCJ hzCJ0N F  J   2 U  8  . @ x  ] h & F^` & F^ & Fgd- & F^ۄ ܄ ݄  ,   " . 2 > t v  ( * t v x ‡ Ї ш ҈ 8 E @ J Y мммемЮмФООмy hmfCJ hzCJh|Cx0J>*CJjhZ )hCJU h-CJjh|CxCJU hz5CJ h-5CJ h|Cx5CJ hKCJ h|CxCJH* h|CxCJh-h|Cx0J>*CJjh-h-CJUjh-hs>LCJU-Y Z Ƌ Nj ˋ 9 : < Y ] Ҏ ӎ ؎ َ { ܏ ] ` p y 0 = ? A ɓ 4 5 F |   H M ] j  jh-h-CJ hzCJ h-CJh{"h{">*CJ h{"CJ h-5CJ h|Cx5CJ *h|CxCJ *h|Cx5CJ h|CxCJ hn8[CJDh  Nj 9 Y  _ ӎ % V { ] & F^gd & F & Fh^h`gd- & F8^8gd- & Fgd- & F^` & Fgd- & F^gd{" & F^ & F^ / ? o ɓ F |  H ] Õ ϕ . ɖ  & F8^8gd*j & FM & F^p^pgd-p^p & F & F^ & F^` Õ ̕ . T W ` c v  r t 8 v f i ۛ ( ) / 1 Q W Y k ʜ ˜ ̜ { 򯃜yhhCJH*hhCJ h#$CJhh5CJ hCJ jhh5CJ h5CJ h|~CJ h %CJh*jh*jCJH* hn8[5CJh %h*j5CJ jh|CxCJ h*jCJ hn8[CJ h|CxCJ h|Cx5CJ/ D T ƙ u v ڛ ۛ ) " Q ֝ _ k  & Fgd & F^gd|~ & F0^`0gd|~^gd|~ & F^gd|~ & F8^8gd*j ŝ ֝ ۝ _ h B C z ן o p ʠ ˠ ̠ Р Ѡ Ҡ Ӡ    7 8 : O ƿЊ~uj_h>Gh>GCJaJh>Gh#$CJaJh#$h#$CJ h +CJ h>GCJh>Gh>G5CJh>Gh>G0J>*jhUh>Gjh>Gh>GU h>Gh>G h>G5CJh#$h#$5CJ h#$CJ h|Cx>*CJ hnPCJhnPh|Cx5CJ h|Cx5CJ h|CxCJ hCJ#k , | o p Ӡ  8 N b & F^gd#$^gd>G & Fgd>G & F^gd + & F^gd>G & F^`gd#$ & F`gd#$ & Fgd#$ & Fa   ^ gdCjR & Fa 8^gdCjRO P > ? } ~ ݣ ޣ N R a b k  C D ɾɜّ{unh\h|~h|~5CJ aJ h|CxCJ h|Cx5CJ h#$CJh#$h#$5CJh>Gh>G5CJaJh>Gh#$CJaJh$hh$h0J>*B*ph$jh$hhB*Uphh$hh>GB*phjh$hh>GB*Uph h$hh>Gh>GCJaJh>Gh>GCJaJh>Gh>GCJH*aJ$ B C l  4 K R & Fp0^p`0$ & Fp`^p``a$ & F^`^gd & Fp`^p``^ & F & F^gd|~ & Fgd#$D J U k l   K N   " # + 3 y { ¨  K L M T A E G c   ' ͹ͳ͖ͥ͐͹Ɖ̓zz͹vh|Cx jh|CxCJ h5CJ hn8[5CJ hCJ *hh|CxB*CJph jh|CxCJmHnHu hzCJ h|Cx>*CJ hn8[CJ h|Cx5CJ h|CxCJh|~h|CxCJ aJ h|~h|~5CJaJh|~5CJ aJ h|~h|Cx5CJ aJ .  A   ' ) 7 Ϋ ) ~ , - ; gds & F^gd & F@ ^@ ` & F^` & F^ & Fb & F^ & F & Fp0^p`0' * 4 7 B q r ƫ ̫  C    * + , . 9 ; r vvoh hn8[5CJ h|Cx>*CJhsh|CxCJaJhsh|Cx5CJaJh|Cxhh0JCJj# hh-ZCJUjhCJU hCJ hqCJ hz5CJh|Cx0J>*CJjThZ )hCJUjh|CxCJU h|Cx6CJ h|Cx5CJ h|CxCJ(; ҭ X Y  4 & F@ ^@ gd3 & F@ ^@ `gd3@ ^@ gdsgds & Fp^p` & F@ ^@ & F@ ^@ ` & F` & F^gds ҭ ӭ Z g h j k v   3 6 R S d ݯ ) M Z [ l n v x & *  ܵџh{"h{"CJaJh{"h|CxaJh- h|Cx5CJ hKchKcCJaJhKc h|Cx>*CJ h3CJhsh|CxCJaJh|Cx hn8[5CJ h|Cx5CJ jh|CxCJmHnHu h|CxCJh|Cx5>*CJ54 6 R S d ) Y ΰ K L M [$\$gdKc[$\$^gd3[$\$^gd3[$\$^`gd3^gd3gdKc & F^` & F^ & FM Z [ l m v w $ % +  L  !  & F pp^pgdQ ^`gd|^gd|  & F^gd| & F^gd| & F^gd| & F` & F $ K L X Z ij ų   ! , J K n p q ´ Ǵ  ~ ŵ Ƶ ѵ ҵ ܵ ݵ ީΙ}t}}} jh|CxCJh|Cx5>*CJ h|CxCJH*h{"h{"0J>*CJj h{"hs>LCJUjh{"h{"CJU jh|CxCJmHnHuh{"h|Cx5CJh{"h{"CJ h{"5CJ h{"CJ h|Cx5CJh|Cx h|CxCJh{"h|CxCJaJ- | ~ ( ) = ^gds & Fp^p`gd| & F^`gd| & F^gd{" & F^gd| & F^gd| & F^gd| & F pp^pgdQݵ > z | ~ Զ ڶ       ( ) * < = > ۸   p q ƹ h|Cx5B* CJphhsh{"5CJaJhsh|Cx5CJaJhsh|CxCJaJhsh{"CJaJ jh{"CJh|h|6CJ h|CJh|h|Cx5CJ h{"CJh|Cx h|Cx5CJh|Cx5>*CJ h|CxCJ3= ظ ٸ   ƹ  $ a y ^`gd| & Fp^pgd|  & F^gd| & F^gd| & F`^``gd| & F^gd|^gdsp^pgds $ %      " # $ y ջ  % p y   K P ) > ( 4 ] f     " # G H   5 6  jh|CxCJmHnHuh|Cx hzCJ h{"CJh{"h{"5CJh|Cx0J5>*CJj^!h|Cx5CJUjh|Cx5CJU h|Cx5CJ hn8[CJ h|CxCJ>y Ѽ  p  . x ־ ( ) ? (  ^gd|  & F^gd| & F^gd| ^`gd| & F^gd|p^pgd| J + , 3 4 N O h^hgdrC hh^h`h^^gd| & F^gd| & F^gd| & F^`gd|6 @ A   4 5 6 B m @ [ c , 3 O b k     0 1 U V W _ ` h|Cx0J>*CJj!hZ )hCJUjh|CxCJUh|CxB* CJphh|Cx5B* CJphh|Cx h|Cx>*CJ0 hzCJ h\ CJ h CJ h|Cx6CJ h|Cx5CJ hn8[CJ h|CxCJ5O b  6 M h i  & Fgdr & F^ & F & Fh^hgdrC & F ^gdQh^hgdrC8^8gdrCh^hgdrC    " #  »ٵٵ٥lVl+j#hrhr5B* CJUph3%jhrhr5B* CJUph3hrhr5B* CJph3hrhrB* CJph3hrB* CJph3h|Cx5B* CJ8OJ QJ ph hzCJ h|Cx5CJ h|Cx>*CJ j"hZ )hCJU h|CxCJh|Cx0J>*CJjh|CxCJUj"h|CxCJU         A Űsf\I:hrhH5B* CJph3%jhrh|Cx5B* CJUph3hrB* CJph3hrh|CxB* CJph3'hrh|Cx0J5>*B* CJaJph3/j-$hrh|Cx5B* CJUaJph3 hrh|Cx5B* CJaJph3)jhrh|Cx5B* CJUaJph3 h|CxCJhrhr5B* CJph3%jhrhr5B* CJUph3#hrhr0J5>*B* CJph3  # _ 1 a  & F & F^gdr & F^`gdr & F^gdrA B C R S U V { | } ֵ}kֵUֵֵ?+j'hrh5B* CJUph3+j6&hrh5B* CJUph3#hrh!0J5>*B* CJph3+jk%hrh5B* CJUph3hrh!5B* CJph3%jhrh!5B* CJUph3hrh|Cx5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+j$hrh5B* CJUph3      ! " # $ H I J ] ^ _ ` λΥ݇q_I_+j.)hrh|Cx5B* CJUph3#hrh|Cx0J5>*B* CJph3+j(hrh|Cx5B* CJUph3h|Cx5B* CJph3#hrh!0J5>*B* CJph3+j'hrh5B* CJUph3%jhrh!5B* CJUph3hrh!5B* CJph3hrh|Cx5B* CJph3%jhrh|Cx5B* CJUph3      : ; < J K M N m n o | }  ֵֵֵֵkֵֵUֵֵ+j+hrh|Cx5B* CJUph3+j*hrh|Cx5B* CJUph3+j"*hrh|Cx5B* CJUph3 hrh|Cx5B* CJaJph3hrh|CxB* CJph3hrh|Cx5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+j)hrh|Cx5B* CJUph3    3 4 6 7 P Q R X Y Z [ ] ^ } ֵֵֵֵֵֵsaֵֵ#hrhn8[0J5>*B* CJph3+j,hrh|Cx5B* CJUph3+j,hrh|Cx5B* CJUph3+j,hrh|Cx5B* CJUph3hrh|Cx5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+j+hrh|Cx5B* CJUph3} ~   ֵjV>Vֵ/j].hrh P5B* CJUaJph3'hrhoj0J5>*B* CJaJph3/j-hrhoj5B* CJUaJph3)jhrhoj5B* CJUaJph3 hrhoj5B* CJaJph3hrh|CxB* CJph3hrh|Cx5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+jk-hrh|Cx5B* CJUph3        6 7 8 O P S T r s t ֵ֦֦֦z֦mXG hrh|Cx5B* CJaJph3)jhrh|Cx5B* CJUaJph3hrh|CxB* CJph3+j/hrh|Cx5B* CJUph3+jG/hrh|Cx5B* CJUph3hrh|Cx5B* CJph3hrhq5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+j.hrh|Cx5B* CJUph3  Ҿҭl]J;hrh|Cx5B* CJph3%jhrh|Cx5B* CJUph3hrhr5B* CJph3'hrhr0J5>*B* CJaJph3/j0hrhr5B* CJUaJph3)jhrhr5B* CJUaJph3 hrhr5B* CJaJph3'hrh|Cx0J5>*B* CJaJph3)jhrh|Cx5B* CJUaJph3/j;0hrh|Cx5B* CJUaJph3   / 0 1 2 G H I _ ` a b w x y ֵֵֵֵֵug^XQJX h|Cx5CJ hrC5CJ h|CxCJhsh|CxCJhrCh|Cx5>*CJ aJ h|CxB* CJphh|CxB* CJph+j 2hrh|Cx5B* CJUph3+j1hrh|Cx5B* CJUph3hrh|Cx5B* CJph3#hrh|Cx0J5>*B* CJph3%jhrh|Cx5B* CJUph3+j;1hrh|Cx5B* CJUph3  7 T U h 9 & F^gdrC  & F^gdrC & F0^`0gdrC & F^gdrC & F & F`gd8+    U g : I J K Z \ c  k s   { ~    ( ' A n o p } ~ Σ hn8[5CJ hzCJhrCh|Cx5CJ h|Cx>*CJ hrCCJ hrC5CJ h|Cx5CJh|Cxh|Cx0J>*CJjv2h|CxCJU h|CxCJjh|CxCJU@9 : I J m p q J z {  % ' H o  & F ^gdrC & F^`gdrC & F^gdrC & F^gdrC & Fo p ~ R S p l m % & & F^gd8+gds & F`gdrC & F & F^`gd2 & F^gd2 & F^gdrC & F^gdrC S ^ p q        9 : ; B C F G ` ſŢ}hZ}h|Cx0J>*B*CJph(j3h2hB*CJUphh2B*CJphjh|CxB*CJUphh*CJj2hZ )hCJUjh*CJ hrCCJ h|CxCJ h|Cx5CJ ` a b i j l m  # & * , ~  # 4 S X p q ĽȶȽȪȶȶȶȶȑȇzqȇdqjO5h|CxCJUh|Cx0J>*CJj4h|CxCJUjh|CxCJU hzCJh2h|CxCJaJh2CJaJh2h|Cx5CJaJ h|Cx5CJ h|Cx>*CJh|Cx h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(jY4h2hB*CJUph'& ~  " # 6 & ' ( Z [ v   & Fgd8+ & F`gd8+ & Fgd8+gds & F^gdrC & F`gdrC & F & F^`gd8+ & F^gd8+`gd2 & ' ( Z [ v t { | }    E R n o ƾvmg^ jh8+CJ hCJh8+0J>*CJj5hZ )hCJUjh8+CJUhqh8+5CJ hCJh8+hLuCJaJh8+CJaJhahaCJaJhaCJaJh8+h8+CJaJh8+h8+5CJaJ h8+5CJh!h8+>*CJaJ h8+CJh|Cx h|CxCJ$ $ r s  D E ^ _ s & Fp^pgdjh & F^gd%}; & F^gdLu & Fp^pgd8+ & F^gd8+ & Fgd8+ & Fgd8+ 5 ^ _ s 2 9 D V   L Z  B P ` b ݎh?h?CJ h?CJ h?5CJ hfCJhfhf>*CJ haCJh8+0J>*CJj6h8+CJUjh8+CJUh8+h8+5CJaJ hCJ h8+5CJhjhhjh5CJ hjhCJ h8+CJ h%};CJ2 0 1 I B C b & F`gd8+ & F^gd8+ & F^gd8+ & F`^``gd8+ & Fp^pgdLu & F^`gd8+ & Fgd8+  a b t  B `  & F^gda & Fgda & F0^`0gdf & F^gdf & F^gdf & Fgd8+b t   B L ` k  C D M N ` e q r ­̟월vo h|Cx0J>*j7hUjh|CxU h|Cx5 h|CxCJ h|Cx5CJ$h|Cxha0J>*B*CJph(j7h2hB*CJUphh2B*CJphjhaB*CJUph ha5CJhaha>*CJ haCJ h8+CJ h8+5CJ+ B C D _ ` $ } ^ _ t  & F^gdf & F0^`0gdf & Fp0^p`0gd2 & F0^`0gd2  & F0^`0 & F & Fgd? & Fgda  $ ' }       & ' ( ) + , K L M \ ] _ t  7 8 ? @ / e f o huh?h?hf5hf hfhfhn8[ h|Cx5CJjZ9h|CxU hn8[0J>*j8h|CxU h|Cx0J>*jp8h|CxUjh|CxU h|Cx5h|Cxh2;  @ f  W Z # < ^gdf^gdf & F0^`0gd? & F^`gd?  & F^gdf & F0^`0gdf  \ z # E G r w } 0 1 = E M N O P Q V ` b  G T U [ x hzCJ h|Cx5CJ h|CxCJhin;hin;5CJ hin;CJ jhin;hin; hin;h|Cx hin;hin;hin; hin;5 h|Cx5h?h?5h?hfh|Cx h|Cx>*=   A x , l p^pgd ^gds^gd ^gds & F^`gdf & F^gdf & F^gdf ^`gdf   ; < N T k v {   d y z  $ C E H J N P Ź hzCJ h|Cx5CJ h|CxCJh|CxhshzCJaJhsh|Cx>*CJaJhshn8[CJaJhsh|Cx5CJaJh h CJaJhmfCJaJh CJaJh 5CJaJhwh|Cx5CJaJhsh|CxCJaJ1 k c d y   - & F^gda & F^gdf & F^gdf  & F^gdf & F^gdsp^pgds & Flgds^gdsP Q p q r u v , e ǼǶtf_Vh+"h+"CJ h+"5CJhyaha0J5>*CJ"j:hZ )h5CJUhyaha5CJjhyaha5CJUh+"h+"5CJ h+"CJ ha5CJ haCJh|Cx h|Cx5CJ h|CxCJhyah|Cx0J>*CJj9hZ )hCJUhyahyaCJjhyahyaCJU - xQRo!no & F`gda & F^gdf & F^gdf & Fp`^p``gda & F^gda & F^gd+" & F`^``gd+" 68:bdfrtvRoHKnoⱨ~xrxg^Th h|Cx5CJh h|CxCJh h|Cx0JCJ hzCJ h|CxCJhah|Cx>*CJhahaCJ ha6CJhaB*CJph h+"CJh+"h+"CJ ha5CJhyaha0J5>*CJ"jO;hZ )h5CJUhyaha5CJjhyaha5CJU haCJh+"haCJ-.kmgs#,3?@AGҾҾҾҴҫtkb\Ҿ hyCJhyhzCJhyh|CxCJhyh|Cx0J5>*CJhyh|Cx0J>*CJj<hyhCJUjhyhyCJUhyhyCJhyh|Cx5CJ h|Cx5CJ h|CxCJH* hn8[CJ h|CxCJ h|Cx0J>*j<hUh#$jh|CxUh|Cx h>GCJ$gAS%PY  /    ,  & F ^gda^gda & F^gda & F^gda & Fp^pgda & F^gdf & F^`gdfGERSe%7P]Y b                   / 8 : ; ` a b ʴ֥ʏ֥~n~j>hZ )hCJUjh|CxCJU h|CxCJH*+j=hZ )h5B*CJUphh|Cx0J5>*B*CJph+jc=hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|Cx>*CJ hzCJ h|Cx5CJ h|CxCJ'b j k     2 :   % -         )*+,ߎ|n|d|hE\hE\0J>*j?hE\hh3UjhE\hE\U hE\hE\ hE\5CJ"jL?h|CxB* CJUphjh|CxB* CJUphh|CxB* CJphh|Cx5B* CJph haCJ hzCJ h|Cx>*CJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ'   ,=BXYjt "$*,35AOsv숕j@h|CxCJUjh|CxCJU h|Cx>*CJ hj%CJ h|CxCJH*hnh|Cx5B*CJphf hCJhnh|Cx5B* CJph3 jh|CxCJ hn8[CJ hnCJ h|CxCJ h|Cx5CJ hE\hE\4.W{]yDU & Fp^pgda & F^gda^gda ^`gda & F^gda^gdj( & F ^gda#.73;W`{]ʠʖِzrzrg` hn8[5CJhnh|CxCJaJhnCJaJhnhnCJaJhnhj(CJaJ hj(CJh]h|Cx5CJh]h|Cx0J5>*CJ"jAh]h-Z5CJUh]h]5CJjh]h]5CJU h|CxCJ h|Cx5CJ hQ2CJjh|CxCJUh|Cx0J>*CJ%]by| #DTUY`s{$&'Q򯥐vjh|Cx5CJUh|Cx0J>*B* CJph(j,BhZ )hB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJH*h|Cx0J>*CJjAh|CxCJUjh|CxCJU hn8[CJ h|Cx>*CJ h|CxCJ h|Cx5CJ*QRS`a ;DYb}%)2Ѿzlhshf0J>*CJaJ#jChshCJUaJjhshfCJUaJhshf5CJaJhshfCJaJhfhf5CJ aJ hfCJ h|Cx5CJ hzCJ h|CxCJh|Cx0J5>*CJjh|Cx5CJU"jBhZ )h5CJU':Y}) ! & F^gda & F` & Fgds^gds ^`gds^gdsgdf & Fgds!,Hb./2CE\]aopk w y }            ! !!!c!j!!!!j"v"}" hmfCJ hn8[CJ h CJh|Cx56CJ hzCJ h|Cx6CJhah|CxCJhah|Cx5CJhaha5CJ h|Cx5CJ h|CxCJhah|Cx5CJ aJ 9!,GHbDEpk   !!!j""#Z#p## & Fp0^p`0gda & F0^`0gda & F^gda & F^gda}"~""""""""""""# #Y#Z#o#|##### $ $$-$.$/$2$3$4$Q${$}$$$$$$%%% %0%b%%%%%񽷱񉷃}} h!gCJ hCJhh|CxCJ"j-Ehh/F5CJU h|Cx5CJ haCJ hzCJ h|CxCJhh|Cx5CJhh|Cx0J5>*CJ"jDhh/F5CJUhh5CJjhh5CJU1##}$% %%%&&&`'''((((( & F & F^ & F & F^gda & Fgd!g & F^gd!g & Fp^pgda & F^gda & Fp0^p`0gda%%%%&&2&3&`&&&&&&&&&3'4'`'i'p'q'z'''''''((((((((&(((((!)2)))))| hCJ hzCJ h|CxhhVb(hVb(0J>*jEhVb(h+<UjhVb(hVb(U hVb(hVb(hVb(5CJ aJ hah|Cx5CJ aJ hah|Cx>*CJ jh|CxCJ jh|CxCJmHnHu h|Cx5CJ h|CxCJ h CJ0( *****+,,,%--@.//=//0122 & F^`gdk & F^`gdk & F^gdk & Fgdt}gds & F^ 7$8$H$^)**************6*7*8*;*<*>*?*@*̾hQK ht}CJ,hoho0J>*B* CJ8OJQJ^Jph4jFhohx,B* CJ8OJQJU^Jph%hohoB* CJ8OJQJ^Jph.jhohoB* CJ8OJQJU^JphhoB* CJ8OJQJ^Jphht}B* CJ8OJQJphh|CxB* CJ8OJQJphh|CxB*CJ8OJQJphh|CxB*CJ8OJQJphh|Cx h|CxCJ@*A*f*g*h*|*}*****************wcKc<hkoh|CxB* CJaJph/jHhkoh|Cx5B* CJUaJph'hkoh|Cx0J5>*B* CJaJph/jGhkoh|Cx5B* CJUaJph hkoh|Cx5B* CJaJph)jhkoh|Cx5B* CJUaJph ht}CJ hkht}0J>*B*CJph(jGhkh$B*CJUphhkht}B*CJph"jhkht}B*CJUph*********+++++,+.+/+F+G+H+M+N+P+Q+q+r+s++++ݤzhzVz"jIh|CxB* CJUph"jIh|CxB* CJUphh|Cx0J>*B* CJph"jIh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph$hkoh_}0J>*B* CJaJph,jHhkoh|CxB* CJUaJphhkoh|CxB* CJaJph&jhkoh|CxB* CJUaJph++++++++++++++++,,,,,,,8,9,﷨vcT>+jKhkh|Cx5B* CJUphhkh|Cx5B* CJph%jhkh|Cx5B* CJUph"jnKh|CxB* CJUphh|Cx0J>*B* CJph"jJh|CxB* CJUphjh|CxB* CJUphh|CxB* CJphh|Cx0J5>*B* CJph%jtJh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph9,:,J,K,M,N,y,z,{,~,,,,,,,,,,,,,,,,,,,ͻͦͻsbͻMbͻ(jMhkh|CxB* CJUph hkh|Cx0J>*B* CJph(j;Mhkh$$B* CJUphhkh$$B* CJph hkh_}0J>*B* CJph(jjLhkhB* CJUph"jhkh|CxB* CJUphhkh|CxB* CJph#hkh|Cx0J5>*B* CJph%jhkh|Cx5B* CJUph,,,,,,,,,,,,,,---#-$-%-&-8-:-;-W-ٻٻٻwh^^O^jh|CxB* CJUphh|CxB* CJphh|Cx0J5>*B* CJph%jNh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph(jvNhkh|CxB* CJUphhkh|CxB* CJph hkh|Cx0J>*B* CJph"jhkh|CxB* CJUph(j Nhkh|CxB* CJUphW-X-Y-c-d-f-g------------------------ .ǵѧǗxiW"jPh|CxB* CJUphh|Cx0J5>*B* CJph%jNPh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphhn8[0J>*B* CJph"jOh|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"jXOh|CxB* CJUph . . .....6.7.8.>.?.@.A.b.c.d.r.s.t.v.w............ǵǥweS"jSh|CxB* CJUph"jRh|CxB* CJUphh|Cx0J5>*B* CJph%j Rh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph"jQh|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"j>Qh|CxB* CJUph .................. ////////0/1/2/:/;/=/>/S/矏pah|Cx0J5>*B* CJph%jTh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|Cx"jSTh|CxB* CJUph"jSh|CxB* CJUphh|Cx0J>*B* CJph"jSh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph!S/T/U/b/c/d/f/g/|/}/~///////////////////////vdR"jVh|CxB* CJUph"jjVh|CxB* CJUph"jVh|CxB* CJUphh|Cx0J>*B* CJph"jUh|CxB* CJUphjh|CxB* CJUphh|CxB* CJphh|Cx5B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%j/Uh|Cx5B* CJUph ////000#0$0%0&0'0<0=0>0A0B0D0E0d0e0f0s0t0v0w000000000˸שwe"jXh|CxB* CJUph"j8Xh|CxB* CJUphh|Cx0J>*B* CJph"jWh|CxB* CJUphh|Cx0J5>*B* CJph%jHWh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphh|CxB* CJphjh|CxB* CJUph!0000000000000011111214151V1W1X1Z1[1]1^1r1s1t1v1w1ǵǥweS"j [h|CxB* CJUph"jZh|CxB* CJUphh|Cx0J5>*B* CJph%jZh|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph"jYh|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"j6Yh|CxB* CJUph w1y1z111111111111111 2 2 222222627282@2A2C2D2E2_2vcv%j\h|Cx5B* CJUphh|Cx0J5>*B* CJph%ja\h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph"j[h|CxB* CJUphh|Cx0J>*B* CJph"js[h|CxB* CJUphjh|CxB* CJUphh|CxB* CJph!2C2l2|3&4'48494444415p55555J666 & F^ & F0^`0 & F^ & F & Fp^p`gdk & F^`gdk & F^gdk_2`2a2h2i2j2k2l2m222222222222222222222223;ܲܲܲܲܲsasSssh|Cx0J>*B* CJph"j^h|CxB* CJUphjh|CxB* CJUphh|CxB* CJph%j-^h|Cx5B* CJUph%j]h|Cx5B* CJUphh|Cx5B* CJphhn8[0J5>*B* CJphh|Cx0J5>*B* CJphjh|Cx5B* CJUph%jQ]h|Cx5B* CJUph3 3 33333=3>3?3Q3R3T3U3o3p3q3x3y3z3{3|3}333333333ǵǣѕDžyfWh|Cx0J5>*B* CJph%j`h|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUphhn8[0J>*B* CJph"j#`h|CxB* CJUph"j_h|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"j%_h|CxB* CJUph33333333334444444$4%4&4'48494K4L4r4s4t4ǵǣߙrhSr(jnbhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUphhsht}CJh|Cx5>*CJ h|CxCJh|CxB* CJ ph"jah|CxB* CJUph"jah|CxB* CJUphh|CxB* CJphh|Cx0J>*B* CJphjh|CxB* CJUph"j ah|CxB* CJUpht4{4|4~44444444444444444555&50555`6a666666Ӿݴݤݔݔݔݍ݀wg[h9h|Cx0J>*CJjYdh9hLsCJUh9h9CJjh9h9CJU h|Cx5CJ h|Cx>*CJh|Cx0J>*CJjchZ )hCJUjh|CxCJU(jchZ )hB*CJUphh|CxB*CJph h|CxCJjh|CxB*CJUphh|Cx0J>*B*CJph!66666666667h77777777777777777718?8r8|888888888'9,9i9j9z999999999hsh|Cx0J>*CJaJ#jdhsh|CxCJUaJjhsh|CxCJUaJhsh|CxCJaJ h|CxCJ,hsh|Cx5CJ, hn8[CJh|Cx5>*CJ h\ CJh|Cx h|CxCJ h|Cx5CJh9h|CxCJ566666667:7h7i7v7w718r8s8888&9'9-9y9z9 & F & F^ & F^`  & F ^ & F^9999-:7:::; ;.;L;M;N;;;;;1<3<4<W<X<Y<\<]<_<<<=*=+=3==۲۬tb[V h|Cx5 h|CxCJH*#h`Uh`U0J5>*B*CJph+jOeh`Uh8Cc5B*CJUphh`Uh`U5B*CJph%jh`Uh`U5B*CJUph h`UCJ jh|CxCJmHnHu h|Cx5CJ h|CxCJH* hzCJ h|Cx>*CJ h|CxCJh|Cxhsh|CxCJaJjhsh|CxCJUaJ!z99999,:-:8:~:::-;.;N;;;;;==*= & F^ & F^` & F & F` & F^ & F0^`0^gds  & Fgds*=+====>*>V>o>p>>>??2?W?????@8^8 h^`h hh^h`h & F^gd`U & F ^gd H^gd`U  ^gd`U========>>l>n>o>{>}>~>>>>>>>>>>>>>>>>??2?W?X?x?y?z?????@@@@@'@(@?@L@ h5CJjgh|CxCJUjigh|CxCJU h|Cx>*CJjfh|CxCJU hn8[CJjqfh|CxCJU h|CxCJH*h|Cx0J>*CJjeh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJ3@'@>@?@W@@@@A*CJ h|Cx>*CJ hmfCJ h5CJjKih|CxCJUjhh|CxCJUh|Cx0J>*CJjihh|CxCJU h|CxCJjh|CxCJU h|Cx>*CJ*BBBBB%C*C4CVCCCCCCCCCCCCCCCCCDDDD D!D/D@DZDaDټrlf`lZl` hmfCJ heCJ h)xjCJ hCJheh|Cx0J5>*CJ"jiheh|Cx5CJUheh|Cx5CJjheh|Cx5CJUhehe>*CJ h|Cx>*CJheh|Cx>*CJ h|Cx5CJ h+HCJ hzCJ h|CxCJ htCJhthtCJ ht5CJhth|Cx5CJ"B!CVCCCCCCCCDD@DDDDDNEOE & F^ & F^`gd & F^` & F` & F^ & F & F^`gdt & F^`gdtaDbDDDDDDDDDDDDE E"E#EFEGEHEKELEMENEOEZEEEEEǷǭo]ǷSL h|Cx>*CJh5h|CxCJH*#h1Sh1S0J5>*B*CJph+jjh1Shb*5B*CJUphh1Sh1S5B*CJph%jh1Sh1S5B*CJUph h1SCJhehz5CJheh|Cx5CJ h|CxCJ heCJhehe0J>*CJj=jheh"`nCJUheheCJjheheCJUOEbEcEmEEEE@FFFF4GnGGG!H"H3HHHHIII & F^gd)&N & F^` & F^` & F & F^EEEJFTFtFuFvFFFFFF&G3GGG H"H3HyHHHIIIIZI[IpIqIrIuIvIII(J8JJJJJJJJKѺя|w|sht h|CxH*h|Cx htCJhfzhfzCJ h=CJhhb0J>*CJjWkhh3CJUhhCJjhhCJUhbhb5CJ hbCJhXhX5CJ h|Cx5CJ hn8[CJ h)xjCJ hzCJ h|CxCJ-II'J(J8JJJKK6LLLLMJMMuNONP  & F^gd)&N & Fp^pgd)&N & F^`gd)&N 7$8$H$^gd)&Ngds & F ^gd)&N & F^gd)&N & F^gd)&NK K K"K$KNKPKKKKK-L.L/L3L4L5L6LBLLLLLLLMM'MJMPMQMXMMM[NuN{NNNNNN¼sss *hh5CJaJ *hhCJaJhhaJhhh5hh5CJhhCJ h5CJ hCJ hz5CJ h|Cx5 h|Cx0J>*jkh|CxUjh|CxU h|Cx5CJ h|CxH*h|Cxhthz)NNOOOOOPPP P!P"PNPRPPPPQ QQQ2Q4Qɴwmd^X^dLE? h|CxCJ h|Cx5CJhhz5CJaJ haJ h]aJhh|CxaJhh|Cx5aJ'hreqhreq0J5>*B*CJaJph/jlhreqhb*5B*CJUaJph hreqhreq5B*CJaJph)jhreqhreq5B*CJUaJphhreqCJaJhh|CxCJaJhh|Cx5CJaJhhCJaJhh5CJaJNP Q)QQQQR|S@TATcTTUVV=VVV%WX|Y & F^`gd)&N & F0^`0gd)&N & F^gd)&N & F^gd)&N 7$8$H$^gd)&N  & F^gd)&N4Q9QZQQQQQQQQQQQQQQR/R0R1RaRxRRRRRRRRRRRRS.S{S|SSSSSSATvmhth+CJhth+5CJhth|CxCJhth|Cx5CJhth3!CJ h3!CJ hzCJ jhthtCJ htCJ h+CJhtht5CJhthtCJ ht5CJ hJx5CJ h|Cx5CJ hJxCJ hQ~CJ h|CxCJ hywCJ*ATcTnTuTwTxTTTTTTTTTTUU UEUGUHUoUpUqUtUuUvUyUUߺ챧웈ycQK h7CJ#h)&Nh)&N0J5>*B*CJph+jnh)&Nhb*5B*CJUphh)&Nh)&N5B*CJph%jh)&Nh)&N5B*CJUph h)&NCJ h+CJhth+5CJhth+CJh5h50J>*CJj\mh5hCJUh5h5CJjh5h5CJU h|CxCJ h5CJ h|Cx5CJUUUUUUVVVVV/V=VGVIVLVSVTVtVuVvVyVzVVVVVVVV$WXXX|Y~YYYż̨Ӣӕ|pӨjjjjc hB5CJ hCJhh|Cx0J>*CJjnhhH0CJUhhCJjhhCJU hFoCJhh|Cx5CJhh5CJhFohCJ h5CJ h|Cx5CJ h|CxCJ h7CJ h+CJh+h+CJ h+5CJh+h|Cx5CJ%|Y~YYZ[[[[\[\\\\\\\]]]N^O____`C` & F@ ^@ gd)&N & Fp^pgd)&N & F^gd)&N & F^gd)&NY ZZ ZZZ[[2[4[:[D[M[[[^[o[{[[[[[[[\\ \\\p\\\]]]]]N^W^t^v^w^^^^Ǽ趣~+jcoh4hb*5B*CJUphh4h45B*CJph%jh4h45B*CJUph h4CJh4h|CxCJaJh4h|Cx5CJH*aJh4h|Cx5CJaJ h|Cx5CJ h|CxCJ h5CJ hzCJ hBCJ*^^^^^^O_[_a_d_n_p___a`b```````aaaaa a a a5a[aaaaaνζΰνΪΤΝzpjd] h5CJ hCJ hXCJhXh|CxCJH*h)&Nh|Cx0J>*j4ph)&Nh|CxUjh)&Nh|CxU h)&Nh|Cx hJxCJ hn8[CJ hCJ h|Cx>*CJ h|Cx5CJh4h|CxCJH* h|CxCJ h4CJ%jh4h45B*CJUph#h4h40J5>*B*CJph#C`z``` aaa"bkbbbc cccIccc d & F^gd)&N & Fp^p`gd)&N & F. @ ^gdQ & Fp^pgd)&N & F^gd)&N & F@ ^@ gd)&Naaaaaa"b,bkbnbbbbb ccccxdddddddee_eheeeeeeefffff!f"fùíË}rh|Cx5>*CJaJh2h|Cx5>*CJaJ hQ5CJ hCJ hn8[CJ hzCJh|CxB* CJphh|Cx5B* CJphhbB* CJph hbCJhb5B* CJph h5CJ hCJ h|CxCJ h|Cx5CJ hXCJhXhX5CJ) dLdvdwdxddeeeff"f#fgggggh & F0^`0 & F^ & F^ & F & Fp^pgd)&N & F^gd)&N & F^gd)&N & F@ ^@ `gd)&N"f#fffffff4g?gTgbggggggggggggggggggghhuhhhhiiii/i0iiiiiii%jhreqhreq5B*CJUph hreqCJhreqhreqCJ hn8[CJh9h|CxCJjvqh|CxCJUh|Cx0J>*CJj qh|CxCJUjh|CxCJU h|Cx>*CJ h|Cx5CJ h|CxCJhhreqCJaJ.hghhhwhhhii0ijjAkBkSkkkl m m$m1n^` & F & Fp^pgdFop^pgdf & F^ & Fp^p & F^ & F^`iiiiiiijjjj=j>j?jIjJjKjLjMjWjgjqjjAkBkSkWkrkkkkkȶȰwkb\U\U\ hFo5CJ hFoCJhfh|CxCJhfhf0J>*CJjrhfh&CJUhfhfCJjhfhfCJU hfCJ h|Cx5CJ h|CxCJ hreqCJ#hreqhreq0J5>*B*CJph%jhreqhreq5B*CJUph+jqhreqhreq5B*CJUphhreqhreq5B*CJphkkkkkkkkkkklll m m$mBmNmPmRmZmjmlmmmm n"n)n0nnnnnnncooo0p1ppzsm hn8[CJ hS5CJhShS5CJhSh|Cx5CJ hSCJhSh|CxCJhFohFoCJ hFoCJ hFo5CJ h|Cx5CJ h|CxCJ h5CJhFoh|Cx0J5>*CJ"joshFohRf5CJUhFohFo5CJjhFohFo5CJU*1n2nVnsnnocooooopp*CJjuh|CxCJUjh|CxCJU h)&NCJhShS5CJ hSCJhSh|Cx5CJhuh|CxCJhuh|Cx0J>*CJjr@rbrrrrrrrrss.s:s;sssssssssPtRtTtttvtuu"u&uuuuuu~n~jkvhZ )hCJUjh|CxCJU h|Cx5CJh hKrCJhKr0J>*CJjuhZ )hCJUjhKrCJU hKrCJh h CJ h 5CJ jh h CJ hCJ h|CxCJh h 5CJ h 6CJ h CJ'uuuuuvvvvv wxxxx0x2x6xhx,yyyyzz`{y{z{{{{{{{{{{{{{{{{{{{{{ |ӾӸӨ߱߀yyߡ hk 5CJhk hk CJhSh|CxCJ hSCJhShSCJ hS5CJhXhSCJ hX5CJ hk CJ hCJhXhXCJ hn8[CJ hXCJ hKrCJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ/ | |||,|K|L|P|^||||>}?}H}{}|}}}}}}}~~D~N~e~m~o~p~~~~~~~~ 234?п{rh|Cx0J>*CJjwh|CxCJUjh|CxCJUh|Cx0J5>*CJ"j%whZ )h5CJUjh|Cx5CJUh|Cx h|Cx5CJhXhX5CJ hXCJhXhS5CJ hCJ hX5CJ h|CxCJ hS5CJ hSCJ,|>}|}}}}}}}D~e~ JKY & F` & F & F0^`0gd)&N  & F^gd)&N & F^gd)&N & F^gd)&N?@JKYij%'23<GUgrs|݀>@IK{{u{uk{h*h*5CJ h9CJ h*CJh*h*CJh9h*5CJh|CxB* CJphh|Cx5B* CJph hzCJh|Cx5CJH* h|Cx>*CJ h|Cx6CJ hz6CJ h2CJh2h25CJ hn8[CJh|Cx h|Cx5CJ h|CxCJjh|CxCJU)&'>fg~@؁(*+L & Fgd*^gdUf & FVgdUf & F^gd* & F^ & F^gd9 & F^` & F^ & F` & FKLMy{}ׁ؁܁'(4@W‚ /0~()*+6tU_`k…Åɿɿɧ꣟ hzCJ hluCJhluhlu5CJhXh|Cx h|Cx5CJhUfhUf5CJ h*CJH*h*h*CJH* h*CJh*h*5CJ hUf5CJh*h*CJH* h|CxCJh*hUfCJH* hUfCJ5LÅukz + & F   ^ gdQ & F 8^gdQ & F 8^gdQ & F^`gd)&N & F^gd)&N  & F^gd)&N & F^gd)&N & F^`Å̅u}  kxz~͈(6KLÉ  *+45=>?J}~09:YĻկյկըεh&h&5CJ h&5CJ hzCJ h&CJhluhluCJhluh|Cx5CJ h|Cx5CJ h|CxCJhluhlu5CJ hXGCJ hlu5CJ hluCJ h75CJ<+5~cwv2F & F^`gd)&N7$8$H$^`gd)&N & Fp^pgd9- & Fp^pgd)&N & F^gd)&N & F   ^ gdQ & F 8^gdQ & F   ^ gdQYqv~ 8:;[\]`abc 'HJ÷Ï܈{rhb h7CJhXGhlu5CJhXGhXGCJ hXG5CJ hXGCJ hlu5CJ#h7h9-0J5>*B*CJph+jgxh9-h#,5B*CJUphh9-5B*CJph%jh7h9-5B*CJUph h9-CJ h&CJ h|Cx5CJ hluCJ h|CxCJh&h|Cx5CJJKnopstuv͎ώЎ쯩thRt@t#h7hK]0J5>*B*CJph+jyhK]hD5B*CJUphhK]5B*CJph%jh7hK]5B*CJUph hK]CJ hzCJ jhXGhXGCJhXGhXG5CJ hXGCJ h7CJ#h7h70J5>*B*CJph+jyh7hb*5B*CJUphh7h75B*CJph%jh7h75B*CJUph2Dݐ6<nv*+JZ["3>xy~Ƌwh|Cx0J>*CJh|Cx0J5>*CJ"jBzhZ )h5CJUjh|Cx5CJU h&CJ hzCJ h|Cx>*CJh|Cx h|CxCJ h|Cx5CJhXGh!H5CJ hg1CJ h!HCJ hXG5CJ hluCJhXGhlu5CJ hXGCJ.-aݐ6xǑ˒"3 & F @ @ ^@ gd)&N & F@ p@ @ ^@ gdCjRp^pgd)&N & F p@ @ ^@ gd H ^`gd)&N & F^gd)&N & F^`gd)&N & F^`gd)&NzÔȕʕЕ!*>Em˖X^ԗ՗DEHWXcx{֘טߘ"$6К h|CxCJH* hn8[CJ jh|CxCJ hQqCJh|Cx5>*CJ h|Cx>*CJ hluCJhluhlu5CJ hzCJ h|Cx5CJ hCJ h&CJ h|CxCJ=ʕ!lmXHX  & F^`gd)&N & F^gd7 & F^gd)&N & F^gd)&N & F^`gd)&N & Fp^pgd)&N ,>Lv  MYhМҜ֜fhuv & дЮРЙГЌxrihRhRCJ hRCJ hR5CJ hywCJ h)&Nh)&N h|Cx5>* hUfCJ h|Cx>*CJh|CxhXhX5CJ hXCJ jh|CxCJmHnHu h|Cx6CJ h|Cx5CJ h|CxCJ h&5CJ h&CJhXGh|CxCJhXGhXGCJhXGhXG>*CJ' ќҜ֜ghuv9:"B & F & F^ & F^gdywgd)&N & F^gdUf  & F^gd)&N & F^gd)&N^gd)&N & F^gd)&N & Fp^pgd)&N7dfCDEFRUVabjsx̢͢ߢ0R.1}꘍zhR=CJ$aJ$hJxhJxCJ$aJ$hJxhR=CJaJh|CxCJaJ h|Cx5 h|Cx6CJ hb{CJ hzCJ jh|CxCJ h!H5CJ h!HCJ h|CxCJH*h|Cx5CJH* h|Cx5CJ h|CxH*h|Cx hn8[CJ h|CxCJ h?oCJ0B\CDjܤ & F`^``gd)&N & F^gd)&N & Fp0^p`0gd!H & Fp0^p`0gd)&N & F^gd!Hgd  & F^gd)&N & F^gd)&N & F^[Χϧ/x٨"#qrp^pgd)C^gd)C ^`gd)C^gd)C`gd)CgdJx  & F^gd)&Ngd & F^gd)&N&'(+,./PQRabde{|}Χzqf^RhJxhJx5CJaJhJxCJaJhR=hJxCJ$aJ$hUQ5CJaJ&j`|hR=h$5CJUaJhR=5CJaJ&j{hR=h$5CJUaJ&jt{hR=h$5CJUaJhR=hR=0J5>*CJaJ&j {hR=h$5CJUaJhR=hR=5CJaJ jhR=hR=5CJUaJΧϧڧ/35bivwxyz¨ŨҨը"#4:;\]^nopqrṱwlch)C>*CJaJhkh)CCJaJhkhk0J>*CJaJ#j|hkh$CJUaJhkhkCJaJjhkhkCJUaJhkCJaJhkohko>*CJaJhkohJx5CJaJhXI{CJaJhu>CJaJhkoCJaJhkohko5CJaJhJxhJxCJaJ&rѫ:;PQUVW[ʿskcZsZQIsh)CCJaJhu>5CJaJhk5CJaJhkoCJaJhu>CJaJh)Chu>5CJaJh8hRCJaJh8hR5CJaJh8hu>CJaJh8hkoCJaJh8CJaJh8h)CCJaJh8h8CJaJh8h)C5CJaJh8h)C5hR>*CJaJh8h86CJaJh8hR6CJaJr9:^_ѫ:;VWi^gd8^gd ^`gd8 & Fgd8^gd)C8^8gd8[fghiz{|լ֬جڬ۬߬}maTKhPUhPUCJjhPUhPUCJUhshs0J>*CJjV}hshsCJUhshsCJjhshsCJU hsCJhshk5CJhs5CJaJh)Chu>5CJaJ hs5CJh)C5CJaJ jh:zLh:zLCJaJh:zLCJaJhsCJaJhkCJaJhu>CJaJhk5CJaJi۬3UگIJXgd8 & Fmgd8 gdIgdJx^gd8^gds^gds^gd)C ^`gds  03?@DSUa˯JKWXǺǯǕǏǏǟ{sg[shUQhu>5CJaJhUQhUQ5CJaJhUQCJaJhnCJaJhnhn5CJaJ hnCJhshs5CJhsCJaJh}CJaJhshsCJaJ h CJ hs5CJ hsCJhPUhsCJhPUhs0J>*CJjhPUhPUCJUj}hPUhGpTCJUİŰưǰ𽲫mZK?h|CxB* CJaJphhIhIB* CJaJph$hIh_}0J>*B* CJaJph#j~hZ )hCJUaJhIh|CxCJaJjhIh|CxCJUaJhIhICJaJ h|Cx5CJ h|Cx>*CJ hJxhUQCJaJhUQCJaJhUQhUQ0J>*CJaJ#j~~hUQhUQCJUaJhUQhUQCJaJjhUQhUQCJUaJ-./2356KLMPQSTijknoq⢎zfZh8hUQ5CJaJ&jh8h|Cx5CJUaJ&jh8h|Cx5CJUaJ&j!h8h|Cx5CJUaJh8h|Cx5CJaJ'h8h|Cx0J5>*B* CJaJph&jh8h$$5CJUaJh8h$$5CJaJ jh8h|Cx5CJUaJh8B* CJaJphqr S]vwﳯ~tmf`Z`ZQKZ hfCJhfhfCJ h|CxCJ hsCJ hs5CJ hgih|Cxhgihgi0J>*jŁhgihZUjhgihgiU hgihgi hgi5CJhsh|Cx5CJh|Cxh8h|Cx5CJaJh8hUQ0J5>*CJaJ&j\h8hUQ5CJUaJh8hUQ5CJaJ jh8hUQ5CJUaJbų%ҴE%^gd)&N ^`gd)&Ngd8 & F^`gd)&N & F^gd)&N & F   ^ gdQ & F^gd)&N^gd)&NƲbfijųȳڳ۳#$%&GHIMNU[oѺׅygy\yׅׅׅh|Cx0J5>*CJ"jqhZ )h5CJUjh|Cx5CJU hfCJhsh|Cx5CJhshs0J>*CJjhZ )hCJUhshsCJjhshsCJUhshs5CJ hsCJ h|CxCJ h|Cx5CJhsh|CxB* CJphhsh|Cx5B* CJph#DEMN%3ŶֶƷ )ù #TĺźƺϺкʻױ׻עxhQ2h$$0J5>*CJ"j0hQ2h/F5CJUhQ2hQ25CJjhQ2hQ25CJUhkh$$5CJ hQ2CJh$$5>*CJ h$$>*CJ hkCJ h$$CJ h$$5CJh|Cx h|CxCJ hsCJ jhshsCJ.no~ּ+q UVfq & FS T^TgdCjR^gd)&N & F@ pTT^TgdCjR & F@ pTT^TgdCjR & F^gd)&N & Fgd8^gd)&NкԺպ *2;u߻"踱|sm^Th|CxB*CJphjh|CxB*CJUph h|CxCJh|Cx0J>*CJjąh|CxCJUjh|CxCJU h|CxCJ hQ25CJ h|Cx5CJ h|Cx hQ2CJ h$$>*CJ h$$CJhQ2h$$0J5>*CJ"jhQ2h/F5CJUhQ2hQ25CJjhQ2hQ25CJUhQ2h$$CJ"#$?@CDabcklno~ּ5O߽  UV=[ܾȥȠșȏvȥȏfvș` hn8[CJjLhZ )hCJUh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|Cx5CJ h|Cxhh|Cx(jhZ )hB*CJUphh|CxB*CJph h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph(jKhZ )hB*CJUph%q <=]6b0o & F^`gd)&N & Fp^p`gd)&N & F^`gd)&N & F^gd)&N & F^gd8 & F^gd)&N & FS T^TgdCjR 07IJ_`amno|&'(/{?@Uϯulh:zLh:zLCJjh:zLh:zLCJU h#CJh#CJaJh#h#5CJaJh|CxCJaJh8h|CxCJaJh8CJaJh|CxB*CJph h|Cx6CJ h|Cx5CJ h|Cxh|Cx0J>*CJjh|CxCJUjh|CxCJU h|Cx5CJ h|CxCJ&o'({bcy & F^gd:zL & F^`gd:zL & F^gd# & F^gd|Bm^gd|Bm ! & Fgd8 & F^gd)&NUVWZ[]^)acxy-9Ĵ⢜xrkd]V]k hQo5CJ hUQ5CJ hn8[5CJ h|Cx5CJ hzCJh:zLh:zL5CJh:zLh|Cx5CJ h|CxCJh:zLh#5CJ h#CJ h:zLCJh:zLh#0J>*CJjh:zLhRfCJUh:zLh:zLCJh:zLh#CJh:zLh:zL0J>*CJjh:zLh:zLCJUjzh:zLhRfCJUmn(&'A & Fp^pgd|Bm & F 8^gdQ  ^` gd|Bm^gd|Bm & F^gd|Bm & F^gd|Bm!-G`j~mn~ ()KLMRSTq¼¼¶¶ϬϢϛώ~rl h CJhUQhUQ0J>*CJjdhZ )hCJUjhUQhUQCJU h|Cx>*CJh:Yh|Cx>*CJ hUQCJh|Cx h CJ h|BmCJ h|CxCJ h|Cx5CJ h|CxCJh:Yh:Y5CJ h:YCJhUQhUQCJhUQhUQ6CJ h:Y6CJ*&'4589:;{|}ACe4=PQ[ŸŒvrh|Cxh:zLh:zL5CJ h:zLCJ hn8[CJ h MCJ h|Bmh|Bm0J>*B*CJph̙(j%h|BmhfgB*CJUph̙h|Bmh|BmB*CJph̙"jh|Bmh|BmB*CJUph̙h|Bmh|BmCJ h|Bm5CJ h|Cx5CJ h|CxCJ hfoCJ hUQCJ,!4PQq<=I& & F ^ `gd@'F & F^`gd@'F & F^gd@'F & Fgd8 & F^`gd:zL & F^gd:zL & F^gd|Bm & Fp^pgd|Bm'()39:;<=GIJ_`apqtuҽܯҚ܌wqdw[wqwqhz0J>*CJj\hzCJU hzCJjhzCJU h|Cx5CJh|Cxhz0J>*B*CJph(jhZ )hB*CJUphh|Cx0J>*B*CJph(jhZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph h|CxCJ h|Cx5CJ h|Cx5CJ$$;<TUhijmnuvƶ߭觠zmzjh|CxCJUh|Cx0J>*CJjBh|CxCJUjh|CxCJU hn8[CJ h|Cx5CJ h|CxCJh?(0J>*CJjhYhH0CJU hYCJj>hzCJU hzCJhz0J>*CJjhzCJUjōhzCJU)%&'>?ABUVWZ[]^qrsvwyzú٭٠ٓنyjh|CxCJUjKh|CxCJUjh|CxCJUjah|CxCJUjh|CxCJUhn8[0J>*CJh|Cx0J>*CJjh|CxCJU h|CxCJh?(0J>*CJjh|CxCJUjh|CxCJU/%&()CDEYZ\]{|}RST]EFGjhDh|CxU hDh|Cxj)hZ )hCJUh|Cx h|CxCJjh|CxCJUj;h|CxCJUjȓh|CxCJUh|Cx0J>*CJjEh|CxCJU h|Cx5CJ h|CxCJjh|CxCJU1&ST=  & F^gd@'F^gd@'Fgd8 & F^`gd@'F & F^gd@'F & F^gd@'F3'rt=ASVϻϵϧϞϻϻϕϞϑσjh|CxCJUhq4h|Cxh|Cx0J6CJh|Cx5>*CJ jh|CxCJmHnHu h?(CJ h|CxCJH* hDCJ h|Cx5CJ h|CxCJ hDh|CxhDh|Cx0J>*jhDh|CxUjhDh|CxU//0NO VZVWgüٶٶټ٭٭ټٝ{lټe h|CxCJH*h|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph jh|CxCJ h?(CJ h|Cx5CJh|Cx h|Cx5j4h|CxCJU h|CxCJh|Cx0J>*CJjh|CxCJUj˖h|CxCJU'V53P?gd8 & Fp^pgd8 & F^gd@'F & F: ^gdCjR & Fp^pgd@'F  & F^gd@'F & F^gd@'Fghlm?Hij)*+23=>noqw̳rl h?(CJh|Cx0J5>*B*CJph+j hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx0J>*CJjDhZ )hCJUjh|CxCJU h|Cx>*CJh|Cx5>*CJ h|Cx5CJ h|CxCJH* h|CxCJ hn8[CJ$Yb7ĹĹĠđrdđO(jh@'Fhb*B*CJUphh|Cx0J>*B*CJph(jQh@'Fhb*B*CJUphh@'FB*CJphjh|CxB*CJUph hDCJ hl)5CJ h|Cx5 hn8[5CJ h|Cx5CJh|Cx h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jhZ )h5B*CJUphYxoX03 & F^gd@'F & F^gd@'F & F^`gdy<  & Fp^pgdy< x#oxX\/02u{2379jֹݳݭݳݣݙ݌jh|CxCJUjh|CxCJUhh|Cx5CJ hYCJ hCJhhCJ h\ 5CJ h?(CJ h|CxCJH* h|Cx5CJ h|CxCJh|Cx0J>*B*CJphjh|CxB*CJUph7&'FGb12;<+gd8 & F & F^`gd@'F & F ^ `gd@'F & F ^ `gd@'F & F^gd@'F#$'6G\^bis2:;*+EIMdeftu 6Q澲ߚߑ߄zh(*h(*5CJ h(*5CJ h(*CJh|Cx56CJ hn8[5CJh|CxB* CJph h|Cx6CJh|Cx5B* CJphh|Cx h|Cx5CJ h|Cx>*CJ h?(CJhO|h|CxCJ h|Cx5CJ h|CxCJjh|CxCJUh|Cx0J>*CJ-+c t |P~ & Ff pp^pgdCjRp^pgd(* & Fgd(* & F^`gd(* & F^gd@'F & F^gd@'FQstwyQ ABCFGIKV|ʷztzm h|CxCJH* hB='CJ h?(CJ#hkhk0J5>*B*CJph+jhkhb*5B*CJUphhkhk5B*CJph%jhkhk5B*CJUph hkCJ h|CxCJ h|Cx6CJ h|Cx5CJh(*h(*CJ h(*5CJ h(*CJ h_TCJ*)EGHbcdghi#$<=OPqr}~u~Qιۨ|qhh|CxCJaJhh|Cx5CJaJh|Cx jh|CxCJ hCJ h5CJ hn8[CJ h@'Fh@'F0J>*B*CJph(jh@'Fhb*B*CJUphh@'Fh@'FB*CJph"jh@'Fh@'FB*CJUph h@'FCJ h|Cx5CJ h|CxCJ,~BPQ~x  *+Kgd & F & F^gd@'Fp^pgd^gd & F^gd@'F & Fe pp^pgdCjRQiqr}~"$ #$KUx   *ýóɬÙweìì\V h|CxCJ hb{hb{CJ#hkhb{0J5>*B*CJph+j"hL Khb{5B*CJUphhb{5B*CJph%jhkhb{5B*CJUph hb{5CJhb{hb{5CJ hk CJ hb{CJ h|CxCJ h|Cx6CJ h|Cx5CJhhn8[CJaJhh|CxCJaJhh|Cx5CJaJ *+KL]'l$%&ŶŎyoZy(jh@'Fhb*B*CJUphh@'FB*CJphjh|CxB*CJUph h(*CJ#hreqhreq0J5>*B*CJph+jhreqhb*5B*CJUphhreqhreq5B*CJph%jhreqhreq5B*CJUph hreqCJ h?(5CJh|CxB* CJph h|CxCJ h|Cx5CJh|Cx"lz  & F@ ^@ gd@'F & F^`gd@'F & F^gd@'F & F^`gd@'F & F^`gd@'Fgd & F^gd@'F & F^gd&)*,-KLMPQSTrstwxyz01256F3:QXYӾөݢݝݢݏ݂yslݢݢݢݏ h|Cx>*CJ hCJh|Cx0J>*CJjYh|CxCJUjh|CxCJUh|Cx h|Cx>* h|Cx5CJ(jŸh@'Fhb*B*CJUph(j+h@'Fhb*B*CJUphh@'FB*CJph h|CxCJjh|CxB*CJUphh|Cx0J>*B*CJph*9:X<5N & F'^gdxqO & F' ^gdxqO 8h^8`hgd@'F^gd@'F & F^gd@'F & F^gd@'F & F^`gd@'F & Fp^p`gd@'FYpqrvwxyQR`al<Emwwhhkhk5B*CJph%jhkhk5B*CJUph hkCJ hB='CJ h[CJ h[5CJh[h[5CJh?h|CxB* CJphh?h|CxCJ h|Cx6CJ h|Cx5CJhn8[0J>*CJh|Cx0J>*CJjh|CxCJUj h|CxCJU h|CxCJ   ,-.124Zw-־yslsesZOhfV?hfV?CJaJhfV?h[CJaJ h[>*CJ h[5CJ h[CJh|Cx5CJH*h|Cx0J5>*CJ"jԡhZ )h5CJUjh|Cx5CJU h|Cx5CJ h|CxCJ hB='CJ hkCJ#hkhk0J5>*B*CJph%jhkhk5B*CJUph+j/hkhb*5B*CJUph-.45;&(NRTV"%&'2O*+̃uuuqj`jh|CxCJU h ] 5CJh|Cx jh|CxCJmHnHuh|CxCJOJQJ jhxqOCJ hxqOCJhxqO0J5>*CJ"jhxqOhL5CJU hxqO5CJjhxqO5CJU h|CxCJ h|Cx5CJhfV?h[CJaJhfV?B* CJaJphI}hfV?hfV?B* CJaJphI}%N"Pz>mn    n    ? @  & F^gdL K & Fpgd & F^gd@'F & F^gd@'F^gd@'F & F' ^gd@'F+QRS^_z=>Vlmn  8 h u y            m n     S U  źях{uяяяяźuuuяoo hL KCJ hCJhh5CJhh|Cx5CJ h|Cx5CJh ] h ] CJaJh ] 5CJaJh"CJaJh ] CJaJh"h"CJaJh"h"5CJaJ h|CxCJh|Cx0J>*CJjh|CxCJUjUhZ )hCJU hcCJ+       @ S           DPoxUVdgzȽȵȩȠȠȽzodh~h~CJaJh~h|CxCJaJh~hCJaJh Ih]h|Cx5h|CxhRhRCJaJhR5CJaJhRhR5CJaJhCJaJhhCJaJhRCJaJhh5CJaJhh|CxCJaJ h|Cx5CJ h?(CJ hL KCJ h|CxCJ'@ S    DoUVH: & F^`gd@'F & F^gd^gd@'F & F^gd~^gd@'F & F^gd@'F & F^gd@'FGHTwx9:CDhrz A`ſܲܫ}}u}jucu h|Cx0J>*j"h|CxUjh|CxUh|Cxh ICJaJheCJaJh~h~CJaJ h ICJh~h~CJ h~5CJ h~CJ h|Cx5CJ hb{CJhb{hb{CJ hb{5CJ h|CxCJH* h|CxCJ h?(5CJh~h|Cx5CJaJh~h|CxCJaJ&bcehi`abs~%&ȼzzzzzuohoa hu5CJ h|Cx5CJ h|CxCJ h|Cx5hh|Cx5>*aJhh5H*aJhh|Cx5H*aJhh|Cx5aJhh|CxaJh ] h|CxCJaJhh|Cx5CJaJhh5CJaJhhCJaJhhn8[CJaJhh|CxCJaJ h|Cx5CJh|Cx#sqs<lw & F2 pp^pgdQp^pgd@'F^gd@'F^gd>^gd@'F & F^gd@'F & F & F^gd@'F  & F^gd&'(hijnopq67np¶xlxlxlxc\ hXo/5CJhXo/hXo/CJhXo/hXo/CJH*aJhXo/hXo/CJaJhXo/hXo/5CJaJ h|CxCJ hXo/CJhuhXo/5CJhXo/CJaJhXo/5CJaJhuhu>*CJaJhuhuCJaJh>CJaJh>Ghu0J>*jh7qUhujh>GhuU h>Ghu#Ors|ϖ㎇|tnc\R\I@: h|CxCJhth|CxCJhthtCJhth|Cx5CJ ht5CJhuhVCJaJ hVCJhVCJaJhVhVCJaJ hV5CJhtCJaJ$huht0J>*B*CJaJph,j^huhtB*CJUaJphhuhtB*CJaJph&jhuhtB*CJUaJphhuhtCJaJ hXo/CJ jhXo/hXo/CJ   2349:;<O\jw~   $ [ \ } ϖゐxqqga hn8[CJhnh|Cx5CJ h|Cx5CJhtht5CJhtCJaJ hv7CJ htCJ$huht0J>*B*CJaJph,jhuhtB*CJUaJphhuhtB*CJaJph&jhuhtB*CJUaJphhuhtCJaJ h|CxCJ h>CJ hbXCJ% >"7#G##Q$Y$$E%{%%%"&A&{& & F^   ^ gdCjR & F^`gd> & Fp^pgd@'F & F^gd@'F & F^gd@'F & F2 pp^pgdQ} ~          !! !;!h|Cx hnCJh)xjh)xjCJ h)xj5CJhnhn5CJ hbXCJ#hreqhreq0J5>*B*CJph+jhreqhb*5B*CJUphhreqhreq5B*CJph%jhreqhreq5B*CJUph hreqCJhnh|Cx5CJ h|Cx5CJh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJUf!g!!!!!!!!!!!!!!!!!!!!!!!"'"/"<">"B"D"J""""""ɿ훔՛|rleϿe_ h)#CJ h|Cx5CJ hbXCJhbXhbX>*CJhnh|Cx5CJjh>hU h>hnjh>hnUh)xjhnCJh)xjh)xjCJ h)xj5CJhnhn5CJ hnCJ h|CxCJh>h|Cx0J>*jҩh>hU h>h|Cxjh>h|CxU$"""")#*#+#5#6#7#D#F#G###Q$V$$$$$f%g%%%{&|&}&&&&*'.'Z'd'e'f'g's'u'}''''''ⷰ|||hv7h>5CJh>h>CJ h>CJ h?(CJ hn8[CJ jh|CxCJ hnCJ h|Cx5CJ h|CxCJh)#h)#0J>*CJjJh)#h-ZCJUh)#h)#CJjh)#h)#CJU h)#CJh)#h)#>*CJ-{&&*'Z'g'j(r(((*),)k)l))U*V*r*** & F^gd & F^gd> & Frgd & Frgd> & F^gd> & F^`gd@'F & Fp^pgd@'F & F^gd@'F''''''''i(j(r((((((())*)+),)C)I)k)l)))))****T*U*V*r***ľě|ule h|Cx6CJh>h|CxCJ h>6CJh)xjh)xjCJ h)xjCJh;=h)xjCJ h|Cx5CJ h)xj5CJ hmfCJhLuh>5CJ h>CJ h|CxCJ hCJh>h>CJh>h=}0J>*CJj$h>h_CJUh>h=}CJjh>h=}CJU&**** ++C+O++++++++++++,, ,,,,,,,--1-2-E-K---;.P...*CJ"jhZ )h5CJUjh|Cx5CJU h|CxCJ hsxCJ h|Cx5CJ hn8[5CJ7**C+++,E--;.a/b01j111(2_2 ^`gd@'Fp^pgd & F^`gd@'Fp^pgdLup^pgd@'Fp^pgd ^`gd@'F^gd & F^gd & F^gd@'F1111111111_2c2e22P334444<4=4>4B4C444444555!5-5.5/5k5l55555uhh|Cx0J>*CJjhh}CJUhhCJjhhCJU hCJhje%h|Cx5CJj5hZ )hCJU hLuCJ hje%CJ h|Cx5CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ*_2444&6j6k66W7X7l7777R8S88B9C9Z9 & F^gd@'F  & F^gd@'F & F^gd@'Fp^pgd^gd@'F ^`gd@'F^gd55555555555%6&6.606i6k6u6v6w6x66X7l777S8\8]8f88888888888˿˸˲˸˸˸˧˸ˡ{oi h;ECJhShS0J>*CJjhZ )hCJUhShSCJjhShSCJU hSCJh|Cx hn8[5CJ hLuCJ h|Cx5CJ h\ CJ hje%CJ h|CxCJhh|CxCJjhhCJUhh|Cx0J>*CJhh\ 0J>*CJ'889999999;9<9=9@9A9B9C9Z9a9g9999$:D:x:::::::;;,;.;L;N;;;<<򷱧}ttttthhh|Cx5CJ(aJ(h|Cx5>*CJhn8[hSh|Cx h|Cx5CJ h;ECJh;Eh|Cx5CJ h;E5CJhSh|Cx5CJ hSCJ h|CxCJj6hZ )hCJUh;Eh;E0J>*CJjwhZ )hCJUh;Eh;ECJjh;Eh;ECJU(Z99":$:v:x::<<<<<<<<==>? & F(gdA;Z & F^gd & F & F@ ^@ gd & F ^gd@'F & F^gd@'F & F^`gd@'F & Fp^pgd@'F<<<<<<<<<<<========== >>(>>>>???L?U????????????? @@𳬣𬣳𖿳|sh|Cx0J>*CJjhZ )hCJUjh|CxCJU h|Cx6CJ h*CJhA;ZhA;ZCJ hA;Z5CJ hA;ZCJ h CJ h|Cx5CJh|CxB* CJphh|Cxhhn8[CJaJhh|CxCJaJ hCJ h|CxCJh|Cx5CJ(aJ(-?L????'@AAABB.CCC DVDDEE(EEFF_G  & F^gd@'F & F^gd@'F & F^gd@'F & F & F^@'@@@AAAMANAOARASAUArAtAuAAAAAAAAA BBBĮӜzdRKE h\ CJ h|Cx5CJ#h@'Fh@'F0J5>*B*CJph+jih@'Fhb*5B*CJUphh@'Fh@'F5B*CJph%jh@'Fh@'F5B*CJUph#hkhk0J5>*B*CJph+jhkhb*5B*CJUphhkhk5B*CJph%jhkhk5B*CJUph hkCJ h@'FCJ h|CxCJ h|Cx6CJBBBCCC.CCCCCCC DEEE'E(ENEOEPE^EEEEE0F^FjFzFFFF_GhGGGGGGGGGHHh|Cx0J>*CJjh|CxCJUjh|CxCJU hmlCJhmlh|Cx5CJ h+TMCJ h\ CJ jh|CxCJ h|Cx6hn8[h|Cxhh|CxCJ h|Cx6CJ h|Cx5CJh|Cx5B* CJph h|CxCJ h@'FCJ-_GGHHHHH+I,ISIIIIIJJJKL?L@LBLCLHLzL|LLLLL۴ۄۄzۄhDhS5CJ hDCJhDhS0J>*jhDh%U hDhDjhDhDU hShShShS5CJhhCJ hCJ h5CJ hSCJ h|Cx6CJ h|Cx5CJ h|CxCJhh|CxCJ aJ ,KAL{LLUMMM+N,NaNOOOOOPQQQ & F & Fp^pgd ^`gd & F^gd & F^gd<^gd< & Fp^pgdD & F^gdD & F^gd<LLMMMMNMOMRMSMVMYMMMMM+N,NTNUNaNNN&O'O(O)ODOͷܥyfZhreq5B*CJph%jhkhreq5B*CJUph hreqCJ hkCJ h<CJ h|CxCJ hn8[5CJ h|Cx5CJ hSCJ#hDhD0J5>*B*CJph+jnhDh%5B*CJUphhDhD5B*CJph%jhDhD5B*CJUph hDCJhDhD5CJDOEOFOIOJOKOLOMO~OOOOOOOOOOOPPPPP Q*QQ־nh^XRXKRKRERKR hmfCJ h5CJ hCJ hCJhh5CJ h|CxCJ#hkhk0J5>*B*CJph+jhkhb*5B*CJUphhkhk5B*CJph%jhkhk5B*CJUph hkCJ hreqCJ#hkhreq0J5>*B*CJph%jhkhreq5B*CJUph+j'hreqhb*5B*CJUphQQQQQQ\R]R^R|R}R~RRRRRR!S+SnSoSSSSSSSSSSSTT¯ʠn_Sh|Cx5B* CJphh|Cx0J5>*B*CJph+jh@'Fhb*5B*CJUphh@'F5B*CJphjh|Cx5B*CJUphh@'Fh|Cx0J>*B*ph$jqh@'Fhb*B*Uphh@'FB*phjh@'Fh|CxB*Uph h@'Fh|Cx h|Cx6CJ h|Cx5CJ h|CxCJhh|CxCJ aJ QQQR"SSSSTTjTTT UURVV+WWWW%X & F^gd+TM^gd<^gd< & F^gd<^gd< & F^gd<T*B*CJph̙(j hsehfgB*CJUph̙hsehseB*CJph̙"jhsehseB*CJUph̙ hseCJ h\ CJ h|Cx6CJh|Cx0J>*CJjh|CxCJUjh|CxCJUhseh|CxCJ h|Cx5CJh|CxB* CJph h|CxCJ#VV+W4WW#XFXRXVXdXXXXXXXKYNYYYZYyYYYYYYYYYZZZZZZZ[[[[[[򑗇ztjjh|CxCJU h|CxCJ$ h|CxCJ8 h|Cx5CJ8h<h|Cx5CJ hmlCJ h7CJh7h7CJh7h75CJ h\ CJ h<CJh7h|Cx5CJ hn8[CJhh7CJ aJ hh|CxCJ aJ h+TMCJh+TMh+TM5CJ h|CxCJ h|Cx5CJ)%XEXFXdXXYYYYZZZ[ [[)[P[[ & F^`gd< & F^gd< & Fp^pgd< & F^gd< & F^`gd< & F^gd^gd< & F^`gd+TM[[[[[[`\a\i\j\\\\-].]>]?]]]V^X^^gd & F gd<  & F  & F^ & F^ & F` & F & F^gd<[[[[[[[[[[[\\\\!\"\#\.\/\1\2\P\Q\R\^\_\a\h\\-].]>]?]@]V]W]X]a]b]d]e]]rڄ"jѻh|CxB* CJUphjh|CxB* CJUphh|CxB* CJph h|CxCJ8h|Cx h|Cxh h|Cx>*CJjVh|CxCJUjߺh|CxCJUjZh|CxCJUh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ*]]]]]]]]]]]]]]]]]]]]] ^^^^N^O^P^S^T^U^V^X^e^̨̺ߡ|m|b|^h|Cxh|Cx0J5>*CJjh|Cx5CJUjh|Cx5CJU h|Cx5CJ h|Cx5 h|Cx5>* h|CxCJ h|Cx>*CJ$"j*h|CxB* CJUph"jh|CxB* CJUphh|CxB* CJphh|Cx0J>*CJjh|CxB* CJUph"j<h|CxB* CJUph!e^f^^^^^^_______-`.`{`|```````````a{aac\c]ccccccc٪{l{jhrhrCJUaJhrhrCJaJhrhr6CJ hrCJh|Cx h|Cx>*CJhh|CxCJh\ 0J>*CJj|hZ )hCJU jh|CxCJjh|CxCJUh|Cx0J>*CJjh|CxCJU h|CxCJjh|CxCJU'^1__`````aza{aaabbebcc7c  & F^gd & Fp^p & F^ & Fp`^p`` & F^gd<  & F^gd< & F^gd< & F^7c\c]ccc"dQdxdddddd'e f ff{fgg-g & F^gdXm & F^gdXm^gdXm & F gdrh^hgdr & F`gdr & F & F^`ccccc!dddddd'ekeqerewe ff"f.fffg-gjgug9h>h?hbhii?iKibiiiiijj!jUj^jvjzjjjjjjjTkŽŷ h)#CJ hn8[CJ hn8[5CJh|Cx5B* CJph h|Cx5CJ h|CxCJ h|Cx>*CJ hrCJhrCJaJhrhrCJaJhrhr0J>*CJaJjhrhrCJUaJ#jhrh`iCJUaJ4-gg h8h9hbhh?ijvjjTkkkk-l.lQll & F & F^`gdXm & F^gd)#^gdXm & F^gdXm & F pp^pgd & F^gdXmTk]kqkrkkkkkkkkkkkkkk.lQlRlXlYl_llll2m;mxmzmmmnn~nnnnnnnn烈xng h\ 5CJh|CxB* CJphhn8[5B* CJphh|Cx5B* CJph h|CxCJH*h\ h|Cx hn8[5CJ h|Cx5CJ h|CxCJh)#h)#CJH*h)#h)#0J>*CJjh)#h-ZCJUh)#h)#CJjh)#h)#CJU h)#CJh)#h)#5CJ(l2mmmnnnnn3o4oGoooo4pcpdppHqIq_q & Fp^pgdXmgd  & F^gdXm & F^`gdXm & F^gdXm^gdXm & F^gdXm^gdXmn4oDoEoGooo3p4p=pdp|p}ppppHqSqTq_q`qlqmqnqoqqqqqqq rrr)r.rbrdrtrrrrrrrrKsLsXssķ󰩞 hXmCJh~Vh~V0J>*jkh~Vh Ujh~Vh~VU h~Vh~V h~V5CJh3h3B* CJphh35B* CJphh|Cx5B* CJphhXmh|Cx5hXmh|Cx hn8[5CJ h|Cx5CJ h|CxCJ1_q`qqdrLssOuuwwxxxyyzz4z || & F^gdXm^gdXm & F p0^p`0gd< & F^gdXm & Fp0^p`0gd< & F^ & FsssItStTtUttttuOuRuSubucu{u|u}uuuuuuuuuuuuu禮铍wg[OhXmhn8[0J>*CJhXmh|Cx0J>*CJjhZ )hCJUhXmh|CxCJjhXmh|CxCJU h|CxCJ h|Cx5CJhXmhXm0J>*CJj>hXmh6CJUjhXmhXmCJUhg$hg$>*CJ hg$CJ jhXmhXmCJhDEhXm5CJ hXmCJhXmhXmCJ hXm5CJuuuvv'w4wGwjwzwwwwwwwwwxx)xxxxyyyyz4zPzSzWzdzfzrzwzz_{`{p{q{||||=|ƽӧjh|CxCJU h|Cx>*CJh|Cx h|Cx5 h|CxCJH* hDECJ h$5CJhXmh|CxCJ hXmCJhXmhXmCJ hXm5CJ hOCJ h|Cx5CJ hn8[CJ h|CxCJjhXmh|CxCJUhXmh|Cx0J>*CJ.=|>|?|H|I|K|L|\|]|^|b|||||||}#}$}m}z}}}}} ~~~~abcuǾ{qh_Uh hU5CJh h CJhUhUCJhUhU5CJh$hbCJ hbCJhbh%5CJ h CJ hUCJ h%CJ h$CJh$h$CJh%h$CJh%h%CJ h%5CJ h$5CJh|Cx h|CxCJh|Cx0J>*CJjh|CxCJUjzh|CxCJU!|K|L|Z|\|i||||$}}}~~ac@AB^gd  & FgdU^gdU & Fgdb & F`gd% & F & F^gdXmuvwx,-ր."<@BWXaÄX$%12׾zric\c\c\c\c\c h|Cx5CJ h|CxCJh|Cx56CJh CJaJhSHh CJaJh h h CJaJh h 5CJaJh 5CJaJ h h% h hSH h hUhSHhUCJaJ jhSHhSHCJaJhSHhSHCJaJ hSHCJ h%CJ jhUhUCJ hUCJ$BWXbÄWX܅C†ۆ܆D^gd< & F^gd< & F^`gd< & F^gd< & F2;܆()BCVWۈ"+tx̋9:EFXač͍ ʾʴh|Cx6B* CJphh|CxB* CJphhn8[5B* CJphh|Cx5B* CJph hDECJ hn8[CJ h|Cx6CJh|Cx5>*CJ h|CxCJ h|Cx5CJB)stBwxˋ̋^gd< & F^gdr & F^gd< & F^gd<^gd<Xčߍ юҎ!Аѐˑ̑=gd^gdr^gd< ^`gd<^gd< )Ҏ!*89ABIJŏˏ <EѐW`ّ̑ؑ%.HNRY`hs^fhmnv͔Д"1Ǵh|Cx5>*CJhLhL>*CJ hLCJ hn8[5CJ h|Cx>*CJh|Cx h|Cx6CJ hDECJ hn8[CJ h|CxCJ h|Cx5CJ@=8]^ghv!"FGѕ ^`gd4^gd4p^pgd<gdL^gd<^gd<ĕŕЕѕҕoWoJ=hhLB*CJphhh|CxB*CJph/jlhh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph/jhh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphh45B*CJaJph$h4h|Cx5B*CJHOJQJphhh|CxCJ' * hh|Cx5B*CJHOJQJph !2356RSTijlmٕ}pcVGhh|Cx5B*CJphhhRB*CJphhhLB*CJphhh|CxB*CJph/jhh|Cx5B*CJUaJph/jRhh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph/jhh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphٖږۖ'(*+FGHQRٕsbJs6s'hh|Cx0J5>*B*CJaJph/jDhh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphhh|CxB*CJph/jhh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph/jNhh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphRTUstu՗֗חڮڮ~ڮj^I)jhh|Cx5B*CJUaJphh45B*CJph'hh\ 0J5>*B*CJaJph/jhh|Cx5B*CJUaJph/j4hh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph/jhh|Cx5B*CJUaJph)jhh|Cx5B*CJUaJph hh|Cx5B*CJaJph    !"CDEKLNOv®Ÿ}lT}@}l}l'hh|Cx0J5>*B*CJaJph/jhh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphhh|CxB*CJphhh|CxB*CJaJph'hh|Cx0J5>*B*CJaJph)jhh|Cx5B*CJUaJph/j(hh|Cx5B*CJUaJph hh|Cx5B*CJaJphvwx٘ژۘҾҭҭҾ҉tcKt7t'hh|Cx0J5>*B*CJaJph/j>hh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphh4B*CJaJph/jhh|Cx5B*CJUaJph hh|Cx5B*CJaJph'hh|Cx0J5>*B*CJaJph)jhh|Cx5B*CJUaJph/j*hh|Cx5B*CJUaJph'(*+HIJUVXYrпГЂm\Dm0m\m\'hh|Cx0J5>*B*CJaJph/j@hh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJph hhU5B*CJaJph'hhR0J5>*B*CJaJph/jhhR5B*CJUaJph hhR5B*CJaJph)jhhR5B*CJUaJphhhRB*CJphhh|CxB*CJphrstz{|}ҾҜv^J=0hhRB*CJphhh|CxB*CJph'hh|Cx0J5>*B*CJaJph/j*hh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphh45B*CJaJph'hhn8[0J5>*B*CJaJph'hh|Cx0J5>*B*CJaJph)jhh|Cx5B*CJUaJph/jhh|Cx5B*CJUaJph$%'(BCDLMNO®®m®`K)jhh|Cx5B*CJUaJphhh|CxB*CJph/jhh|Cx5B*CJUaJph/j(hh|Cx5B*CJUaJph hh(5B*CJaJph'hh|Cx0J5>*B*CJaJph)jhh|Cx5B*CJUaJph/jhh|Cx5B*CJUaJph hh|Cx5B*CJaJphN+dPC7ן؟ٟgd^gd` ^gd` & Fh^hgdb$ & F ^`gd4^gd4Oefgtuݚޚߚ()CF®®~®f®WJhh|CxB*CJphhh|Cx5B*CJph/jhh|Cx5B*CJUaJph/jhh|Cx5B*CJUaJph/jhh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph)jhh|Cx5B*CJUaJph/j,hh|Cx5B*CJUaJph hh|Cx5B*CJaJphFbd~ƛǛțқӛ՛֛ 789NOPjӪӂlV+jhh|Cx5B*CJUph+jhh|Cx5B*CJUph+jhh|Cx5B*CJUph#hh|Cx0J5>*B*CJph+jhh|Cx5B*CJUph%jhh|Cx5B*CJUphhh|Cx5B*CJphhh|CxB*CJph hh|Cx5B*CJaJph!jkl$%&кߨВߨ߅{fU=f/j(hh|Cx5B*CJUaJph hh|Cx5B*CJaJph)jhh|Cx5B*CJUaJphhB*CJphhhRB*CJph+jhh|Cx5B*CJUph#hh|Cx0J5>*B*CJph+jhh|Cx5B*CJUphhh|Cx5B*CJph%jhh|Cx5B*CJUphhh|CxB*CJph&ABCDdefܝȳvȳ^vQB9hh|CxCJhhL5B*CJphhhLB*CJph/j*hhL5B*CJUaJph'hhL0J5>*B*CJaJph/jhhL5B*CJUaJph hhL5B*CJaJph)jhhL5B*CJUaJphh5B*CJaJph)jhh|Cx5B*CJUaJph'hh|Cx0J5>*B*CJaJph%&(578\]^efgh岣ۂ|p|j`TJC h|Cx5CJhh|Cx56hh|Cx56CJhWth|Cx5>* hb$CJ jh_h_CJ h_CJ"jvh_h+a5CJUjh_h_5CJUh_hb$5B*CJphh_hb$CJh_h_0J5>*CJ"jh_h+a5CJUh_h_5CJjh_hb$5CJU h4CJ h|CxCJޞߞ',VW؟ٟ,-.4567Gr^NhShs0J5>*B*ph̙'jhShfg5B*Uph̙hShs5B*ph̙!jhShs5B*Uph̙hShs5h|Cx hCJ hn8[CJ h|Cx5CJ"jhb$h5CJU h|CxCJhb$h|Cx0J5>*CJ"jhb$h5CJUhb$hb$5CJjhb$hb$5CJUٟ7^_iأ,-xyzҤ  & F^ & Fgd|) & F^`gd` & F^`gd` ^`gd`^gd`^gd`^gd`GHefgknosàŠ:;<?@ABCrgSGhSB*CJaJph̙&jhShSB*CJUaJph̙hShSCJaJh|Cx0J5>*B*CJph+j+hbVhb*5B*CJUphhbV5B*CJphjh|Cx5B*CJUph hn8[CJ hSCJ h|CxCJhDE0J5>*CJh|Cx0J5>*CJ"jvhZ )h5CJU h|Cx5CJjh|Cx5CJU#$FGH[\]_i !շygyc]Mjh|Cx5B*CJUph hDECJh|Cx"jhZ )h5CJUh|Cx0J5>*CJjh|Cx5CJU h|Cx5CJjh|Cx5CJU h|CxCJhSh|CxCJaJhShSCJaJ$hShS0J>*B*CJaJph̙&jhShSB*CJUaJph̙,jhShfgB*CJUaJph̙!NOPSTVWͣΣϣգ֣ף,.οιοι~iXRL h|)CJ hDECJ hSh=0J>*B*CJph̙(j=hShfgB*CJUph̙hShSB*CJph̙"jhShSB*CJUph̙ h=CJ+jhbVhb*5B*CJUph h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jhbVhb*5B*CJUphhbV5B*CJph.DFGpqruvzҤ')ͷܥ||pgXgMhs hs CJaJhs hs B* CJaJphhs 5CJaJh|CxB* CJH*phhDEB* CJphh|CxB* CJphh|CxB* ph h|CxCJ h|Cx5>*#h|)h|)0J5>*B*CJph+jh|)hb*5B*CJUphh|)h|)5B*CJph%jh|)h|)5B*CJUph h|)CJh|)h|)5CJҤX=>Tvstէ֧BC!) h^`hgdWt^gdWt ^`gdWt @ ^@ `^^` & F^=Tv>Jst쨠}rfrfr[rUKBh_hCJh_h|Cx>*CJ hlCJhsehDECJaJhseh|Cx5CJaJhseh|CxCJaJhs h|CxCJaJhs h|Cx5CJaJhs hs 5CJaJh|CxCJaJhs hs CJaJ$hs hs 0J>*B*CJaJph̙,jhs hzNB*CJUaJph̙hs hs B*CJaJph̙&jhs hs B*CJUaJph̙ɧʧ˧ҧӧԧէCWX^_`zdUEjhTB5B*CJUphh|Cx0J5>*B*CJph+jmhbVhb*5B*CJUphhbV5B*CJphjh|Cx5B*CJUph hTBCJ h|Cx5CJ h|CxCJh_h|CxCJh_hCJ h_h0J>*B*CJph̙(jh_h+aB*CJUph̙h_hB*CJph̙"jh_hB*CJUph̙¨ !'ީߩgh~οιοιοι}wqhqwqwbwYhTBhTBCJ hn8[CJhPjhPjCJ hPjCJ h5/%CJh5/%h5/%5CJ h|CxCJ+jlhTBh5N5B*CJUph+jhTBh5N5B*CJUph hTBCJhTB0J5>*B*CJphjhTB5B*CJUph+jhTBh5N5B*CJUphhTB5B*CJph")QߩR  6g ^`gdWt^gdWt^gdWt ^`gdWt & FgdJ/W8^8gdWt & F ^gdQʪ QR[`nt  ̬οιzqzkd hn8[5CJ h/CJhJ/Wh5/%CJhJ/WhJ/WCJ hJ/W5CJ hJ/WCJ hDECJh5/%h5/%5CJ hPjCJ h|CxCJ h|Cx5CJ h5/%CJ hTBCJhTB0J5>*B*CJphjhTB5B*CJUph+jhTBh5N5B*CJUphhTB5B*CJph$̬ͬ߬  89:=>?@A\]^abde˿˚teSFhsehseB*CJph̙"jhsehseB*CJUph̙h|Cx0J5>*B*CJph+jehehb*5B*CJUphjh|Cx5B*CJUphhe0J5>*B*CJph+jhehb*5B*CJUphhe5B*CJphjhe5B*CJUph heCJ h]2CJ h|Cx5CJ hn8[CJ h|CxCJ h\ CJ#$%JKLOPQRS¼†zdUL:"jhh_B*CJUph̙hh_CJhse0J5>*B*CJph+jhehb*5B*CJUphhe5B*CJphjhse5B*CJUph h]26CJ h|Cx6CJh]25B* CJphh|Cx5B* CJph h|CxCJ hseCJ hsehse0J>*B*CJph̙"jhsehseB*CJUph̙(jhsehfgB*CJUph̙SˮӮQZ¯Яѯݯޯ\gνδyuk_h|Cx5B* CJphh]2h|Cx5CJhDEjhU h|Cx0J>*jGhUjh|CxUh|Cx h|Cx5 h|Cx5CJ h|CxCJhh_CJ hh_0J>*B*CJph̙"jhh_B*CJUph̙(jrh_h+aB*CJUph̙h_B*CJph̙!QNPG}/޵67 ^`gdWt^gdWt^gdWt^gdWt^gdWt !#$OPQTUWXŹŔŹ~ŔŹhŔŹRŔ+jh+hx5B*CJUph+jAh+hx5B*CJUph+jh+hx5B*CJUphh]20J5>*B*CJph+jh+hx5B*CJUphh+5B*CJphjh]25B*CJUph h]2CJ h]26CJhO#h|Cx6CJhO#h|CxCJhO#h|Cx5CJ PS/16Pabcޣwmff_Y hSCJ hS5CJ h|Cx5CJhO#hO#6CJhO#h|CxB*CJph3f h|CxCJhO#hO#CJ hO#CJhO#h|Cx6CJ+jTh+hx5B*CJUphh]20J5>*B*CJph+jh+hx5B*CJUphh+5B*CJphjh]25B*CJUph h]2CJ!cd?@ADEFG^d.8k\VP hn8[CJ hDECJh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h]26CJ h|Cx6CJ h|CxCJ h|Cx5CJ hSCJ hsehS0J>*B*CJph̙(jhShfgB*CJUph̙hSB*CJph̙"jhsehSB*CJUph̙޵7F[]^ж +DQ\·÷ηз޷͸קodh|Cx0J5>*CJ"jZhZ )h5CJUjh|Cx5CJU hs CJ hs >*CJ h|Cx>*CJ hDECJ hsehse0J>*B*CJph̙(jhsehfgB*CJUph̙hseB*CJph̙"jhsehseB*CJUph̙ hseCJ h|CxCJ h|Cx5CJh|Cx'*+'(۸ܸaĺƺbi^gdWt & Fgd ^gd`^gd` @ ^@ `gd`^gdWt  &'()MNOVW۸ܸݸaйѹҹ VڽڽڽzphseB*CJph̙"jhsehseB*CJUph̙ hseCJ hDECJjh|Cx5CJU"jhZ )h5CJUh|Cxh|Cx0J5>*CJ"jhZ )h5CJUjh|Cx5CJU hO#CJ h`CJ h|CxCJ h|Cx5CJ%VWX^_aƺϺѺҺ   VWX¼pcNp(jhhP8hP8B*CJUph̙hP8hP8B*CJph̙"jhP8hP8B*CJUph̙ hP8CJhP8hP8CJh|Cx0J>*CJjh|CxCJUjh|CxCJUh|Cx h|Cx5CJ h|CxCJ hseCJ hsehse0J>*B*CJph̙"jhsehseB*CJUph̙(jhsehfgB*CJUph̙X^_`abcrtĻŻƻɻʻ˻ӻջֻ   ¯x¯bxRjhe5B*CJUph+jhP8h+a5B*CJUph#hP8hP80J5>*B*CJph+jUhP8hP85B*CJUphhP8hP85B*CJph%jhP8hP85B*CJUph hP8CJ h|CxCJ heCJhP8hP8CJ"jhP8hP8B*CJUph̙ hP8hP80J>*B*CJph̙ *+,/0189xyμۼ/0UVWZ[_iοιt^Oh|Cx0J5>*B*CJph+j0hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hn8[5CJ h|Cx5CJ hn8[CJ h|CxCJ hP8CJhP8hP8CJ heCJhe0J5>*B*CJphjhe5B*CJUph+jhehe5B*CJUphhe5B*CJphirʽ˽̽սֽؽٽ`pxyz{ľžƾܭ܄}we[Fe(jAhh+aB*CJUph̙hB*CJph̙"jhP8h)B*CJUph̙ h)CJ h)6CJ h|Cx6CJhhCJaJhh5CJaJhhb$CJaJ"jhZ )h5CJUh|Cx0J5>*CJ"jhZ )h5CJU h|Cx5CJjh|Cx5CJU h|CxCJhP8h|Cx5CJ_`Ͼz{HaZN & F4gd;a & F5gd;a ^`gdWt^gdWt^gdWt ^`gd^gdƾ̾;ξϾ $%-BCDefgjkm z{ǺysisWMh^]B*CJph̙"jhP8h^]B*CJUph̙h^]h^]5CJ h^]CJhJx0J5>*B*CJph+j.hJxhb*5B*CJUphhJx5B*CJphjhJx5B*CJUph hJxCJ hn8[5CJ h|CxCJ h|Cx5CJhP8h)CJ"jhP8h)B*CJUph̙ hP8h)0J>*B*CJph̙=>?EFGH    Vٿn]TMF h)6CJ h|Cx6CJhP8h)CJ hP8h)0J>*B*CJph̙(jhh+aB*CJUph̙hB*CJph̙"jhP8h)B*CJUph̙ h)CJ h)5CJ h|Cx5CJ h|CxCJ h^]CJhP8h^]CJ hP8h^]0J>*B*CJph̙"jhP8h^]B*CJUph̙(jh^]h7SB*CJUph̙VWX^_`aou+AZ[k?ٿ}sic hcCJjh|CxCJUh;ah|Cx5CJh;ah;a5CJh;ah;a6CJ h;a6CJ hDE5CJ h;aCJ h|Cx6CJ hDECJ h|CxCJ h|Cx5CJhP8h)CJ hP8h)0J>*B*CJph̙"jhP8h)B*CJUph̙(jhh+aB*CJUph̙$?@AJKLMNkz%&)9:;<Z[\ִրzobYIbjhs h|CxCJUhs h|CxCJjhs h|CxCJUhs h|CxCJaJ h|CxCJ h|Cx5CJ h|Cx0J>*B*CJph(jChZ )hB*CJUphh|CxB*CJphjh|CxB*CJUph hWtCJ h|Cx5CJ hCJ h|CxCJh|Cx0J>*CJjh|CxCJUj|hZ )hCJUN()d56mntu fguv`gd & F ^gd^gdWt^gdWt\ijmn Yݾyg]hB*CJph̙"jhP8hB*CJUph̙ hCJ h5CJ h|Cx>*CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJh|Cx h|CxCJjghs h|CxCJUhs h|CxCJhs h|CxCJjhs h|CxCJUhs h|Cx0J>*CJYZ[abc-./236EFGHٿxqjdZEٿqq(jhh+aB*CJUph̙hB*CJph̙ hCJ h5CJ h|Cx5CJh|Cx0J5>*B*CJph+jLhehb*5B*CJUphhe5B*CJphjh|Cx5B*CJUph h|CxCJhP8hCJ hP8h0J>*B*CJph̙"jhP8hB*CJUph̙(j_hh+aB*CJUph̙#,P\n}~uî͔͝xiSx+jh|)hb*5B*CJUphh|)h|)5B*CJph%jh|)h|)5B*CJUphh|)h|)CJhP8hCJ hP8h0J>*B*CJph̙(jhh+aB*CJUph̙hB*CJph̙"jhP8hB*CJUph̙ hCJ h5CJ h|Cx6CJ h|Cx5CJ h|CxCJ guvȶ}vpibv[UKBheheCJhh6CJ hCJ he5CJ h`5CJ h|Cx>*CJ h|CxCJ h|Cx5CJhP8hCJ hP8h0J>*B*CJph̙(jlhh+aB*CJUph̙hB*CJph̙"jhP8hB*CJUph̙h|)hCJh|)h|)CJ%jh|)h|)5B*CJUph#h|)h|)0J5>*B*CJph"#$*+,-FRg쬚xg[UF@ h|CxCJh`h|Cx5B*CJph hCJhh|Cx56CJ hehe0J>*B*CJph̙(j heheB*CJUph̙heheB*CJph̙"jheheB*CJUph̙heheCJ#hehe0J5>*B*CJph+jYhehb*5B*CJUphhehe5B*CJph%jhehe5B*CJUphv-M^XYc%5^gd`p^pgdWt^gdWt^gdWtgnosMSTU[\]^_b{ݺoib h|Cx>*CJ hn8[CJ h`h0J>*B*CJph̙(jhhgB*CJUph̙hB*CJph̙"jh`hB*CJUph̙h`hCJhhCJ hn8[5CJ h|Cx5CJ h|CxCJ hCJ h|Cx6CJhh|CxB*CJphhh|Cx5B*CJph$     MNOUVWYtѻݬo^WNEh~t"h7CJh7h7CJ h|Cx6CJ h`h`0J>*B*CJph̙(jah`h`B*CJUph̙h`h`B*CJph̙"jh`h`B*CJUph̙h`h`CJh|Cx0J5>*B*CJph+jh7hb*5B*CJUphh75B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJ h|CxCJ_i쯦raWPJDJ=J h|Cx5CJ h\ CJ h|CxCJ h|Cx6CJh`h|Cx5CJ h`h`0J>*B*CJph̙(j h`hgB*CJUph̙h`h`B*CJph̙"jh`h`B*CJUph̙h`h`CJh~t"h7CJ#h7h70J5>*B*CJph+j8 h7hb*5B*CJUphh75B*CJph%jh7h75B*CJUph!cm"#$*5X.89ACżztnh h6iCJ hDECJ hECJ h`h`0J>*B*CJph̙(j h`hgB*CJUph̙h`B*CJph̙"jh`h`B*CJUph̙h`h`CJ h`6CJ h|Cx6CJ h|Cx5CJ hn8[CJ h|CxCJh|CxCJmHnHu jh|CxCJmHnHu%CDhijmno쯩u_Mu#h6ihU"0J5>*B*CJph+j hU"hb*5B*CJUphhU"5B*CJph%jh6ihU"5B*CJUph hU"CJh`h`CJ h`CJ h|CxCJ h6iCJ#h6ih6i0J5>*B*CJph+jq h6ihg5B*CJUphh6ih6i5B*CJph%jh6ih6i5B*CJUph5>45OP^_fgstuv־yriWMhB*CJph̙"jh`hB*CJUph̙h`hCJ h5CJ h|Cx5CJ h|Cx>*CJ h|CxCJ h6ih6iCJaJ h6iCJ h<4CJh<4h6i5CJhEh|Cx5CJ h|CxCJ hU"CJ#h6ihU"0J5>*B*CJph%jh6ihU"5B*CJUph+j hU"hb*5B*CJUph55OP^_fg-^gdWt^gdJx^gdWt^gdWt & F^gd<4^gd6i ^`gd` 567HI_`ٿxqhUFhJxhJx5B*CJph%jhJxhJx5B*CJUphhJxhJxCJ h5CJ h|Cx5CJ hn8[CJh|Cx0J>*CJ"jh|CxB* CJUphh|CxB* CJphjh|CxB* CJUph h|CxCJh`hCJ h`h0J>*B*CJph̙"jh`hB*CJUph̙(j< hhgB*CJUph̙"#$*+,-ֻ~md^W^QGQ7jhJx5B*CJUphhJxhJx5CJ hJxCJ h|Cx5CJ h|CxCJhJxh|CxCJ hJxh0J>*B*CJph̙(jhJxhgB*CJUph̙hJxhB*CJph̙"jhJxhB*CJUph̙hJxhCJhJxhJxCJ#hJxhJx0J5>*B*CJph%jhJxhJx5B*CJUph+j|hJxhb*5B*CJUph    -./234567οιuf^VE!jhh5B*Uph̙hh5hh3H5h3Hh3H0J>*B*ph$jh3Hhb*B*Uphh3Hh3HB*phjh3Hh3HB*Uphh3Hh3H5hh|Cx h|CxCJ hJxCJhJx0J5>*B*CJphjhJx5B*CJUph+jhJxhJx5B*CJUphhJx5B*CJph7wxy&'(ξ{tkXI3X+jhhb*5B*CJUphhh5B*CJph%jhh5B*CJUphhhCJ h6CJ hWt6CJ h|Cx6CJ h|Cx5CJ h|CxCJhh|Cx5 h3Hh3Hjhh5Uhh0J5>*hh0J5>*B*ph̙!jhh5B*Uph̙'j hhg5B*Uph̙hh5B*ph̙(+,-/0nopvwyz  67oxȶ}ng}X}g}g}g}R}I}h|Bmh|CxCJ hBCJhh|Cx5B*CJph h|Cx5CJhh|Cx5B* CJph h|CxCJ hh0J>*B*CJph̙(jhhgB*CJUph̙hhB*CJph̙"jhhB*CJUph̙hhCJhhCJ%jhh5B*CJUph#hh0J5>*B*CJphyz  \,h^gd6i p^p`gd6i^gd @ ^@ `gd6i^gd6igd  UZ[\]Ϻ٩vjTvEvhJ90J5>*B*CJph+j>hJ9hb*5B*CJUphhJ95B*CJphjhJ95B*CJUph hJ9CJ h|BmCJhh|CxCJ h6i5CJ h|Cx5CJ h`h|Bm0J>*B*CJph̙(jghBh|BmB*CJUph̙h|BmB*CJph̙"jh`h|BmB*CJUph̙h`h|BmCJ h|CxCJ h6iCJ@ABEFH[\zdULh`h|BmCJh|)0J5>*B*CJph+jh|)hb*5B*CJUphh|)5B*CJphjh|)5B*CJUph h|)CJ hCJ h6iCJ h|Cx5CJ h|CxCJ h|BmCJ h|Bmh|Bm0J>*B*CJph̙(jh|BmhfgB*CJUph̙h|Bmh|BmB*CJph̙"jh|Bmh|BmB*CJUph̙'67`abeftx xbSh|Cx0J5>*B*CJph+j2hZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hP8CJ h|Cx6CJ hn8[5CJ h|Cx5CJ h|CxCJh`h|BmCJ h`h|Bm0J>*B*CJph̙(j[hh|BmB*CJUph̙h|BmB*CJph̙"jh`h|BmB*CJUph̙ *+hlntKLMNijknopqr¼{r`VhB*CJph̙"jh`hB*CJUph̙h`hCJhm]0J5>*B*CJph+jhbVhb*5B*CJUphhbV5B*CJphjhm]5B*CJUph hm]CJ h]25CJ hm]5CJ hm]>*CJ h|Cx>*CJ h E>*CJ h E5CJ h ECJ h|CxCJ h|Cx5CJXdC-h1HIgd ^`gd^gd^gdm]^gdm]^gdm]aijdm!"#&')*ٿrcMc+jh hb*5B*CJUphhm]0J5>*B*CJph+jGh hb*5B*CJUphh 5B*CJphjhm]5B*CJUph h]25CJ h8,5CJ hm]CJ hm]5CJh`hCJ h`h0J>*B*CJph̙"jh`hB*CJUph̙(jphhgB*CJUph̙*STUXY[\CLοιοι~iXQMQF hm]>*CJhm] hm]5CJ h`h0J>*B*CJph̙(jhhgB*CJUph̙hB*CJph̙"jh`hB*CJUph̙h`hCJ+jNh hb*5B*CJUph hm]CJhm]0J5>*B*CJphjhm]5B*CJUph+jh hb*5B*CJUphh 5B*CJph,-9  ]^_efg~gTIhhn8[CJaJ$hh0J>*B*CJaJph̙,jhhgB*CJUaJph̙hB*CJaJph̙&jhhB*CJUaJph̙hhCJaJhh5CJaJhh|CxCJaJhh|Cx5CJaJhhm]CJaJ h|)CJ *hm]CJ jhm]CJmHnHu hm]CJ hm]5CJ /0=>HI\]deuRSvwx{|}~žj[U hJxCJh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh|Cx5B* CJph h|CxCJ h|Cx>*CJhh|CxCJ h|Cx5CJ h|Cxhhn8[CJaJhCJaJhh|CxCJaJhh5CJaJhh|Cx5CJaJ I\]de 9:R\gd @ ^@ `gdS^gd ^gd  ^gd @ ^@ `gd=^gd @ ^@ `gd~7:Inq︲rkeZF&jhd=h=B*CJUaJph̙hd=h=CJaJ h=CJ h|Cx>*CJh=h|Cx5B* CJph3h|Cx5B* CJphh|CxB*CJphh=h|Cx5B*CJphh|Cx5B*CJph h|CxCJ hJxCJhJx0J5>*B*CJph+jDhJxhb*5B*CJUphhJx5B*CJphjhJx5B*CJUph=>?PQRWXZ[]^ȵȪzmcYLYLHDh=h|Cxh=h|Cx5B*ph̙h|Cx5B* phh|Cx5B*phh=h|Cx5B* ph3h|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJh=B* CJphhd=h=CJaJ$hd=h=0J>*B*CJaJph̙&jhd=h=B*CJUaJph̙,jh=hfgB*CJUaJph̙h=B*CJaJph̙*+\gmnop|wriWMhBB*aJph̙"jhd=hBB*UaJph̙hd=hBaJ hBh h|Cxhh|Cx5B*hph hn8[CJ h|CxCJh|Cx5B*CJphh|Cx5B* phh|Cxh=B* ph hd=h=0J>*B*aJph̙(jE h=hfgB*UaJph̙h=B*aJph̙"jhd=h=B*UaJph̙hd=h=aJ/012pqrxٿthQt>$hd=hS0J>*B*CJaJph̙,j!hShfgB*CJUaJph̙hSB*CJaJph̙&jhd=hSB*CJUaJph̙hd=hSCJaJ hSCJ h|CxCJ h|Cx5CJh|Cx5B* CJph h|CxhhBB* phhd=hBaJ hd=hB0J>*B*aJph̙"jhd=hBB*UaJph̙(j!hBhfgB*UaJph̙xyz{}ceuwxʫѤљxjRx/j"h hb*5B*CJUaJphh 5B*CJaJph)jhd=h|Cx5B*CJUaJphhd=h|Cx5CJaJhd=h|CxCJaJ h|Cx6CJ hn8[5CJ h|Cx>*CJ hShShS hDECJ h|Cx5CJ h|CxCJhSB* CJphhd=hSCJaJ&jhd=hSB*CJUaJph̙MdeJK-Gj`p & Fgdn`^`gdd=gdd= @ ^@ `gdd=^gdgdSmnoKֽֽˁpXMhd=hDECJaJ/j$hd=h5B*CJUaJph hd=h|Cx5B*CJaJphhd=h|Cx5CJaJ/j$h hb*5B*CJUaJph/jo#h hb*5B*CJUaJphh 5B*CJaJphhd=h|CxCJaJ)jhd=h|Cx5B*CJUaJph'hd=h|Cx0J5>*B*CJaJphK]^ghi ͜ݑ}qZ}G}<hd=h|CxCJaJ$hhd=0J>*B*CJaJph̙,j&hd=hgB*CJUaJph̙hd=B*CJaJph̙&jhhd=B*CJUaJph̙hhd=CJaJhJ90J5>*B*CJph+jl%hJ9hb*5B*CJUphhJ95B*CJphjhJ95B*CJUph hJ9CJhJ9CJaJhd=CJaJhd=h|Cx5CJaJ ,Z\  GPjnps݀͜͜thbV5B*CJph hn8[CJ+j'hhb*5B*CJUphh|Cx0J5>*B*CJph+j&hhb*5B*CJUphh5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx5CJhd=h|CxCJaJhd=h1MCJaJ*(_`opqS]Ľķwi^PPĽĽLh|Cx jh|CxCJmHnHuhnhYCJaJhnh|Cx0J>*CJaJ#j(hnhCJUaJhnh|CxCJaJjhnh|CxCJUaJhnhY5CJhnhn5CJ hYCJ h|Cx5CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+j(hbVhb*5B*CJUph"bS%89`agdd=^gd"gd ^`^gd g^ %(*+>@AWxy̖zog\og\Tg\g\g\g\g\h+ECJaJh+EhYCJaJh"CJaJh+Eh+ECJaJh"h+E5CJaJ h|CxCJhd=h|Cx5CJ$hhd=0J>*B*CJaJph̙,j~)hd=hgB*CJUaJph̙hd=B*CJaJph̙&jhhd=B*CJUaJph̙hhd=CJaJ hd=CJ h|Cx6CJ h|Cx5CJ)9:;<z{|069L[\]^ĸĎvbVhd=B*CJaJph̙&jhhd=B*CJUaJph̙hhd=CJaJ hd=6CJ h|CxCJ$hhk+0J>*B*CJaJph̙,jU*hk+hfgB*CJUaJph̙hk+B*CJaJph̙&jhhk+B*CJUaJph̙hhk+CJaJ hk+6CJ h|Cx6CJ h|Cx5CJ hk+5CJշxi^RG3&jhd=hd=B*CJUaJph̙hd=hd=CJaJhd=h|Cx5CJ aJ hd=h|CxCJaJh|Cx0J5>*B*CJph+j,hhb*5B*CJUphh5B*CJphjh|Cx5B*CJUph h|CxCJ h|Cx6CJhhd=CJaJ$hhd=0J>*B*CJaJph̙&jhhd=B*CJUaJph̙,j,+hd=hgB*CJUaJph̙UVW]^_.3%'.236>?@ȵȪ}smsc\PjhoSCJUaJ ha /5CJhEh|Cx5CJ hECJhEhE5CJ h|Cx>*CJ hDECJ h|Cx5CJ h|CxCJhd=CJaJhd=h|CxCJaJhd=hd=CJaJ$hd=hd=0J>*B*CJaJph̙&jhd=hd=B*CJUaJph̙,j,hd=hgB*CJUaJph̙hd=B*CJaJph̙a*+I% -.%&`gdm]^^ ^` & F^gdd=@ ͺڲ~k\WPEjhEhEU hEhE h|Cx5hsehse0J>*B*ph̙$jH.hsehfgB*Uph̙hseB*ph̙jhsehseB*Uph̙hseh|CxhEhEh5hECJaJh|CxCJaJ$hoSha /0J>*B*CJaJph̙hoSha /0JCJaJjhoSCJUaJ#jq-hoShfgCJUaJhoSCJaJMqrR^gdd= & F`gdd= ^`` & F4gdE^ ,-MNqr    Jxe_Y hd=CJ h|CxCJ$hd=hd=0J>*B*CJaJph̙,j/hd=hgB*CJUaJph̙hd=B*CJaJph̙&jhd=hd=B*CJUaJph̙hd=hd=CJaJ hd=5CJ h|Cx5CJh|CxB* CJphhEhEhE0J>*jhEhEUj/hEh\xU hEhEJKLRSTBCDOPQcdշwn^wRwnnLChch|CxCJ h|CxCJ hr&hd=0J>*CJj1hr&hd=CJUhr&hd=CJjhr&hd=CJU hd=CJhr&hd=5CJhr&h|Cx5CJh|Cx5B* CJph h|Cx5CJ h|CxCJhd=hd=CJaJ$hd=hd=0J>*B*CJaJph̙&jhd=hd=B*CJUaJph̙,j0hd=hd=B*CJUaJph̙ 2349:VWXbcxy»£»sjE4hch|CxCJUj3hch|CxCJUjI3hch|CxCJUhch|Cx0J>*j2hch|CxU hch|Cxjhch|CxUhch|Cx0J>*CJji2hch|CxCJUhch|CxCJjhch|CxCJU&49dx[!6f  O }     ^gdd= & F^gdd=^gdd=^gdd=BCDYZ[\ 67UVWdefgͽ͍ͭ͝}jE7hch|CxCJUj6hch|CxCJUjW6hch|CxCJUj5hch|CxCJUjE5hch|CxCJUhch|CxCJhch|Cx0J>*CJjhch|CxCJUj4hch|CxCJU*    + , - M N O P p q r { | }         ǷͣtpjpjdjdZhY'hY'5CJ hCJ h|CxCJh|Cxj99hZ )hCJUhch|Cx0J>*j8hch|CxU hch|Cxjhch|CxUhv 0J>*CJj#8hv h%&CJU hv CJhch|CxCJhch|Cx0J>*CJjhch|CxCJUj7hch|CxCJU"       #        h   ! " 8  ^`gdY' ^`gdY'^gdY'^gdd= ^`gdd=^gdd=^gd & F " # 7 8 9 : J W X Y Z                 Ʋ|th\Ʋh|Cx5B* CJphhY'5B* CJphh|CxCJaJ$hd=hY'0J>*B*CJaJph̙,j9hY'hY'B*CJUaJph̙hY'B*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hY'5CJhY'hY'CJhY'h|CxCJhY'h|Cx5CJ h|CxCJ hY'CJ       = P Q R S         շu^K?3h|Cx5B* CJphhY'5B* CJph$hY'hY'0J>*B*CJaJph̙,j;hY'hgB*CJUaJph̙hY'B*CJaJph̙&jhY'hY'B*CJUaJph̙hY'hY'CJaJ hY'CJhY'hY'CJh|CxCJaJhd=hY'CJaJ$hd=hY'0J>*B*CJaJph̙&jhd=hY'B*CJUaJph̙,j:hY'hgB*CJUaJph̙             [ \ ] c d e f h m o p          ȴ~tdt[tT h|Cx5CJhY'0J>*CJjR=hZ )hY'CJUjhY'CJU$hd=hY'0J>*B*CJaJph̙,j{<hY'hgB*CJUaJph̙hY'B*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ h|CxCJH* hY'CJ h\ CJ h|CxCJhY'CJaJhY'5B* CJph                   " 9 ? O P i j k u v x y    ]d}~ɗ hY'6CJ h|Cx6CJ hv 5CJ hY'5CJj?h|CxCJUj[?h|CxCJUh|Cxj>h|CxCJU h|Cx5CJ hY'CJh|Cx0J>*CJj>hZ )hCJU h|CxCJjh|CxCJU08 9 x y   ,\]!o?:   & Fngd ^`gdp^pgd^gd^gdgd !"+-0479Co{789<=վu_Ph0J5>*B*CJph+jAhhb*5B*CJUphh5B*CJphjh5B*CJUph hCJ h|Cx5CJ h|CxCJ h|Cx6CJ$hd=hY'0J>*B*CJaJph̙,j=@hVhgB*CJUaJph̙hVB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ=>@S:GW^}  ,.<=>Z[Ĵʫtjh|Cx5B*CJUph hv CJ h|Cx6CJh|Cx hCJhhCJ h5CJh|Cx0J>*CJjAhZ )hCJU hcCJjh|CxCJU hDE5CJ h\ CJ hn8[CJ hDECJ h|Cx5CJ h|CxCJ hCJ, =tLXY+>'  ^`gdp^pgd ^`gd^gdgd@ ^@ gd^gd & Fp^p`gd & F@ ^@ gd & F^`gd[xyz}~  BCDGHOPklmpqοιέοιοιkοιUο+j Ehhb*5B*CJUph+jkDhhb*5B*CJUph+jChhb*5B*CJUph+jChZ )h5B*CJUphh|Cx5B*CJph h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jBhhb*5B*CJUphh5B*CJph!q/013KLUXYkǼ|eRNhV$hd=hV0J>*B*CJaJph̙,jEhVhgB*CJUaJph̙hVB*CJaJph̙&jhd=hVB*CJUaJph̙hd=hVCJaJhV5CJaJhVhV5CJaJhVhVCJaJhVh|CxCJaJhhCJaJ hCJ hn8[CJ h|Cx5CJhh|Cx5CJ h|CxCJklníϞl]R>&jhd=hY'B*CJUaJph̙hd=hY'CJaJh|Cx0J5>*B*CJph+j GhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUphh0J5>*B*CJph+jtFhhb*5B*CJUphh5B*CJphjh5B*CJUph hCJ h]2CJ h|Cx6CJ h|CxCJ h-u5CJ !"()*<='035;<efgstȵȪsasVsh|Cx0J5>*CJ"jHhZ )h5CJUjh|Cx5CJU h|CxCJH*h|Cx hn8[CJ hDECJ h|Cx5CJ h|Cx6CJ h|CxCJhd=hY'CJaJ$hd=hY'0J>*B*CJaJph̙&jhd=hY'B*CJUaJph̙,jGhVhgB*CJUaJph̙hVB*CJaJph̙!t   2GHVWXY~rkdM~,j1JhVhgB*CJUaJph̙ hY'6CJ h|Cx6CJh5B* CJphh|Cx5B* CJph$hd=hY'0J>*B*CJaJph̙,jZIhVhgB*CJUaJph̙hVB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hY'5CJ h|Cx5CJ hDECJ h|CxCJH* h|CxCJ 12D]45[\~;$"~$"$"$" ^`gd & F_gdPU ^`gdp^pgd^gd^gd ^`gdAMuv9:;ABCDNYl{ž󧜈|eR$hd=hY'0J>*B*CJaJph̙,jKhVhgB*CJUaJph̙hVB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hY'6CJ h5CJhVhVCJ hV5CJ h|Cx5CJh|Cxh|Cx0J>*CJjKhZ )hCJUjh|CxCJU h|Cx6CJ h|CxCJ {OS'5RSTU ƺƐypj_hd=ha /CJaJ ha /CJh|Cx0J>*CJjMh|CxCJUjh|CxCJU$hd=hY'0J>*B*CJaJph̙,jLhghgB*CJUaJph̙hgB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hY'5CJ h|Cx6CJ h|Cx5CJ h|CxCJ PQRXYZ\~ $"$"$":$";$"j$"w$"~$"$"$"$"$"$"$"$"$"$"$"쫣~xxtotottjf]hd=hY'aJhY' hY'>* h|Cx5h|Cx hPUCJU h)M6CJh)Mh)MCJ h|CxCJ h)MCJ h|Cx5CJha /CJaJhd=ha /CJaJ$hd=ha /0J>*B*CJaJph̙,jMha /hfgB*CJUaJph̙ha /B*CJaJph̙&jhd=ha /B*CJUaJph̙"n to infection, drugs (usu. started 1-3 wks before onset) common: phenytoin, barbiturates, sulfonamides, penicillins, NSAIDs More severe: Stevens-Johnson syndrome and Toxic epidermal necrolysis EM Minor [HYPERLINK "http://dermis.net/dermisroot/en/30218/diagnose.htm"dermis] acute, self-limited or recurrent / duration: 1-4 weeks from onset to healing / Symmetrically-distributed, fixed lesions lasting > 7 days / discrete, round, erythematous rings or blisters / concentric color changes / target or iris lesions (concentric circles, middle white, outer red) / mucous membrane involvement absent or limited to one surface, usually the mouth / hands [HYPERLINK "pics/erythemamultiforme2.jpg"pic] / feet / arms [HYPERLINK "pics/erythemamultiforme1.jpg"pic] / legs / back [HYPERLINK "pics/erythemamultiforme3.jpg"pic] / palms (back) / soles (top) / extensor Target lesions [HYPERLINK "pics/erythemamultiformetarget1.jpg"pic][HYPERLINK "pics/erythemamultiformetarget2.jpg"pic][HYPERLINK "pics/erythemamultiformetarget3.jpg"pic] ( > 3 rings ( better prognosis?) EM Major abrupt onset, high fever, prostration followed by extensive lesion eruption, widespread bullae [HYPERLINK "pics/emmajor1.jpg"pic] / involvement of two or more mucosal membranes (oral, lips [HYPERLINK "pics/erythemamultiformemajor1.jpg"pic], ocular, nasal, genital, rectal) (severe oral involvement distinguishes from TSST) Stevens Johnson Syndrome (SJS) [HYPERLINK "pics/stevensjohnson.jpg"pic] [HYPERLINK "http://dermis.net/dermisroot/en/30254/diagnose.htm"dermis] 10-15% of epidermis / 5-10% mortality / sulfa drugs, vancomycin, and others / mechanism for dapsone is different Toxic epidermal necrolysis (TEN) [HYPERLINK "pics/ten1.jpg"pic] > 25% of epidermis / 25-50% mortality / treat at burn center / daily opthalmological exams Leukocytoclastic vasculitis purpura (90%), urticaria (10%) / infection, drugs, autoimmune, malignancy / includes  HYPERLINK \l "hsp" Henoch-Schnlein Purpura (children) / complement attracts neutrophils (fibrinoid necrosis of vessels), increases permeability Drug eruptions [HYPERLINK "http://dermis.net/dermisroot/en/13645/diagnose.htm"dermis] Skin changes from cancer chemotherapy dystrophic nail changes, sterile cellulitis, phlebitis, ulceration of pressure areas, urticaria, angioedema, exfoliative dermatitis, flagellate hyperpigmentation from bleomycin [HYPERLINK "pics/drugbleomycin.jpg"pic] Other drug-induced skin changes Argyria from silver [HYPERLINK "pics/argyria.jpg"pic] Hyper-pigmentation from amiodarone [HYPERLINK "pics/drugamiodarone.jpg"pic] Specific Drug Reactions Morbilliform [HYPERLINK "pics/drug-morbilliform.jpg"pic][HYPERLINK "pics/drugmorbilliform.jpg"pic][HYPERLINK "pics/drugmorbilliform2.jpg"pic] 7-10 morbilliform drug reaction skin/drug-morbilliform / skin biopsy differentiates from viral exanthem / eosinophils Urticaria usually itch [HYPERLINK "pics/drug-urticaria1.jpg"pic][HYPERLINK "pics/drug-urticaria2.jpg"pic] symptoms that may indicate more serious drug reaction: duration, fever, itching, affected areas, sore throat (SJS), red eyes, painful skin Treatment: topical steroids? / antihistamines? Lichenoid [HYPERLINK "pics/lichenoid.jpg"pic] Drugs: gold, tetracyclines, bromides work them up for HCV Pustular [HYPERLINK "pics/drugpustular.jpg"pic] Drugs: Dilantin, penicillin, tetracyclines, lithium, imipenem, antimalarials, norfloxacin Specific Drugs  HYPERLINK "pharm.doc" \l "phenytoin" Phenytoin (10%) [HYPERLINK "pics/drug-dilantin2.jpg"pic] occurs within 3 wks / generalized eruptions, patient feels sick / missing epoxide hydrolase? Dilantin hypersensitivity [HYPERLINK "pics/drug-dilantin1.jpg"pic] / more likely with high loading dose Common: fever, periorbital facial edema, lymphadenopathy Complications: hepatitis, nephritis, pneumonitis Labs: elevated WBCs, LFTs  HYPERLINK "pharm.doc" \l "tegretol" Carbamazepine (5%) exfoliative dermatitis, eczema, photosensitivity or even a lupus like syndrome, even TEN  HYPERLINK "pharm.doc" \l "lamictal" Lamotrigine (Lamictal) (20%) [HYPERLINK "pics/drug-lamictal1.jpg"pic][HYPERLINK "pics/drug-lamictal2.jpg"pic] fever (100%), eosinophilia (20%),  HYPERLINK \l "dic" DIC (10%), LAD (12%), liver > renal > musculoskeletal rash: exanthomatous (75%), more severe (20%), SJS (5%), TEN (10%) (higher risk with combined use of Lamictal and VPA)  HYPERLINK "pharm.doc" \l "warfarin" Warfarin - coumadin necrosis 0.7% of coumadin users / women > men / 3-5 days onset / most frequently affects fatty areas (single/multiple thighs, breasts, buttocks, shoulders) / localized pain then erythema, bullae [HYPERLINK "pics/drugwarfarin1.jpg"pic], necrosis [HYPERLINK "pics/drugwarfarin2.jpg"pic] / happens in patients with protein C deficiency (< 50% normal levels) as vitamin K block lowers PrC levels before other clotting factors / fibrin thrombi in venules / can this mimic classic SC fat necrosis? NSAIDS can cause the whole gambit / even TEN Tetracyclines not that common, but do happen / urticaria, morbilliform, photosensitivity, onycholysis, fixed drug reaction, lichenoid / minocycline is an exception for causing skin pigmentation changes (common) and serum sickness (~ day 16), hypersensitivity syndrome of hepatitis, pneumonitis, cellulitis, folliculitis et al (~ day 24), drug-induced lupus (2 yrs) Congenital Disorders (Skin Involvement)  HYPERLINK \l "ehlers" Ehlers-Danlos syndrome /  HYPERLINK \l "nf1" NF1 /  HYPERLINK \l "ts" Tuberous Sclerosis /  HYPERLINK \l "sturge" Sturge-Weber /  HYPERLINK \l "ktw" KTW Ehlers-Danlos syndrome [HYPERLINK "http://dermis.net/dermisroot/en/39866/diagnose.htm"dermis] 10 types of faulty collagen synthesis / stretchy skin with poor wound healing, hypermobile joints AD (type IV) - ecchymoses, arterial rupture (acute aortic insufficiency) AR (type VI) - retinal detachment, corneal rupture) XLR (type IX) / (type 1) - diaphragmatic hernia Neurofibromatosis (NF 1 and NF2) [HYPERLINK "http://dermis.net/dermisroot/en/23420/diagnose.htm"dermis] 1 in 3000/4000 (NF 2 is 1 in 50,000), AD, 50% of cases are new mutations, variable expression, paternal age effect Must meet 2 of diagnostic criteria: caf au lait, Crowes sign, more Skin hyperpigmentation or  HYPERLINK \l "cafe" caf au lait spots (97%) (more than 6 big ones, shape is variable), freckling (81%) (Crowes sign) in axillary areas?, which is pathognomonic [ HYPERLINK "pics/neurofibromatosis.jpg" pic] CNS  HYPERLINK \l "neurofibroma" neurofibromas, plexiform neurofibromas (more aggressive invasion, rare), CNS tumors (5-10%), optic gliomas, astrocytomas, acoustic neuromas (classic NF-2 tumor), neurilemmomas, meningiomas, neurofibromas, intracranial tumors usually detected in first decade Opthalmological Lisch nodules (30%) (balls of tissue on iris that do not impair vision, get a consult) Skeletal pseudoarthroses (bones look bent, osteopenia on XR, common in tibia, use brace to give support), kyphoscoliosis, macrocephaly of post-natal onset (soft signs, absolute or relatively large, not correlated with other features of disease) GI constipation Renal hypertension (should have BP checks, usually occurs in adulthood) Associated malignancies: neurofibromasarcomas, malignant peripheral nerve sheath tumors, schwannomas (more NF II), Wilms tumor, rhabdomyosarcoma, leukemia, pheochromocytoma Genetics: defective chromosome 17, diagnostic testing usually not necessary Tuberous Sclerosis Complex (see NF) 1:9000, autosomal dominant, high spontaneous mutation rate, variable expression skin, brain, retina, heart, kidneys Prognosis: only small percentage have premature death (often from CNS features, renal failure) Diagnosis: major/minor criteria Genetics: chromosome 16 (next to APK gene) / TSC1 on 9q34 Skin facial angiofibromas (can look like acne), hypomelanotic macules, ungal fibromas, (can be removed, usually grow back), shagreen patch (peau dorange, pigs skin), fibrous plaques, dental pitting (5-10%) CNS seizures, retardation, brain tumors (astrocytoma et al) Opthalmological pigmentary changes, hamartomas (may be associated with peculiar SZs) Renal angiomyolipomas (renal failure, prognostic factors unknown), cysts similar to APK? Cardiac rhabdomyomas (regress with time unique) Pulmonary lymphangiomyomatosis (seen almost exclusively in women) Other hamartomas Sturge Weber syndrome [HYPERLINK "http://dermis.net/dermisroot/en/42574/diagnose.htm"dermis] Rare, sporadic, defect arising in limited part of cephalic neural crest Skin ipsilateral facial angiomatous nevus (laser therapy, begin as early as possible on infant) CNS telangiectatic venous angioma of the leptomeninges overlying the occipital, parietooccipital regions or entire cerebrum, more? / CT > age 2 yrs may reveal gyriform intracranial calcification in parietooccipital region / association with pheochromocytoma Opthalmological choroidal angioma, glaucoma Presentation: may cause contralateral hemiparesis/hemisensory loss Treatment: control seizures or surgical removal Klippel-Trenaunay-Weber [HYPERLINK "http://dermis.net/dermisroot/en/42531/diagnose.htm"dermis] Rare, sporadic, can effect any part of body Skin hemangiomatous nevi (may fade with time), localized overgrowth phenomenon may spread with time (require resection, amputation of extremity), more- CNS ? Opthalmological ? Skeletal bone hypertrophy Vascular - ? cavernous . deeper, larger vessels Skin Ulceration Ulcers of Legs and Feet Arterial insufficiency ( HYPERLINK \l "pvd" see PVD) toes, heels, anterior shin and extended over malleoli Venous insufficiency above lateral or medial malleoli Lymphedema Neuropathic ulcers under metatarsal head, over toe joints, under heel, on inner side of first metatarsal head, over malleoli Thromboangiitis obliterans Cholesterol embolization Antiphospholipid antibody syndrome Vasculitis (cryoglobulinemia, Wegeners, RA) DIC HIT Warfarin skin necrosis Osteomyelitis Necrotizing fasciitis (Clostridium, Group A Strep, Vibrio) Tb Fungus (cryptococcus, coccidioides) Hematological disorders PRV Essential thrombocythemia Hydroxyurea Necrobiosis lipoidica diabeticorum pretibial area Pyoderma gangrenosum Sweets syndrome Erythema nodosum Weber-Christian disease Cancer (squamous cell carcinoma)  HYPERLINK \l "calciphylaxis" Calciphylaxis Environmental Pathology / Toxicology Metals and Inorganic Ingestibles Aluminum (Al3+) Chronic hemodialysis patients get too much / acute toxicity: obtundation, coma, seizures / Treatment: deferoxamine (carries risk of mucormycosis?) Lead (Pb) binds to disulfide group of proteins Exposure: ceramics, demolition, plumbing, soldering, exposure to leaded fuels Acute intoxication: pallor, abdominal pain (lead colic), lethargy, convulsions, coma, renal failure, cerebral edema Chronic intoxication (anemia, neuropathy, hypertension): CNS impairment (ataxia, memory loss), demyelination (foot and wrist drop), SZ, coma, pyuria,  HYPERLINK \l "fanconis" Fanconis syndrome, azotemia, chronic interstitial nephritis leading to uricemia, lead lines may be seen at gingiva-tooth border Labs: Pb > 10,80 ug/dl (children, adults), free protoporphyrin > 35,50 ug/dl (blocks Hb synthesis via inhibition of ferrochetalase and ALA dehydrase, [HYPERLINK "pics/lir-porphyria.jpg"see diagram]) Micro: microcytic anemia (binds Hb causing hemolysis), basophilic stippling, deposits in epiphyses of growing bones Route of entry: inhalation, ingestion (PICA) Metabolism: stored in bone (80%), blood (10%), soft tissues, kidney, brain / excreted in feces 90%), urine (10%) Treatment: EDTA, dimercaprol, D-penicillamine, succimer (children, oral, side effects: GI/rash) Arsenic (As) binds SH groups (As3+), uncouples oxidative phosphorylation (AsO4 substitutes for PO4i), As5+ reduced by glutathione in liver (low levels) Sources: insecticides, herbicides, wood preserving, smelting, glass manufacturing, microelectronics, contamination of deep water wells, folk remedies) acute ingestion: GI necrosis (hypovolemia), fatty change in liver, renal failure, burning, NVD, cyanosis, HT, DT, hemolysis, eosinophilia, ATN, garlic breath, cardiomyopathy (cardiac arrhythmias) chronic ingestion: 2-8 wks, erythroderma [HYPERLINK "pics/chronicerythroderma.jpg"pic], hyperkeratosis, hyperpigmentation, exfoliative dermatitis, laryngitis/tracheitis/bronchitis, Aldrich-Mees lines (white transverse lines of fingernails) [HYPERLINK "pics/aldrichmeeslines.jpg"pic], polyneuritis, predispose for SCC arsine gas (fatal): hemolysis (binds Hb), abdominal pain, hematuria, jaundice, NVD, tachycardia, dyspnea, acute renal failure (from excessive hemolysis) / development Diagnosis: radiopaque abdomen on XR, elevated levels in hair/ nails, 24 hour urine sample / absorption of inorganic > organic / liver, kidney, spleen by 24 hrs / skin, hair, bones by 2 wks / crosses placenta, not BBB / renal excretion (90%) Treatment: emesis (ipecac) / gastric lavage (charcoal) / dimercaprol, D-penicillamine (chronic), succimer Nitrites Cause  HYPERLINK \l "methemoglobinemia" methemoglobinemia / including nitroglycerin, amyl nitrate / can occur in well water / venous blood drawn will be brown and not turn bright red when shaken in air Treatment: methylene blue, helps reduce methemoglobin to hemoglobin preventing methemoglobinemia Mercury (Hg) usu. presents with variable CNS effects elemental, salts (topicals, plastics, cathartics), organic (paints, fungicides, seeds, cosmetics) vapor: interstitial pneumonitis / tremor, amnesia, insomnia, anorexia, weight-loss (hydrophobic: brain and placenta, but quickly oxidized and long-lived in these tissues) mercury triad: excitability, tremors, gingivitis inorganic acute: ATN, GI necrosis (ingestion, low absorption) inorganic chronic: nephrotic syndrome (readily absorbed by skin/GI and stored in most tissues) organic: requires metabolism and mixed excretion (binds cysteine, mimics methionine, actively shuttled across BBB and placenta causing severe CNS toxicity) Treatment: emesis/lavage, dimercaprol, D-penicillamine (oral, leukopenia causes stomatitis/gingivitis) Note: organic Hg is NOT chelated (makes it worse), but you can use polythiol resin in GI / hemodialysis is not effective since most of Hg inside RBCs Cadmium mining, shellfish, cigarettes / absorbed by lungs (chemical pneumonitis), GI (nausea and vomiting), yellow teeth cadmium-metalothionin complex gets concentrated in lungs (emphysema) and kidneys (renal tubules) Treatment: ?EDTA (do NOT use dimercaprol) Iron (see  HYPERLINK \l "ida" Iron Deficiency Anemia) children overdosing on someone elses Fe supplements / Fe disrupts mucosal cells, penetrates freely (not coupled to Tf) Presentation: Stage I: gastroenteritis (abdominal pain, vomiting, bloody diarrhea), CNS (coma, seizures) Stage II: up to 48 hrs of quiescence Stage III: shock, acidosis, coma, death (may have hepatic damage), leukocytosis common Stage IV (late sequelae): pyloric and antral stenosis and hepatic cirrhosis, atrophy of tongue papilla (also occurs with vitamin B deficiency) Treatment: lavage, carbonate salts (fecal excretion), phlebotomy / deferoxamine (Desferal) has high affinity for Fe (does not remove protein bound Fe, may cause local reaction at injection site, not for chronic use) Fe ingestion over 25 mg/kg is toxic / 300-500 mg/dL use chelating agent / > 500 high risk of shock Organochlorides (DDT, etc.) prolongs falling phase, neuronal hypersensitivity / tremors, SZ, respiratory depression / increased p450, infertility / cholestyramine, BZs for SZ Organophosphates (irreversible) irreversibly phosphorylates AChE / muscarinic, nicotinic, CNS Treatment: decontamination (remove clothes, etc.) anticholinergics (atropine) anticonvulsants (only benzodiazepines are effective; not other types of SZ meds; may have to give large doses, ~ 40mg) 2-pralidoxime (2-PAM) (effective early, does NOT cross BBB, not effective for carbamates determine dose by pseudocholinesterase activity) / TOCP causes MS-like demyelination Note: some nerve agents create aged complexes which are refractory to oxime treatment Organocarbamates (reversible, mild Sx) CCl4 free radical (lipid peroxidation) / liver, CNS, renal failure benzene linked to acute leukemia, CNS toxicity hexane peripheral neuropathy Alcohols Ethanol (ETOH) CNS depression, hypoglycemia, vasodilation (CNS depresses peripheral vasculature) chronic: cirrhosis / FAS intoxication or inebriation, 100-150 mg/dL loss of muscle coordination, 150-200 mg/dL decreased level of consciousness, 200-300 mg/dL death, 300-500 mg/dL Methanol (MeOH) Mechanism: alcohol dehydrogenase (ADH) metabolizes MeOH to formic acid (acidosis) and formaldehyde (retinal ganglion cell blindness, bilateral putamen and claustrum necrosis) at 1/7 th rate of EtOH Treatment: hemodialysis if early, ethanol competes for ADH, increased excretion of MeOH, but the latest treatment is fomepizole (inhibitor of ADH) which acts in similar mechanism as ETOH but less toxic, more controlled Prognosis: 1/3 recover, 1/3 severe blindness, 1/3 die Isopropanol worse than ethanol, not as bad as methanol / slower oxidation, longer CNS effects Ethylene glycol CNS depression (EG), renal failure (oxalate stones), metabolic acidosis (oxalate/formate), hypocalcemia Treatment: hemodialysis, ethanol, bicarbonate, Ca supplement (oxalate chelates Ca) Other chemicals Chlorinated aromatic compounds (TCDD agent orange, PCB) induces p450 and others by signal transduction pathways / acute: N&V, HA, irritation, burns causes chloracne / chronic symptoms: elevated porphyrin excretion, hyperpigmentation, CNS, PNS, liver, teratogen/carcinogen? Inhalants can cause fatal arrhythmias when combined with catecholamines (such as with exercise after inhalant use) Bioterrorism (HYPERLINK "http://www.acponline.org/bioterro/"acp resources) Anthrax ( HYPERLINK "micro.doc" \l "anthrax" see micro) Smallpox (HYPERLINK "micro.doc" \l "smallpox"see micro) Yersinia pestis Tularemia  HYPERLINK "micro.doc" \l "hemorrhagicfevers" Level IV Viruses ( HYPERLINK "micro.doc" \l "lassa" Lassa, Rift,  HYPERLINK "micro.doc" \l "ebola" Ebola, Yellow fever) Radioactivity ( HYPERLINK "more/acuteradiationsyndrome.pdf" pdf) acute radiation sickness prodrome: hours to days / nausea, vomiting, diarrhea latent phase: 2 to 6 wks with dose-dependent and variable effects / bone marrow suppression (at 2-3 weeks), GI (malabsorption), SZ, death Nerve Gases ( HYPERLINK "http://www.acponline.org/bioterro/nerve_gas.htm" acp) ( HYPERLINK "http://pier.acponline.org/physicians/public/d890/d890.html" pier) Vapor, early symptoms ( eyes, rhinorrhea, salivation, lacrimation Later symptoms ( nausea, vomiting, diarrhea, muscle fasciculations, central apnea, status epilepticus Treatment:  HYPERLINK \l "organophosphates" see organophosphates Sarin (tabun, soman, cyclosarin) organophosphates / onset within minutes to hours VX more stable, can last in environment longer than others, symptoms can occur long after exposure Mustard Gas (sulfur mustard) onset 2 hrs to 2 days / skin (erythema), eyes (conjunctivitis, blepharospasm, pain, corneal damage), airway obstruction / late bone marrow suppression (7-21 days) / no antidote / Treatment is supportive Cyanide colorless, smell of almonds / eye irritation, flushed skin, confusion, tachypnea, tachycardia, ARDS, hypoxemia, lactic acidosis / Treatment: sodium nitrate, sodium thiosulfate Drugs of Abuse ( HYPERLINK "pharm.doc" \l "drugsofabuse" see pharm) Nutritional Pathology / Vitamins Water soluble  HYPERLINK \l "thiamine" B1 (thiamine) /  HYPERLINK \l "riboflavin" B2 (riboflavin) /  HYPERLINK \l "niacin" B5 (niacin) / HYPERLINK \l "_pyridoxine"B6 (pyridoxine) /  HYPERLINK \l "b12" B12 /  HYPERLINK \l "folate" folate /  HYPERLINK \l "vitaminc" vitamin C Fat soluble  HYPERLINK \l "vitamina" A /  HYPERLINK \l "vitamind" D /  HYPERLINK \l "vitamine" E /  HYPERLINK \l "vitamink" K Kwashiorkor lack of protein despite sufficient caloric intake / apathy, edema, subcutaneous fat, enlarged fatty liver, low serum albumin / sometimes pigment changes (flaky-paint sign) / anemia due to decreased iron, protein, transferrin Marasmus starvation (lack of caloric intake) / alert and hungry (unlike Kwashiorkor) / stunted growth, loss of subcutaneous fat, muscle atrophy / no edema or liver enlargement Malnutrition unintentional weight loss > 10% body weight in < 3 months body weight < 90% ideal for height (< 80% malnourished, < 70% severely malnourished, < 60% incompatible with life) BMI < 18.5 Thiamine (B1) precursor of TPP, a cofactor of pyruvate dehydrogenase (alpha-ketoglutarate), transketolase (hexose and pentose phosphate shunt pathways) Sources: yeast, pork, beef, legumes, whole grains, nuts Note: coffee/tea reduces levels (by destroying enzyme) Dosing: can be given IM or IV / always give thiamine to alcoholic before sugar to prevent acute  HYPERLINK \l "Wernickes" Wernickes (from carbohydrate load) Dry Beri-beri (peripheral neuropathy, Wernicke-Korsakoff) Wet Beri-beri (peripheral arteriolar dilatation, high output heart failure) occurs e" 3 months of thiamine deficiency Treatment: thiamine Ddx (for high-output heart failure):  HYPERLINK \l "Pagets" Paget s, hyperthyroid, AVM, anemia, pregnancy Riboflavin (B2) malnutrition, alcoholism / FMN, FAD precursors / dermatitis, neuritis (carpal-tunnel, spinal cord pain, joint pain), mucous membrane Dosing: oral replacement biotin, pantothenic acid necessary choline, carnitine undetermined Niacin (B5) severe malnutrition, alcoholism / NAD, NADPH precursors Deficiency: pellagra [HYPERLINK "pics/pellagra.jpg"pic][HYPERLINK "pics/pellagra-hands.jpg"pic] (dermatitis, dementia, diarrhea), photosensitivity oral replacement / corn-based diets are low in niacin, tryptophan / high dose treats hyperlipidemias ( HYPERLINK "pharm.doc" \l "niacin" see pharm) / Symptoms: pruritis, flushing, HA Hartnups disease [ HYPERLINK "pics/hartnups.jpg" pic] defect in GI uptake of neutral amino acids, increased renal tubular loss / (tryptophan is a precursor which can be converted to niacin, corn is low in tryptophan) / causes attacks of cerebellar ataxia, which resolve spontaneously / Treatment: can be reversed by nicotinic acid Pyridoxine (B6) converted to cofactor in amino acid metabolism (including homocysteine to cysthionine) / increases peripheral DOPA decarboxylase (so contraindicated for Parkinsons) / found in  HYPERLINK "http://en.wikipedia.org/wiki/Legume" legumes, nuts, wheat bran, meat Decreased by: malnutrition, INH, L-Dopa, penicillamine, ethanol Deficiency: dermatitis, glossitis, stomatitis, cheilosis, neuritis, carpal tunnel, microcytic/hypochromic anemia Excess: large amounts over time can cause neuropathy Cyanocobalamin (B12) Physiology: acid pH in stomach cleaves B12 from binding protein, intrinsic factor (IF) binds B12 which is then absorbed by ileum and distributed to liver et al via transcobalamin / B12 necessary for conversion of methylmalonyl-CoA to succinyl-CoA Diagnosis: can check serum B12 levels, serum methylmalonyl-CoA levels may be ! in cases with equivocal or normal B12 levels Deficiency: (note: normal diet can produce enough B12 stores for 10 years!) folate trapping ( hyperhomocysteinemia  HYPERLINK \l "megaloblasticanemia" megaloblastic anemia (most commonly macrocytic anemia but can cause pancytopenia) CNS myelin problems (malonyl CoA carboxylation) ( progressive dementia subacute combined degeneration ( ataxia, spasticity, loss of proprioception degeneration of the corticospinal tracts ( (+) Babinski, weakness degeneration of large sensory fibers ( paresthesia, hyporeflexia, absent joint position, vibratory sensation, sensory ataxia diarrhea Replacement: must make diagnosis and replace immediately to prevent permanent neurological damage / SC or IM (PO is usually useless) Folic acid (Folate) deficiency from enterohepatic recycling disease, duodenal/jejunal disease (sprue), surgery, 1st trimester syndrome Deficiency: megaloblastic anemia, neural tube defects (1st trimester deficiency), ischemic heart disease (via homocysteinemia as folate is required for conversion of homocysteine to methionine) Replacement: PO or IM for alcoholics (do not let folate therapy mask B12 anemia) / found in cows milk and breast milk (not in goats milk), green leafy vegetables Pregnancy: DM and VPA therapy necessitates an increase of 4 mg/day folate to prevent neural tube defects Vitamin C (ascorbic acid) hydroxylation reactions (collagen crosslinking) / facilitates Fe absorption in GI tract / anti-oxidant immune function (wound healing, infection) / neurotransmitter synthesis / scurvy (skeletal changes, hemorrhages; perifollicular papules, capillary fragility) Replacement: oral replacement / high doses give false positive urine glucose, false negative guaiac / megadose gives diarrhea, renal damage (oxalate stones), can precipitate hemolysis in G6PD patients Vitamin A (retinoids) stored in liver / retinol binding protein / eye: 11-cis-retinal plus opsin gives rhodopsin / tissue: retinoic acid (hormone-like action) induces cell growth and differentiation (morphogenesis, epithelial regeneration) Deficiency: night blindness, xeropthalmia (Bitots spots), GI/respiratory barrier disruption Used for treatment of  HYPERLINK \l "psoriasis" psoriasis (topical, systemic),  HYPERLINK \l "acne" acne (topical RA and oral  HYPERLINK "pharm.doc" \l "accutane" accutane), keratinization disorders, photoaging,  HYPERLINK \l "leukemia" acute promyelocytic leukemia, head and neck CA chemoprevention / B-carotene (anti-oxidant) may decrease risk of lung cancer Excess: Acute: neurological (increased ICP, vertigo, diplopia, seizures), exfoliative dermatitis Chronic (>15mg/d for months): lymphadenopathy,  HYPERLINK \l "pseudotumor" pseudotumor cerebri, hepatic fibrosis, hepatic fibrosis bone demineralization (hyperostosis, spurs, fusion) Teratogenic (congenital malformations, spontaneous abortions) Vitamin D ( HYPERLINK \l "vitamind" see parathyroid) Vitamin E anti-oxidant (A,C,E) / reduces cholesterol oxidation, decreases atherosclerosis / deficiency causes spinocerebellar degeneration, skeletal muscle changes,  HYPERLINK \l "hemolyticanemia" hemolytic anemia in infants Vitamin K (phytonadione) carboxylation of prothrombin (II)-complex proteins, VII, IX, X / made by GI flora Deficiency: malabsorption (including antibiotic-induced deficiency, biliary insufficiency), poor dietary intake, liver disease / transient deficiency of newborn (pre-colonization) increased PT first, then aPTT will also go up later / IM therapy, prophylaxis for newborns Treatment: can give SC or PO (can give IV but some people think there is increased risk of anaphylaxis; some studies say no) / effect is delayed (so if trying to correct asymptomatic mildly elevated INR, be careful not to give too much) Deficiencies with Short Bowel Syndrome Essential fatty acids Eczemoid dermatitis, INCLUDEPICTURE "http://home.mdconsult.com/images/isochar/uarr.gif" \* MERGEFORMATINET 20:3/20:4 fatty acid ratio in serum Vitamin A night blindness, impaired dark field adaptation Vitamin E in vitro platelet hyperaggregation and H2 O2 -induced red blood cell hemolysis; signs and symptoms suggestive of subacute combined degeneration (posterolateral columns) in the presence of a normal serum B12 level Biotin scaly dermatitis, alopecia [ HYPERLINK "http://dermis.net/dermisroot/en/34987/diagnose.htm" dermis] Thiamine Wernickes syndrome (encephalopathy, orthostatic hypotension), refractory lactic acidosis, cardiac failure (different?) Cobalamin (B12 ) weakness, paresthesia, diarrhea, dementia, megaloblastic anemia, subacute combined degeneration Zinc nasolabial and perineal acrodermatitis, alopecia, decreased T cell function, decreased alkaline phosphatase, dysgeusia Excess: nausea, vomiting, fever / chronic (immune dysfunction and hypochromic anemia from secondary copper deficiency) Chromium glucose intolerance, peripheral neuropathy Copper neutropenia, anemia, scorbutic bone lesions,  INCLUDEPICTURE "http://home.mdconsult.com/images/isochar/darr.gif" \* MERGEFORMATINET ceruloplasmin, kinky hair, impaired central nervous system development Excess: hepatic toxicity and chronic (same as  HYPERLINK \l "Wilsons" Wilsons disease) Selenium myalgias, cardiomyopathy,  INCLUDEPICTURE "http://home.mdconsult.com/images/isochar/darr.gif" \* MERGEFORMATINET glutathione peroxidase and serum selenium Molybdenum tachycardia, tachypnea, central scotomas, irritability,  INCLUDEPICTURE "http://home.mdconsult.com/images/isochar/darr.gif" \* MERGEFORMATINET uric acid Surgery Pre-op evaluation  HYPERLINK \l "trauma" Trauma/Burns  HYPERLINK \l "transplant" Organ Transplantation Cardiac Pre-Op Evaluation/Clearance [ HYPERLINK "pics/cardiacpreop-acp1.jpg" ACP guidelines 1] [ HYPERLINK "pics/cardiacpreop-acp2.jpg" ACP guidelines 2] General Pre-Operative Cardiovascular use of perioperative B-blockers recommended for patients with CV risk factors or known disease; however, its use is probably not as helpful in low-risk patients / risk of postoperative cardiovascular complications does not appear influenced by stable HTN, elevated cholesterol, obesity, cigarette smoking or BBB Post-Operative Fever atalectesis occurs early low temp wound infection (Abx, drainage) early: Streptococcus (common), Clostridium (uncommon) late: staphylococcus / includes IV site infections Note: 85% of postoperative S. epidermidis or MRSE (so vancomycin) intra-abdominal sepsis/abscess 5-7 days (get CT abdomen) Pre-Operative DVT prophylaxis 1/07 current recommendation is to stop Lovenox either night before surgery (12 hrs or some now are saying full 24 hrs before to allow anticoagulation effect to fully wear off) DVT prophylaxis (in general) reduces risk of DVT by 50% and PE 60% relative risk increase of severe bleeding episodes 1.3 Post-Operative DVT prophylaxis many types of surgery requires DVT post-op prophylaxis Current recommendation for elective surgery for abdominal cancer is 4 weeks Lovenox Preoperative Endocarditis Prophylaxis ( HYPERLINK \l "endocarditisprophylaxis" see other) Fluids Note: can get tachycardia with volume overload as well as volume depletion Note: FFP and PRBCs stay in blood compartment thus, can have more lasting effects on fragile heart or lungs Orthostatics: increase of > 15 HR or > 15 mm Hg (less if diastolic BP) Other Air in body cavity (iatrogenically caused) Prevertebral emphysema [ HYPERLINK "pics/prevertebralemphysema.jpg" pic] Trauma/Burns Trauma Airway Breathing Circulation IV access: 2 large-bore (Q = l/r4 / volume status: check urine output O2: give oxygen to increase O2 sat and dissolved O2 Plain Films: chest (1st), cervical, pelvis Labs: CBC, H/H, UA, drug screen, amylase? must keep spine immobilized (can r/o cervical spine trauma in awake/alert patient) thoracic spine / cord transection / rectal exam (feel for prostate/rectal tone) Causes of internal hemorrhage spleen (1st), liver, kidney, mesentery, pancreas, Jejunum more likely to rupture bladder (then spleen, liver) most commonly injured intra-abdominal organ from blunt trauma diagnostic peritoneal lavage (DPL) decompress stomach and bladder open laparotomy if high RBC (over 10,000) r/o with CT abdomen triple contrast (oral, rectal, IV) to r/o ureteral injury, colon if high-prostrate or frank blood in urine ( dont put a Foley / get retrograde urethrogram Chest Trauma In-depth exam / upright CXR (if possible) / ABG, pulse oximetry / ECG Blunt cardiac injury Myocardial contusion (10% with shock or arrhythmias) Widened mediastinum (10% with aortic rupture) Pulmonary contusion Within 12 hrs of injury worsens for 48 hrs then gets better or progresses to ARDS Tip: r/o esophageal rupture with barium contrast when suspecting oral-pleural communication because water-soluble contrast creates an ARDS-like picture Eye Trauma 1 million cases/yr / get optho consult within 24 hrs with acid/base burns, decreased visual acuity, severe conjunctival swelling, corneal clouding Foreign body (25% of eye trauma) ( consult with any intraocular foreign body (even without physical exam findings) / Woods lamp (fluorescein dye given now and serially every day) / antibiotics Fe, steel, Cu ( inflammatory reaction Glass, lead, stone ( decreased inflammatory reaction Vegetable ( purulent endopthalmitis DO NOT examine a ruptured globe / patch and refer to optho STAT eyelid laceration can be repaired after ruling out lid margin and lacrimal apparatus involvement Burns Rule of 9s / palm = 1% Get CO-Hgb levels Fluids: 2-4 ml/kg per % of involved surface area give of total in first 8 hrs, next in next 16 hrs (based from time of injury) Lacerations Basic laceration repair [HYPERLINK "procedurevids/"video] Arterial Lines Placement of arterial lines [HYPERLINK "procedurevids/"video] Organ Transplantation  HYPERLINK \l "livertransplant" Liver  HYPERLINK \l "lungtransplant" Lung  HYPERLINK \l "renaltransplant" Renal  HYPERLINK \l "hearttransplant" Heart Bone Marrow (see below) Types of Immunosuppressants OKT3 (antibodies) decreases T-cell numbers ALG (antibodies?) decreases T-cell numbers Steroids moves lymphocytes into RES and decreases Il-2 production Radiation Azathioprine (Immuran) decreases DNA synthesis Cyclosporine (Sandimmune) blocks IL-2 / decreases T-cell numbers Types of Rejection Hyperacute rejection (mins to hours) vasculitis, thrombosis, necrosis antibodies to MHC, ABO blood groups Acute rejection (months) Repeated attacks Chronic rejection Eventual fibrosis Problems Neutropenia (common) Cystitis (with Cytoxan) Oral mucositis, alopecia (common) Venoocclusive disease of liver (from hypercoagulable state; peak incidence ~day 16) Bone marrow transplantation (BMT) used for AML and others / immunosuppressive agents then used to prevent graft versus host disease ( HYPERLINK \l "gvhd" GVHD) of skin, liver, GI tract, eye, ~kidney / timeline of pulmonary complications after BMT [HYPERLINK "pics/bmt-complications.gif"diagram] / syngeneic (identical twins) are less likely to cause GVHD than allogeneic transplants (however they are also less likely to cure malignancy because of lack of tumor-versus-host effect) Problems Gonadal dysfunction: both men and women Total body irradiation: cataract formation, thyroid dysfunction Cognitive dysfunction: reasons not entirely clear Neutropenic Fever Neutropenia: neutrophil count < 500 cells/mm3 or < 1000 cells/mm3 with predicted decrease to < 500 cells/mm3 Fever: single oral e" 38.3 C (101 F) or e" 38.0 (100.4 F) for e" 1 hour Nadir of WBCs 10-14 days after chemotherapy / risk of infection increases with duration/severity of neutropenia (>7-10 days) 5-10% of cancer patients die from neutropenia-associated infections elderly and immunosuppressed may not mount febrile response: cellulitis may not be obvious, pneumonia without infiltrate on CXR, meningitis without typical CSF findings, UTI without pyuria, etc. necrotizing enterocolitis (typhlitis): cecum > large bowel/ileum / may result in bowel perforation or infarction Treatment: remove (non-tunneled) lines/catheters; talk to ID about more permanent/tunneled lines in case there is a need to attempt to treat through it)  HYPERLINK "micro.doc" \l "staph" S. aureus and  HYPERLINK "micro.doc" \l "staphepidermidis" S. epidermidis (coagulase negative) are most common (more likely to be able to treat through line infection with coagulase negative Staph; most other organisms (fungus, gram negative, etc.) or if patient is septic/hemodynamically compromised, line will almost certainly require removal  HYPERLINK "pharm.doc" \l "zosyn" pip/tazo or  HYPERLINK "pharm.doc" \l "cefepime" cefepime consider adding cipro or tobramycin for double coverage of Pseudomonas (e.g. if pneumonia suspected) add vancomycin if suspect gram positive or (+) lines if PCN allergic ( tobra/cipro/metro if fever persists 3-5 days, can add  HYPERLINK "pharm.doc" \l "amphob" amphotericin B and/or vancomycin empirically  HYPERLINK "pharm.doc" \l "gcsf" G-CSF or GM-CSF can be used to decrease neutropenia if pt has history of febrile neutropenia with previous round of chemotherapy if pt has 40% of becoming neutropenic give before pt becomes neutropenic (takes 3-5 days to start working) GCSF has been shown to reduces hospitalization and duration of neutropenia following chemotherapy (no overall change in mortality demonstrated as of time of this notation 8/04) Note: use of G-CSF once patient already neutropenic controversial 8/04 HYPERLINK "pharm.doc" \l "epo"Erythropoietin can be used to increase red blood cell count but it takes weeks to work, and will probably not work if patients own erythropoietin levels already > 100 mU/mL Emergency Medicine (not in other places) Frostbite Rapid rewarming in bath 37-40 / give analgesics / can lower temperature if too painful No medications proven to improve outcome as of 1/07 Usu. best to defer decision about amputation until viable tissue margins become demarcated Long term complica$"$"%"%"%"%"%"%"%"%"%"%"%"%"%"%"6&"8&"&"&"&"&"&"&"&"&"&"&"&"&"yeXyh|Cx0J5>*B*ph'jOhhb*5B*Uphh5B*phjh|Cx5B*UphhY' h|Cx5h|CxB*ph h|Cx>*h|Cxh)M hY'aJhd=hY'aJ hd=hY'0J>*B*aJph̙(jNhghgB*UaJph̙hgB*aJph̙"jhd=hY'B*UaJph̙$"%"j'"k'"B("C("N(")")"6*"*"*"*"O+"P+"m+"Y,"Z,",","gdp^pgd^gd^gd)M^gd p^p`gdp^pgd@ ^@ gd^gd&"&"&"&"'"'"'":'";'"<'"?'"@'"j'"z'"|'"}'"'"'"'"'"'"'"'"'"'"'"'"'"'"'"("("("("("-(".("D("®̩•ma jh|CxmHnHu'jShhb*5B*Uph'jbRhhb*5B*Uph'jQhhb*5B*Uph h|Cx5'jQhhb*5B*Uphh5B*phh|Cxh|Cx0J5>*B*phjh|Cx5B*Uph'jUPhhb*5B*Uph%D("L("M("N("O("t("("("("("("("("(")")">)"?)"@)"C)"D)"g)")")")")")")")")")")")"ϻٮϚٮ珈ztdXh5B*CJphjh|Cx5B*CJUph h|CxCJ h]25CJ hDE5CJ hn8[5CJ h|Cx5CJhPU'jeThhb*5B*Uphh|Cx0J5>*B*ph'jShhb*5B*Uphh5B*phjh|Cx5B*Uphh|Cxh)M hY'h|CxhY' h|Cx>* )")")")")")")")")"+*",*"-*"3*"4*"5*"6*"L*"[*"c*"k*"u*"*"*"*"*"*"*"*"ľmf_XffTPKFKF h]25 h|Cx5h[fh|Cx *h|CxCJ *h)MCJ h|Cx5CJ$hd=hg0J>*B*CJaJph̙(jUhghgB*UaJph̙hgB*aJph̙&jhd=hgB*CJUaJph̙hd=hgCJaJ hgCJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jUhhb*5B*CJUph*"*"*"*"*"*"*"*"*"*"*" +"+"O+"P+"k+"l+"m+"+"+"+"+"+"+"+"+"+"+"+"+"+","K,"L,"ti^Uih|Cx0J>*CJh\ 0J5>*CJh|Cx0J5>*CJjWh|Cx5CJUjh|Cx5CJU hCJ h|CxCJ hY'5CJ h|Cx5CJh|CxOJQJ *h|Cxh)M h|Cx5hgh|Cx0J5>*B*ph'jVhhb*5B*Uphh5B*phjh|Cx5B*Uphh|Cx!L,"Y,"Z,"h,"i,"j,"k,",",",",",",",",",",","-"-"-"-"-"-"-"-"-"-"-"¸ymWyHyyh|Cx0J5>*B*CJph+j_Xhhb*5B*CJUphh5B*CJphjh|Cx5B*CJUph h|Cx5CJ$hd=hg0J>*B*CJaJph̙(jWhghgB*UaJph̙hgB*aJph̙&jhd=hgB*CJUaJph̙hd=hgCJaJhg5CJ$aJ$hWth|Cx5CJ$aJ$h|Cx h|CxCJ,","-"-"-"."c."d."|."}." /"/"/"0"0"0"0" 1"E1"F1"1"1"1" ^``^^ ^`gdY'^gdY'^gdY'-" ." ." ."."."+."5."7."8."[."\."]."`."a."d."|."}."."."."."."."."."."."."."."."."."."."."/"οιοιyοιcοι+jZhhb*5B*CJUph+j2Zhhb*5B*CJUph h]2CJ h|Cx>*CJ+jYhhb*5B*CJUph h|Cx5CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jXhhb*5B*CJUphh5B*CJph%/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/"/" 0" 0" 0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"1"ľķİĪٞٞrľkķİķdٞ h]25CJ h|Cx>*CJ+j\hhb*5B*CJUph+j%\hhb*5B*CJUphh5B*CJph h]2CJ h|Cx6CJ h|Cx5CJ hY'CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+j~[hhb*5B*CJUph'1"1"1"1"1"1"1" 1"F1"N1"O1"W1"X1"Y1"z1"{1"|1"1"1"1"1"1"1"1"1"1"1"2"2"2" 2"!2"(2"ľķı٥ľĉĂvdvYvh|Cx0J5>*CJ"j^hZ )h5CJUjh|Cx5CJU h|Cx>*CJ hDECJ+j^hhb*5B*CJUphh5B*CJph h]2CJ h|Cx5CJ hY'CJ h|CxCJh|Cx0J5>*B*CJphjh|Cx5B*CJUph+jk]hhb*5B*CJUph 1"1"1"\2"2"'3"`3"3"3"3"3"A4"B4"4"W5"5"5"6"k6"6"q7"7"8"8" 8"48"58"`^ ^`^(2"/2"02"12"T2"U2"V2"Y2"Z2"[2"\2"2"2"2"2"2"2"2"2"3"3"3"3"3"3"3"3"3"~ocQcFch|Cx0J5>*CJ"j`hZ )h5CJUjh|Cx5CJUh]20J5>*B*CJph+j `hhb*5B*CJUphjh]25B*CJUph h]2CJ h|Cx5CJh|Cx0J5>*B*CJph+jh_hhb*5B*CJUphh5B*CJphjh|Cx5B*CJUph h|CxCJ h]25CJ3"84"@4"B4"C4"h4"i4"j4"u4"v4"4"4"4"4"4"4"4"4"4"4"4"4"4"4"4"4"4"4"5" 5"5"5" 5"lbUbjzch|CxCJUjh|CxCJU+jbhhb*5B*CJUphh|Cx0J5>*B*CJph+j8bhhb*5B*CJUphh5B*CJphjh|Cx5B*CJUph h]25CJh|Cx0J5>*CJ"jqahZ )h5CJUjh|Cx5CJU h|Cx5CJ h|CxCJ 5"#5"$5"5"5"5"5"5"5"5"5"5"5"5"5"5"5"5"6"6"6"6"6"6"6"6"7"7"*7"+7",7"/7"07"17"27"غ̯染}n染Xn+jIehhb*5B*CJUphh|Cx0J5>*B*CJph+jdhhb*5B*CJUphh5B*CJphjh|Cx5B*CJUphh|Cx0J5>*CJ"jchZ )h5CJUjh|Cx5CJU h|Cx5CJ h|Cx>*CJ h|CxCJjh|CxCJUh|Cx0J>*CJ"27"7"8"8" 8"8"8"68"C8"D8"E8"8"8"l9"x9"9"9"9"9"9"9"9":":":":":":":" :"!:"$:"%:"9:"::";:"M:"N:"Q:"R:"j:"k:"l:"x:"y:"|:"}:":"ééé|éj'gh|Cx5CJUjfh|Cx5CJUjWfh|Cx5CJUh|Cx0J5>*CJjeh|Cx5CJUjh|Cx5CJU h|Cx5CJ hDECJhWth|Cx5CJ hWtCJ h|Cx5CJ h|Cx6CJ h|CxCJ/58"D8"8"8"S9"9"9"9"9":":":";";" <" <"z<"<"3=")>"S?"?"@"^gd^gd^gdh^hgd^l & FgdL^ ^`:":":":":":":":":":":":":":":":"^;"`;";";";";" <"<",<"-<".<"/<"m<"wqqqqe[QhY'B* CJphh|CxB* CJphh|Cx5B* CJph h|CxCJ$hd=hY'0J>*B*CJaJph̙,jgh=hfgB*CJUaJph̙h=B*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hY'5CJ h|Cx5CJh|Cx0J5>*CJjh|Cx5CJUjgh|Cx5CJUm<"n<"o<"u<"v<"w<"x<"y<"z<"<"="&="3="7="N="O="P="f="g="h="t="u="="="="="="="="="շqf`M%jhJxhJx5B*CJUph hJxCJh|Cx0J5>*CJjih|Cx5CJUjh|Cx5CJU h|Cx5CJ hDECJ h|CxCJh|CxhY'B* CJphh|CxB* CJphhd=hY'CJaJ$hd=hY'0J>*B*CJaJph̙&jhd=hY'B*CJUaJph̙,jhh=hfgB*CJUaJph̙="!>"">"#>"&>"'>"(>")>",>"/>"0>"N>"O>"P>"]>"^>">">"S?"b?"?"?"?"?"(@"8@"@"@"@"@"A"&A"HA"hA"rA"sA"tA"A"A"A"A"A" B"ȶȰ}wqwq hn8[CJ h8,CJh|Cx0J5>*CJjjh|Cx5CJUjh|Cx5CJU h|Cx5CJ h|CxCJ hJxCJ#hJxhJx0J5>*B*CJph%jhJxhJx5B*CJUph+jjhJxhb*5B*CJUphhJxhJx5B*CJph*@"@"A"A" B" B"/B"B"B"C""C"\C".D"lD"D"E"SE"E"E"E"F"\F"F"G"G" & F^gd & F^gd^gd^gd B".B"/B"B"B"C" C""C"*C"\C"`C"C"C"C"C".D"2D"JD"KD"kD"{D"D"D"D"D"E"&E"SE"\E"E"E"E"E"E"E"E"F"F"F" F" F" F"\F"`F"F"F"F"F"G"̸| hDECJ$hd=hY'0J>*B*CJaJph̙,j:khBhfgB*CJUaJph̙hBB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJ hn8[CJ h|Cx5CJ h|CxCJh|CxB* CJphh|Cx5B* CJph0G" G"G"G"G"G"G"G"G"G"5H">H"fH"}H"~H"H"H"H"H"H"H"H"H"H"H"I"I"I"I"I"I"I"I"I"I"I" J" J"$J"?J"¶Œ{p{hIhICJaJ hICJhIhICJ$aJ$$hd=hY'0J>*B*CJaJph̙,jlhBhfgB*CJUaJph̙hBB*CJaJph̙&jhd=hY'B*CJUaJph̙hd=hY'CJaJh|Cx5B* CJph h|Cx5CJ h|CxCJ hDECJ'G"5H"eH"fH"H"H"I"I"I"I"I"I" J" J"$J"&J"J"J"J"0K"]K" ^`gdI @ ^@ `gdIgdI ^gd^gd^gd ^`gd?J"@J"UJ"VJ"WJ"^J"_J"`J"J"J"^K"xK"yK"K"K"`M"aM"M"M"M"M"M"M"M"M"M"M"M"M"M"M"UN"aN"N"N"N"N"zszlclz]zlzl hDECJh|Cx5CJH* h|Cx5CJ h|Cx>*CJ h|CxCJ h|CxCJ8h\Ghy;CJh\Ghy;0J>*CJjQmh\GhCJUh\Gh\GCJjh\Gh\GCJU hy;CJ hICJhIhI0J>*CJjlhIhCJUhIhICJjhIhICJU$]K"yK"K"K"K"K"K"L"L"RL"VL"{L"L"L"L"L"L"M"M"'M"?M"`M"M"M"M"M"M"M"`gdy;gdIM"M"M"M"M"M"N"N"N"N"O"tO"P"tQ"Q"R"R"R"R"R"S"T"T"$V" & Fgd  & F6gd ^gd  & F7gd ^gd*^gd*N"N"N"N"O"O"tO"{O"O"O"O"O"O"O"O"O" P" P"%P"&P"'P"0P"9P":P"xP"P"P"P"P"P"3Q"8Q"@Q"AQ"cQ"dQ"eQ"ʥwa+jAnhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph hDECJh5kh|Cx0J>*CJh5khDE0J>*CJjmh5kh;~%CJUh5kh5kCJjh5kh5kCJUhMhM5CJ hMCJ h|Cx5CJ hlCJ hDCJ h|CxCJ$eQ"pQ"qQ"tQ"yQ"Q"Q"R"!R"-R"1R"9R">R"R"R"R"R"R"R"R"R"R"R"R"R"R"R"R"R"R"S" S" S"S"S"8S"9S"LS"MS"OS"SS"TS"US"S"S"T")T"+T"DT"FT"RT"]T"kT"lT"T"T"T"T"ڶگǥڞǞǘڒ hVKCJ hMCJ h 5CJh h CJH* h|CxCJH*h h|CxCJH* h CJH* h CJ hDECJ h|Cx5CJ h|CxCJjh|Cx5B*CJUphh|Cx0J5>*B*CJph9T"T"T"T"U" U"1U"2U"3U"6U"7U"U"U"U"U"U"U"U"U"U"V""V"#V"$V"/V"5V"ѻݬte[RKBhVKh CJ h 5CJh h CJh h 5CJhM0J5>*B*CJph+johMhL5B*CJUphhM5B*CJphjhM5B*CJUph h CJh|Cx0J5>*B*CJph+jnhVKhD5B*CJUphhVK5B*CJphjh|Cx5B*CJUph h|Cx5CJ h|CxCJ hMCJ5V"8V"AV"NV"\V"V"V"V"V"V"V"W"W"$W"W"W"W"W"W"W"W"W"W"W"W"X"(X"0X"1X"7X"8X"[X"\X"]X"nX"oX"pX"Y" Y" Y"Y"aY"bY"nY"qY"ɽɛɑ{wp h 5CJh|Cxh|Cx5B*CJphh*h|Cx5CJh|CxB* CJphh|Cx0J5>*B* CJph%j0ph|Cx5B* CJUphh|Cx5B* CJphjh|Cx5B* CJUph hM5CJ hMCJ h|Cx5CJ h|CxCJ h 5CJ h CJ,$V"V"W"'X"(X"1X"Y"aY"bY"Y"Y"Z"Z"["w["\"z\"]"]"]"p^pgd*p^pgdLw ^`gdLw & FgdLwgd^gdM^gdM^gd*^gd* & Fgd qY"Y"Y"Z"Z"Z"Z"Z"Z"Z"Z"+["5["["["["["["["["\"\"\"+\"-\"8\"Q\"[\"z\"~\"\"\"\"]"]"]"g]"z]"{]"]"]"]"]"^"^" ^"^"^"^"#^"$^"9^":^";^"α嫥厛jph|CxCJUjh|CxCJU hCJ hMCJhLwhLwCJ h|Cx6CJ h*CJ h|Cx5CJ hLwCJh*hLw5CJ hLw5CJ h|CxCJh h|Cx6CJh h 6CJ5]"]"]"^"^"T^"^"^"5_"Z_"_"@`"a"a"a"a"0b"2b"Sb"b"b"b"b"Xc" & FWgdS ^`gd*^gd*^gd*^gd^gd ;^"Q^"R^"w^"x^"^"^"^" _")_"+_"@`"I`"`"`";a"Ea"a"a"2b"Bb"Qb"b"b"b"b"b"b"b"b"b"b"b"Xc"Zc"ec"gc"lc"mc"c"c"c"c"d"^d"_d"`d"od"d"d"d"e"e"ĺͺͺħ͡ha#ha#5CJ ha#5CJ ha#CJhSh|CxCJhSh|Cx5CJhShS5CJhShSCJ hSCJ h*CJ h|Cx5CJ hn8[CJ h|CxCJjh|CxCJUh|Cx0J>*CJ4Xc"d"^d"_d"d"d"d"d"e"e""e"#e"3e"e"e"e"e"%f":f";f"Kf"g" & F pp^pgdQ^gd* ^`gd*^gd*p^pgdS & FWgdSe"!e"#e"*e"Ce"Oe"Qe"]e"e"e"e"e":f";f"Cf"Kf"Tf"f"f"f"f"g"g"g"g"g"g"g")g"g"g"h""h"$h"/h"1h"2h"h"h"h"h"h"h"h"i" i"i"Ri"bi"ci"ni"xi"i"i"i"i"i"i"i"j" j"Qj"῵ hn8[5CJ hn8[CJ h^lCJ hDECJh*h*CJH* h*CJhpuXhpuXCJaJhpuXh|CxCJaJ hpuXCJ h|CxCJ h|Cx5CJ h*5CJh*h*>*CJ=g"g"#h"$h"2h"h"h"h"h"Qi"Ri"bi"ci"i"zj"{j"j"j"j">k"@k"|k"k"k"^gdL^gd^l ^`gd*^gd*^gd*Qj"Tj"Vj"Yj"zj"{j"j"j"j"j"j"j"j",k"-k".k"0k";k"k"@k"Gk"Ik"Jk"nk"ɾysicVMhBhBCJjhBhBCJU hBCJhBhL5CJ hKCJh6ChLCJ aJ h6C0J>*CJaJh6Ch6C0J>*CJaJ#jqh6Ch\xCJUaJjh6Ch6CCJUaJh6Ch6CCJaJh6Ch6CCJ aJ hLhL>*CJ aJ hhCJhh|CxCJ h|CxCJ h|Cx5CJnk"ok"pk"yk"zk"{k"|k"k"k"k"k"k"k"k"k"k"k"k"k"k"k"k"k"k"l"l"l"ʂxnx_UC_"jashC1h}'5CJUhC1hC15CJjhC1hC15CJUhKhL5CJhKhK5CJ hKCJhlhl0J>*CJjrhlh\xCJUhlhlCJjhlhlCJU hlCJhlhL5CJ hLCJ hBCJhBhB0J>*CJjhBhBCJUjqhBh\xCJUk"k"l"l"l"l"m"m"m"Nn"On"n"n"@o"Ao"bo"o"o"o"o"o"p"p^pgdS^gd6C ^`gd6C^gdS & FXgdK`gdl^gdll"l"l"l"l"l"l"l"Cl"Dl"El"Ll"Ml"ol"pl"ql"vl"wl"l"l"l"l"l"l"ööxnh[RBjuh6Ch\xCJUh6Ch6CCJjh6Ch6CCJU h6CCJh6Chl5CJjthC1h}'CJUhC1hKCJhC1hK0J>*CJj:thC1h}'CJUhC1hC1CJjhC1hC1CJU hKCJjhC1hC15CJUhC1hK0J5>*CJhC1hC10J>*CJhC1hC10J5>*CJl"l"l"l"l"l"l"l"m"m"m"m"m"m"m"m"m"m"m"m"En"Fn"Gn"Kn"Ln"On"fn"gn"n"n"o"o"(o"xxkbhShSCJjhShSCJU jhShSCJ hSCJj>wh6Ch\xCJU h6Ch6C0J>*B*CJphjmvh6Ch\xCJUh6Ch6CCJhSh6C5CJ hKCJ hZoCJ hlCJ h6CCJh6Ch6C0J>*CJjh6Ch6CCJU (o")o"*o">o"?o"@o"Ao"Fo"ao"bo"vo"o"o"o"o"o"o"o"o"o"o"p"p"p"p"p"/p"4p"p"p"p"p"p"q"q"q"ǽǩПЕztk_hh5CJaJhLhuCJ hCJ hZoCJhmBhmBCJ hCJ hmBCJhmBhmB5CJh6Ch*5CJ hLCJ hL5CJ hS5CJh6ChL5CJhShSCJ hSCJhShS0J>*CJjhShSCJUj%xhShf1CJU#p"p"p"p"q"q"q"q"q"q" r" r"r"@s"As"Ms"s"s"s"t"t"t"tu"^gd|)^gd|)gd`gdL^gdLgd^gd6C^gdmBq"q"q"q"q"q"q"q"q"q"q"q"q" r"r"r"3r"4r"5r"Br"Cr"Fr"Gr"cr"dr"er"tr"ur"xr"yr"r"r"r"r"r"r"r"r"ȿȸ~o~`~jazh|Cx5CJUjyh|Cx5CJUh|Cx0J5>*CJjwyh|Cx5CJU h|Cx5CJjh|Cx5CJU h|CxCJ h|Cx5CJ$ hDE5CJ$hhCJ hCJhh0J>*CJjxhh+aCJUjhhCJUhhCJ%r"r"r"r"r"r"r"r"r"r"r"r"r"r" s" s" s"s"s"s"s"s"2s"3s"4s"=s">s"@s"Ms"Ns"hs"is"js"ks"ls"os"ps"s"s"s"s"s"s"s"s"ӵӛӕӆwj}h|Cx5CJUj|h|Cx5CJU h|CxCJj!|h|Cx5CJUhL0J5>*CJj{h|Cx5CJUjI{h|Cx5CJU h|Cx5CJh|Cx0J5>*CJjh|Cx5CJUjzh|Cx5CJU,s"s"s"s"s"s"s"s"s"s"s"s"s"s"s"t"t"t"t"Vu"su"tu"uu"vu"u";v"Fv"Gv"Iv"Vv"Yv"iv"v"v"v"v"v"v"v"v"v"v"w",w"Cw"Dw"dw"jw"ӺӺӓӺӺӺӺyh6yh6y>*CJh6yh6y5CJ h6yCJh|Cx5CJH*h4Yh4Y5CJ h4Y5CJ h|Cx6CJ h4YCJ h|CxCJh|Cxj}h|Cx5CJU h|Cx5CJh|Cx0J5>*CJjh|Cx5CJUjz}h|Cx5CJU/tu"uu"u"u"/v":v";v"Iv"v" w"Dw"w"w"Hx"Jx"x"4y"\y"z"z".z"z"z"z"p^pgd_ ^`gd|)^gd6y^gd|) & FYgd4Y^gd|)jw"w"w"w"w"w"w"w"w"w"w"w"x".x"Jx"Px"Rx"dx"x"x"x"x"2y"4y"Fy"Jy"\y"by"y"y"y"y"y"y"y"y"z"z"z"+z"qeh_h_0J>*CJj~h_hA-CJUh_h_CJjh_h_CJUh_h_5CJ h_CJ h\ 5CJ hDECJ h|CxCJ hDE5CJ h|Cx5CJhih6y0J>*CJj`~hih}'CJUhih6yCJjhih6yCJU h6yCJ'+z",z".z"z"z"{"{"{"{"{"{"W{"a{"c{"k{"l{"m{"n{"{"{"{"{"{"{"{"{"{"{"{"{"{"{"{"̿xbxXhwLB* CJph+jhwLhg5B*CJUph#hbhwL0J5>*B*CJph+jDhwLhg5B*CJUphhwL5B*CJph%jhbhwL5B*CJUphhbhwLB* CJphhwL56CJh|Cx56CJ hCJ h6yCJ h|CxCJ h|Cx5CJh|Cx5CJH* z"z"{"{"{"W{"{"|"|"|"}"}"~""U""""""|""b"-"t"" & F pp^pgd Hgd^gd|)^gd|){"{"|"6|"V|"X|"Y|"||"}|"~|"|"|"|"|"|"|"|"|"|"|"|"|"|"|"|"޹񭡭yfWAf+j%hbhg5B*CJUphhbhb5B*CJph%jhbhb5B*CJUphhbhbB* CJphhb5B* CJphhbh|Cx5B* CJphhn8[5B* CJphh|Cx5B* CJphhdhd0J>*CJjzhdhGpTCJUhdhdCJjhdhdCJU hdCJ h|CxCJhbhbCJ|"|"|"|"5}"?}"E}"O}"f}"i}"q}"}"}"}"}"}" ~" ~"~"~"~"~"~"~"~"~"#"1"5"L"T"U"_"`"m""""""Ǻyrrkrr hi5CJ h 5CJh9h 0J>*CJjh9hICJUh9h9CJjh9h9CJU h CJh|Cx5CJH* hCCJ h|Cx5CJ h|CxCJhbhbB* CJph%jhbhb5B*CJUph#hbhb0J5>*B*CJph'""""""" """9";"o"q""""$"&"5""h"l"z"|""""""""4"6"b"d""""̃"꿶ꔊxjh4h|Cx0J5>*CJ"jsh4hb*5CJUh4h45CJjh4h45CJU jh|CxCJhywhywCJH*hywhywCJ hywCJ h|CxCJH*h|Cx5CJH* h|Cx5CJh|Cxh h|Cx5CJ h|CxCJ h 5CJh h CJ'̃"΃"ڃ"܃"ރ"+","]"^"k"s"t"""""""""""'"(""""" "!"""~""ſ~r~k`hSLh|CxCJaJ hh|Cxhh|Cx>*CJaJhh|CxCJaJhh|Cx5CJaJ h|Cx5 jh|Cxh|Cx jh|Cx5CJ h|Cx5CJ jh|CxCJ h|CxCJ hkCJ hKCCJ hKC5CJjh4h4CJUh4h|Cx0J5>*CJh4h|Cx0J>*CJ """" """""W""d"e"""M"N"d">""" " & F^gd|)^gdSL^gd|)^gd|)^gd & F pp^pgd H & F pp^pgd H""W"b"""""ڇ"ۇ""""""" ""e"n"o"~"""͈"""0"6"J"U""""""""‰"҉""迹{o{hh h|Cx6CJh"hb5CJaJhbh|CxCJaJhbhbCJaJhbh|Cx5CJaJhbh|Cx5CJhbh|CxCJhbh\ CJ h|CxCJ h|Cx5CJhSLhywCJaJhSLhn8[CJaJhSLh|CxCJH*aJhSLh|CxCJaJhSLh|Cx5CJaJ(""""" "L"N"d">"H"n"o"""΋"ϋ"Ћ"ً"ڋ""""" " ""$"%"J"K"L"T"U"~"""""""݌"""""ѷѷxjh|CxCJUh|Cx0J>*CJj܃hZ )hCJUjh|CxCJUjqh|Cx5CJUh|Cx0J5>*CJjh|Cx5CJUjh|Cx5CJU hn8[CJh|Cx h"CJ h|Cx5CJ hDECJ h|CxCJ-" "%"&"5"B"y"""""ƍ"Ǎ"ȍ"ۍ"܍"5"6"@"A"r"s"t"}"""""""""""T"U"v"w"x""""""""ýÖyý hywCJhSLhyw5CJjh|CxCJU hSL5CJh|Cx0J>*CJjh|CxCJUjh|CxCJU h|CxCJ h|Cx5CJhd0J>*CJjhdCJUjhdCJUhdhdCJ hd5CJ hdCJ- "y"5"s"t""""""""""""'"("ђ"Ғ" ""^ & F^gdSL^gdSL^gd|)^gd|) & F^gd|) & F^gdd""Џ""""" "E"G""""""Ð"""""""'"("="R"S"""""ђ"ے"ݒ"ޒ""""" "@"A"C"D"""""""""Ƽ hseCJ h|CxCJH*hh|Cx6CJhh6CJ hCJjh|CxCJUjh|CxCJUh|Cx hbCJhihi5CJ h|Cx5CJ hiCJ h|CxCJhih|CxCJ3"""_"`"""S"T"Е"H"I"~""U"""]"^""" " """%"^gdQ^ @ ^@ `""S"T"U"["\"^"_"`"h"q"r"""""""T"X"Y"Z"""Е"ו"G"H"I"Q"S"T"""""""|vmcjh|CxCJUh"h"CJ h"CJ h"5CJ *h|CxCJ hCJh|Cx5CJH* hn8[CJ h|Cx5CJ h|CxCJhseh|CxCJ hseCJ hsehse0J>*B*CJph̙(jhsehfgB*CJUph̙hsehseB*CJph̙"jhsehseB*CJUph̙&" " " ""U"\""""""""""""""ؗ"ٗ"0"1"2"3"^"h"j"k"""""""" " "ó̧ٞ}tkhSLh|CxCJhSLhiCJj<h|CxCJUjŠh|CxCJU hCJ h|Cx5CJh"h"CJh>0|h"0J>*CJjQh>0|hGpTCJUh>0|h>0|CJjh>0|h>0|CJU h"CJ h"5CJj׈h|CxCJUjh|CxCJU h|CxCJ& """"$"%"&">"?"@"L"M"N"O"k"l"m"""""vjVvFvj? h|Cx5CJ h"Ph"P0J5>*CJaJ&j%h"Ph%sz5CJUaJh"Ph"P5CJaJ jh"Ph"P5CJUaJh595CJaJh59h590J5>*CJaJ&jh59h.C5CJUaJh59h595CJaJ jh59h595CJUaJh59hl&CJaJh59h59CJaJhSLh|CxCJh|Cx5B* CJ`OJQJph%"N"""""(")"1"2"O""""ě"""N" & FgdD & F 8^gdQ^gd & FgdD^gd{>gd{> & F & F & F ^gdQ & F^gdQ"""""ԙ"ՙ"֙""""""""%"&")"1"2"O"""""&"2"N"R"ʴ֥ʏ֥拄}r}k`U`IhDhD5CJaJhDhDCJaJhDh|CxCJaJ h|Cx5CJhDh{>CJaJ h{>5CJ h{>h{>h|Cx+jChZ )h5B*CJUphh|Cx0J5>*B*CJph+jhZ )h5B*CJUphh|Cx5B*CJphjh|Cx5B*CJUph h|CxCJ h595CJ h59h59>*CJaJN""˜"̜""""ޝ"""5"m"ž"Þ"""#"*"+"v"^gd^gd & Fgd)s^gd)s^gd?<^gd?<h^hgdD & F 8^gdQ h^`hgdDR""œ"ɜ"̜""""""%")"4"6"7"`"a"n"""Þ"""""""" "!"""#"*"+"̿ؿxh\xV h{>CJhDhD0J>*CJjhDhxCJUhDhDCJjhDhDCJU hDCJhDhD5CJ hDECJ h|CxCJ hDE5CJ hl&5CJ h595CJ h|Cx5CJ hHCJ h)sCJ h?<CJ h?<5CJhDh59CJaJhDh|CxCJaJhDhDCJaJ!+"/"v"z"""."/"5"6"|"}"""""""""""Ǡ"ɠ"ʠ"Ѡ"Ҡ"Ӡ"۠"ͺzodXdOIOI h"6CJh|Cx5>*CJhh|Cx6CJ aJ hh|CxCJ aJ hh|CxCJ4aJ4hhCJ#hh0J5>*B*CJph+j{hh95B*CJUphhh5B*CJph%jhh5B*CJUph hCJhSLhCJ h>*CJhSLh|CxCJ hn8[CJ h|CxCJ h|Cx5CJv"""."/"5"6"c""""""Ƞ"ɠ"Ҡ"ܠ"""/"d""""^gd^gd"6gd ^`gd^gd^gd۠"ܠ"ݠ"""" " "/"0"1"L"M"N"a"b"d"o"y"{""" "_"j"}"~""""*"O"Y"""" "!")"."M"Z"ߤ""""""!",""̦"""9":""ɺ hSLCJ h|Cx>*CJ hn8[CJh|CxCJmHnHu jh|CxCJmHnHu hDECJh|Cx5CJH*h|Cx h|CxCJH*h|Cx5CJH* h|CxCJH* h|Cx5CJ h"6CJh|Cx5>*CJ h|CxCJ8" "_"`"~"Ϣ"*"+"O"n""""L"M"Z"[""""""/"^^gdSL & F h88^8gdQ & F h88^8gdQ`/""" "!","-""""ݧ"""B"""""è"ը""X" ^`gd^gdgd & F h88^8gdQ`^ ^`"""""""""""""ը"ۨ"X"Y"d"e"""""""""믣{oY{G{#hLkhLk0J5>*B*CJph+j*hhq5B*CJUphh5B*CJph%jhLkhLk5B*CJUphhLkhLkCJhLkh|Cx6CJ aJ hLkhLk6CJ aJ hLkh|CxCJ h|Cx5CJ hn8[CJ hSLCJh|Cx6CJ aJ hh|Cx6CJ aJ hSLh|CxCJ aJ h|CxCJ jh|CxCJmHnHuX"Y"e"f""""""""""?"i"""ڪ"۪"""%"Q"""Ϋ"""^gdVd^gd"""ԩ"թ"֩""""""""""""6"7"8"=">"@"A"a"ưҞ嘇rhVrHrhrhh"Ph"P0J5>*CJ"jxh"Ph%sz5CJUh"Ph"P5CJjh"Ph"P5CJU h"PCJ h)h|Cx5B* CJ$aJ$ph h|CxCJ#hLkhLk0J5>*B*CJph+jёhhq5B*CJUphh5B*CJph%jhLkhLk5B*CJUphhLkhLkCJhLkhLk6CJ aJ hLkCJa"b"c"g"h"j"k""""""""""""""ª"ͪ"۪""""""#""""""""""ǵǣǝǝ}sj}j}d h)CJhVdhVdCJhVdhVd>*CJ hVdCJ hDECJ h|CxCJ hVd>*CJ h|Cx>*CJ h"PCJ"jh"Ph%sz5CJU"jxh"Ph%sz5CJUh"Ph"P5CJh"Ph"P0J5>*CJjh"Ph"P5CJU"jh"Ph%sz5CJU%"#"$"I""""""Ϭ"""""""@""""""""^gd)gd)^gdVd ^`gdVd^gdVd^"""""""""3"4"5"9":""""""Į"Ů"""X"Z"ϻzp[zMzC?h)hVdh)>*CJh)0J>*B*CJph(jhZ )h)B*CJUphh)B*CJphjh)B*CJUphhnh)0J>*CJjzhnh)CJUhnh)CJjhnh)CJU h)CJh)>*B* CJ aJ ph h)h)>*B* CJ aJ phh)h)B* CJ aJ ph h)h)5B* CJ aJ ph"""""X"Z"\"""\""p""w""""""k"ж"")" & Figd) & Fgd) & Fgd)h`hgd) & Fgd)gd)`gd)Z"\""""ڰ"ܰ"""X"Z"\"f"w"""""" """"""""""""""""q"""")"xijh-h)5CJUjMhZ )h)CJUh-h)0J>*CJjhZ )h)CJUh-h)CJjh-h)CJU h)5CJh-h)5CJ h+TMCJhgh)CJhgh)CJH*hgh)5CJh)h)5CJ aJ h)CJ')"*"+"3"4"8"9"^"_"`"h"i"k"{""""Զ"޶"""M"N"q"r"s"""""ķ"ŷ"Ʒ"˷"̷"з"߾Ȧ߾ߦxf[h)0J5>*CJ"johZ )h)5CJU h)5CJjh)5CJU"jhZ )h)5CJU jh)CJ h)CJ"jhZ )h)5CJUh-h)5CJh-h)CJh-h)0J5>*CJjh-h)5CJU"j$hZ )h)5CJU#)""""H"n""d"""|"}"~"""""""D""h#h#^gdKP`gdVdgd) & Fk 88^8gd H^gd)gd) & Figd)з"ַ""""˹"̹"͹"۹"ܹ"}"~""""""""""h#~h#h#h#h#h#h#h#h#h#h#򿹳~odRo#jhMphKJCJUaJhMphMpCJaJjhMphMpCJUaJhMphMp5CJaJhMpCJaJUhKPCJaJhKPhKP5CJaJhKPhKPCJaJ hMpCJ4 hKPCJ4 hCJ4h)0J5>*CJ"j.hZ )h)5CJUjh)5CJUh) h)CJ h)5CJtions: neuronal injury with abnormal sympathetic tone, cutaneous carcinomas, nail deformities, epiphyseal damage (in children) Methemoglobinemia ( HYPERLINK \l "methemoglobinemia" see other)  HYPERLINK \l "environmental" Environmental / poisonings / ingestions / etc Other Topics Evidence Based Medicine RRR (relative risk reduction) ARR (absolute risk reduction) NNT (number needed to treat) = 1/ARR Randomization using volunteers eliminates lead time, selection, and length bias (overdiagnosis) Does not eliminate generalizability error Trials using volunteers ( efficacy studies Population-based subjects ( effectiveness studies Disclaimer: The information on this site is intended for educational purposes only. The information provided on this site is not to be used in the provision of health care to any individuals.     PAGE  PAGE 93 h#h#h#h#h#h#h#h#h#i#i#i#i#i#)i#+i#Ci#Hj#Ij#uj#vj#j#j#j#j#Qk#Rk#Sk#Ͼσ}wnwewew^XTPwHjhPUh8h|Cx h|CxCJ h|Cx5CJ jh|CxCJh|Cx>*CJh h|CxCJ h|CxCJ4hKPhMpCJaJhMphMp0J5>*CJaJ&jphMphKJ5CJUaJhMphMp5CJaJ jhMphMp5CJUaJhMpCJaJhMphMpCJaJjhMphMpCJUaJhMphMp0J>*CJaJh#h#h#i#i#i#)i#*i#+i#Ci#Di#bi#i#i#i#j#0j#[j#j#j#j#j#j#j#Rk#Tk#Uk# & Fj ^gd H^gdbaSk#Uk#Vk#Xk#Yk#[k#\k#^k#bk#ck#ik#jk#kk#mk#nk#tk#uk#wk#xk#yk#k#k#k# h|CxCJh=1?0JmHnHu hil0Jjhil0JUhiljhPUhPUk#Wk#Xk#Zk#[k#]k#^k#_k#`k#ak#bk#kk#lk#mk#yk#zk#{k#|k#}k#~k#k#k#k#h]h&`#$7 0P/ =!"#$%0 'wDyK  disclaimeroDyK cardiowDyK  hematologysDyK  oncologyuDyK  endocrinewDyK  infectiousmDyK neuromDyK renalmDyK lungsgDyK gimDyK liver{DyK  RheumatologykDyK bonemDyK jointsDyK  myopathykDyK maleoDyK femaleqDyK allergywDyK  immunologyyDyK  dermatologyqDyK surgeryyDyK  orthopedicssDyK  acidbaseuDyK  metabolic{DyK  electrolytes}DyK ophthalmology}DyK environmentaluDyK  nutritionyDyK  developmentuDyK  emergencyDyK F pharm.docpharm.docDyK F micro.docmicro.docDyK Fddx.docddx.docDyK yK 6procedurevids/yX;H,]ą'cDyK yK pics/icu1.jpgDyK yK pics/icu2.jpgwDyK  immunologyDyK immunoglobulinswDyK  complementDyK immunodeficienciesoDyK tcellssDyK  digeorgeiDyK cmcoDyK bcellskDyK cvidqDyK brutonsqDyK duncansgDyK btmDyK scidsiDyK adaDyK wiskottaldrichDyK ataxiatelangiectasiawDyK  phagocytesDyK cyclicneutropeniakDyK cd18kDyK jobsDyK chediakhigashiwDyK  connectivegDyK raiDyK sleuDyK  sjrogrens{DyK  polymyositisyDyK  sclerodermayDyK  sarcoidosis{DyK  vasculitidesuDyK  giantcelluDyK  takayasusuDyK  kawasakisiDyK pansDyK  wegenerssDyK  buergersmDyK churgDyK yK 4pics/bsl-tcellsurface.jpgDyK yK 4pics/bsl-tcellsurface.jpgDyK yK .pics/bsl-antibody1.jpgyDyK  typeonedermDyK atopicdermatitisyDyK  typetwodermuDyK  pemphigusDyK hemolyticanemiaDyK bullouspemphigoidDyK herpesgestationisDyK epidermolysisbullosa}DyK typethreederm}DyK serumsicknessiDyK bmtDyK yK *pics/hymes-gvhd1.jpgDyK yK fhttp://dermis.net/dermisroot/en/33214/diagnose.htmDyK  F micro.docmicro.dochivyDyK  sarcoidosisiDyK sleiDyK cllkDyK cvidiDyK cmcuDyK  sinusitiswDyK  perniciousDyK  F pharm.docpharm.doc pneumovaxDyK asepticmeningitisuDyK  lymphomabsDyK  lymphomaDyK yK bhttp://www.ubriaco.com/sounds/air-biological.wavDyK yK jhttp://content.nejm.org/cgi/content/full/343/23/1703wDyK  cellulitisiDyK amluDyK  pneumonia{DyK  liverabscessoDyK feltysDyK  F labs.doclabs.doc complementDyK yK 0pics/bsl-complement.jpgh$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2h$$If!vh5 5.#v #v.:V l'5 5.4ayt{V2$$If4!vh5e5#ve#v:V l t05e54a4yt{V2DyK cryoglobulinemia$$If4!vh5e5#ve#v:V l t05e54a4yt{V2$$If4!vh5e5#ve#v:V l t05e54a4yt{V2kDyK mpgniDyK sle{DyK  endocarditis$$If4!vh5e5#ve#v:V l t05e54a4yt{V2DyK  Fddx.docddx.docsyncopeDyK erythemamultiformeiDyK sjsiDyK tenkDyK comaiDyK hbsDyK conjunctivitiskDyK boneDyK bonemalformationsuDyK  fractureswDyK  bonecancer}DyK osteomyelitismDyK jointgDyK raiDyK sleyDyK  sclerodermasDyK  sjogrensiDyK jrayDyK  sarcoidosisgDyK oakDyK goutwDyK  pseudogoutDyK infectiousarthritiswDyK  ankylosinguDyK  psoriaticqDyK reiters{DyK  Fibromyalgia{DyK  polymyositisDyK dermatomyositisiDyK pmrmDyK rs3peDyK eosinophilicfasciitisDyK eosinophilicmyositisDyK Fmyopathyother{DyK  vasculitidesuDyK  giantcelluDyK  takayasusuDyK  kawasakisiDyK pansDyK  wegenersmDyK churgsDyK  buergersyDyK  orthopedicsyDyK  lowbackpainkDyK kneeiDyK ctsqDyK rheumhpDyK hlaassociationsiDyK pmriDyK osaDyK yK $pics/raynauds.gifDyK rheumaticfeverkDyK cppdsDyK  whipplesDyK hypothyroidismwDyK  hemophilia{DyK  referredpain{DyK  referredpain$$If!vh55 555#v#v #v#v#v:V l055 5554a$$If!vh55 555#v#v #v#v#v:V l055 5554a$$If!vh55 555#v#v #v#v#v:V l055 5554a$$If!vh55 555#v#v #v#v#v:V l055 5554aoDyK testes}DyK polyarticularDyK infectiousarthritiskDyK goutwDyK  pseudogoutDyK hydroxyapetitekDyK caoxgDyK oagDyK raiDyK jraDyK spondylarthropathiesuDyK  psoriaticwDyK  ankylosingqDyK reiterssDyK  gaucherssDyK  whipplesoDyK crohnsgDyK ucDyK  F micro.docmicro.doc parvovirusDyK  F micro.docmicro.docrubellaDyK  F micro.dochcvDyK  F micro.docmicro.doc coxsackieDyK  F micro.docmicro.doccmv{DyK  fibromyalgiaDyK hemochromatosisqDyK behcetsDyK  F micro.doclymeDyK  F micro.docmicro.doc gonococcusDyK bronchogeniccaDyK yK Rhttp://mdtruth.com/pics/hoa-bonescan.jpg{DyK  osteoporosisuDyK  menopauseDyK yK (pics/oa-dip-pip.jpgDyK yK "pics/oahands.jpgoDyK pagets}DyK synovialfluidDyK yK $pics/ra-hands.jpgDyK yK $pics/swanneck.jpgDyK yK *pics/boutonniere.jpgDyK yK ,pics/boutonniere1.jpgDyK peripheralneuropathyaDyK yK http://content.nejm.org/cgi/content/full/344/13/997?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=rheumatoid+nodules&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=20&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jouiDyK spn{DyK  pericarditisyDyK  myocarditisDyK anemiaofchronicdiseaseiDyK dr4DyK  F pharm.docpharm.doc steroidsDyK  F pharm.docpharm.docmtxDyK  F pharm.docpharm.doc tnfalphaDyK  F pharm.docpharm.doc rituximabDyK  F pharm.docpharm.docimmuranDyK  F pharm.docpharm.docgoldDyK  F pharm.docpharm.docpenicillamineuDyK  legulcersDyK  F labs.doclabs.doc ferritinDyK  F micro.docmicro.doc neisseriaDyK  F micro.docmicro.doc syphilisDyK  F micro.docmicro.docHACEKDyK yK \http://content.nejm.org/cgi/video/354/19/e19/DyK  F micro.docmicro.doctbDyK  F micro.docmicro.doc borreliauDyK  psoriasisDyK adrenalinsufficiencyDyK diabetesinsipidusDyK infectiousmonoarthritisDyK  F pharm.docpharm.doc colchicineDyK  F pharm.docpharm.doc probenecidDyK  F pharm.docpharm.doc allopurinolDyK _hemochromatosisyDyK  amyloidosisDyK  F pharm.docpharm.doctcaoDyK lungcasDyK  breastcawDyK  prostatecaDyK yK 0pics/chondroma-hand.jpgyDyK  irradiationgDyK raDyK  F micro.doctineaDyK  Fddx.docddx.doc alopeciaiDyK apaDyK pleuraleffusionwDyK  lungcancerDyK yK :pics/cnslesion-lupus-ddx.jpg{DyK  schistocytesiDyK htnDyK  F labs.doclabs.docanaDyK yK thttp://content.nejm.org/cgi/content/full/344/22/1701?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1701&journalcode=nejmkDyK gerdkDyK pftsDyK cardiomyopathyiDyK ibmDyK yK $pics/dm-shawl.jpgDyK yK 6pics/dm-telangiectasia.jpgDyK yK :pics/dm-calcinosis-elbow.jpgDyK yK fhttp://dermis.net/dermisroot/en/37886/diagnose.htmDyK yK :pics/dm-calcinosis-elbow.jpgDyK yK 0pics/raynauds-scars.jpgDyK yK fhttp://dermis.net/dermisroot/en/33886/diagnose.htmDyK porphyriacutaneatardaDyK yK fhttp://dermis.net/dermisroot/en/17039/diagnose.htmDyK erythemanodosumsDyK  vitiligowDyK  langerhansDyK yK 4pics/neurosarcoidmri1.jpgDyK  F pharm.docpharm.docdmardsDyK erythemanodosumiDyK panDyK hairycellleukemiasDyK  wegenerssDyK  hodgkinsiDyK gcaiDyK hspiDyK gcauDyK  takayasusiDyK panuDyK  kawasakismDyK churgsDyK  wegenerssDyK  buergersiDyK hspDyK cryoglobulinemiaDyK paraneoplasticDyK  F pharm.docpharm.doccocaineDyK  F micro.docmicro.doc rickettsiaDyK  F micro.docmicro.dochtlvkDyK rcvsDyK vasculitisinfectionDyK yK Dpics/primarycnsvasculitismri1.jpgDyK yK Dpics/primarycnsvasculitismri2.jpgDyK yK Dpics/primarycnsvasculitismri3.jpgDyK yK Dpics/primarycnsvasculitismri4.jpgDyK  F micro.docmicro.docLeptospirosis$$If!vh5 5 5 #v #v #v :V$l* t065 5 5 aytR0iDyK pmruDyK  typethreeh$$If !vh5 5#v #v:V l5 54a ytLkoDyK livedoh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkh$$If !vh5 5#v #v:V l5 54a ytLkDyK  F labs.doclabs.docpancaDyK  Fddx.docddx.doc hemoptysisoDyK feltysgDyK ucsDyK  typefourDyK  Fddx.docddx.doc hemoptysisuDyK  hematuriakDyK rpgnDyK yK 6pics/wegeners-chestCT1.jpgDyK yK 6pics/wegeners-chestCT2.jpgDyK yK 6pics/wegeners-chestCT3.jpgiDyK dahaDyK yK http://content.nejm.org/cgi/content/full/343/12/864?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=buerger&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nej_DyK yK http://content.nejm.org/cgi/content/full/343/13/953?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=churg&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nejmDyK eosinophilicpneumoniaiDyK hspaDyK yK http://content.nejm.org/cgi/content/full/341/17/1284?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=%22oral+ulcers%22&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jourDyK yK "pics/behcets.jpgDyK yK "pics/behcets.gifuDyK  retinitissDyK  hypopyonDyK yK $pics/bsl-hla1.jpg~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLkgDyK ms~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLk~$$If!vh55,5~ #v#v,#v~ :V l55,5~ 4aytLkDyK yK `http://www.annals.org/cgi/content/full/146/1/34DyK yK pics/rcvs.jpgwDyK  ankylosinguDyK  psoriasisqDyK reitersiDyK ibdgDyK aiuDyK  psoriasisDyK yK Bpics/psoriaticarthritishands.jpgDyK yK 0pics/psoriasishands.jpgDyK  F pharm.docpharm.docnsaidsDyK  F pharm.docpharm.docmtxDyK  F pharm.docpharm.docpenicillamineDyK  F pharm.docpharm.docgoldDyK  F pharm.docpharm.dochydroxychloroquineDyK  F pharm.docpharm.doc misoprostolDyK rhabdomyolysisDyK malignanthyperthermiaDyK ethyleneglycolqDyK cyanideqDyK arsenicDyK  F pharm.docpharm.doc amiodaroneoDyK niacin$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5555 55#v#v#v#v #v:V l0*5555 54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLkiDyK vwf$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLk$$If!vh5(55F5#v(#v#vF#v:V l5(55F54aytLkDyK F CARDIO~1.HTM$cardiology.htmlyDyK  circulatoryiDyK htnmDyK edemawDyK  thrombosisgDyK peiDyK dicmDyK shockiDyK chf{DyK  corpulmonaleDyK hyperlipidemiaDyK atherosclerosisiDyK pvdiDyK cadoDyK anginagDyK migDyK miDyK cardiomyopathyDyK restrictivecardiomyopathykDyK hocmyDyK  ArrhythmiasyDyK  bradycardiawDyK  heartblockkDyK afib}DyK atrialflutteriDyK svtiDyK matgDyK vtgDyK qtsDyK  torsadessDyK  valvulargDyK asDyK mitralstenosisgDyK argDyK mrgDyK trDyK rheumaticfeverDyK antibioticprophylaxisiDyK aaaDyK aorticdissection{DyK  endocarditisyDyK  myocarditis{DyK  pericarditisDyK pericardialeffusionDyK acutepericarditisDyK InfectiousPericarditisuDyK  dresslersDyK uremicpericarditisDyK restrictivepericarditisDyK cardiactamponade}DyK cardiactumorssDyK  pedheart{DyK  cardiacpreopDyK cardiacphysiologyDyK cardiacphysicaliDyK ekgoDyK milabsDyK yK ,pics/cardiaccycle.jpgDyK yK pics/jvp.jpgsDyK  swanganzDyK yK rhttp://home.mdconsult.com/das/book/view/882?sid=21483771DyK yK 2pics/systolicmurmurs.jpgDyK yK 4pics/diastolicmurmurs.jpgb$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4ab$$If!vh55 #v#v :V l55 4aiDyK pvc/DyK yK http://www.uni-duesseldorf.de/WWW/MedFak/Herz-Kreislauf-Physiologie/lehre/sounds/html/asd.htmlkDyK afibDyK yK pics/jvp.jpgDyK constrictivepericarditisDyK  Fddx.docddx.docsyncopeDyK yK &pics/limbleads.jpgDyK yK more/ekg.htmluDyK  heartrateyDyK  heartrhythmuDyK  intervals}DyK axisdeviationyDyK  hypertrophyyDyK  ekgischemiamDyK lytesDyK yK ,pics/ecgpotassium.gifsDyK  torsadesDyK  F pharm.docpharm.docclassiDyK  F pharm.docpharm.doc classiiiDyK  F pharm.docpharm.doctcaDyK  F pharm.doc digitalisDyK yK &pics/limbleads.jpgDyK yK Bpics/fn-heartvesselsanterior.jpgDyK yK Dpics/fn-heartvesselsposterior.jpgiDyK wpwDyK yK ,pics/twavechanges.jpgDyK yK ,pics/ecgpotassium.gifDyK yK &pics/stchanges.jpgDyK yK Dpics/stelevationsandchestpain.jpgDyK hypokalemiaecgDyK  F pharm.docpharm.docdigoxinDyK  F pharm.docpharm.docclassiDyK hypokalemiaecgDyK yK .pics/ekg-potassium.gifDyK yK >pics/ekg-tuwave-cnsdisease.gifDyK yK $pics/ekg-lqts.gifsDyK  torsadeswDyK  stresstestDyK  F pharm.docpharm.docdigoxin{DyK  thrombolysisiDyK ladmDyK edemayDyK  hypothermiayDyK  HypovolemiamDyK shockiDyK chfiDyK htn{DyK  corpulmonaleiDyK dicDyK yK fhttp://content.nejm.org/cgi/content/full/348/3/243uDyK  diastolicgDyK cmiDyK jvpDyK pulmonaryedemaDyK cardiacenzymesDyK  F labs.docbnpDyK  F pharm.docaceiDyK cardiactransplantgDyK mimDyK connsDyK  Fddx.docorthostatichypotensionDyK pulmonaryhypertensionkDyK apkdDyK hyperthyroidismDyK primaryhyperaldosteronismsDyK  cushingsDyK pheochromocytomawDyK  acromegalyiDyK rccyDyK  proteinuria$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<$$If<!vh5 5x#v #vx:V l05 5x4a<DyK AtherosclerosisgDyK dmiDyK cadDyK yK jhttp://content.nejm.org/cgi/content/full/356/12/1241DyK yK *pics/pad-imaging.jpgDyK yK "pics/pad-ddx.jpgDyK buergerdiseaseDyK fibromusculardysplasiauDyK  takayasusDyK  F pharm.docpharm.doc cilostazolDyK yK 8pics/pad-surgeryorstent.jpgDyK  F labs.doclabs.docldlDyK  F labs.doclabs.dochdlDyK  F pharm.docpharm.docstatinsgDyK dmuDyK  chestpainoDyK anginagDyK miDyK yK dhttp://www.annals.org/cgi/content/full/139/10/824oDyK folateuDyK  xanthomasDyK  Fddx.docddx.doc chestpainDyK aorticdissectiongDyK pekDyK gerdkDyK sdes{DyK  pancreatitisuDyK  chestpain{DyK  stableanginaDyK unstableanginayDyK  prinzmetalsuDyK  syndromexwDyK  stresstestDyK  F pharm.docpharm.doc clonidineiDyK gbsoDyK milabsyDyK  mitreatmentDyK micomplicationsyDyK  miprognosiswDyK  mifollowupDyK othercausesofmi{DyK  thrombolysisDyK  F labs.doclabs.docckh$$If!vh5 5#v #v:V l(5 54ayt\DyK  F labs.doclabs.docckmbh$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\h$$If!vh5 5#v #v:V l(5 54ayt\DyK  F pharm.docpharm.doc thrombolysisuDyK  dresslersDyK papillaryruptureiDyK vsdDyK cardiactamponadeDyK ventricularaneurysmqDyK digiamiDyK thrombocytosisgDyK mmDyK methemoglobinemiaDyK yK dhttp://content.nejm.org/cgi/content/full/337/1/32$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*tDdJ  S &Alebbn~^-mnbn~^-PNG  IHDR~tRNSbKGD#2 cmPPJCmp0712Om,IDATc ρx~ ~ !j1.NpIENDB`$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*$$If!vh555U5! 5#v#v#vU#v! #v:V l6555U5! 54ayt0*DyK bicuspidaorticvalveDyK  Fddx.docddx.docsyncopeqDyK ascitessDyK  anorexiaDyK yK .pics/fn-esophagus1.jpg{DyK  endocarditisDyK papillarymuscleiDyK mvpDyK yK jhttp://content.nejm.org/cgi/content/full/355/19/2022DyK endocarditisprophylaxisDyK yK pics/jvp.jpgqDyK hornersiDyK svcDyK yK (pics/esophagus1.jpgDyK yK fhttp://content.nejm.org/cgi/content/full/348/9/834DyK yK jhttp://content.nejm.org/cgi/content/full/345/18/1318DyK  F micro.docmicro.dochacekDyK  F micro.docmicro.doc coxiellaDyK  F micro.docmicro.doc EnterococcusDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc groupbstrepDyK  F micro.docmicro.doc rhusiopathaeDyK yK Lpics/endocarditis-culturenegative.jpgDyK yK *pics/oslersnodes.jpgDyK yK ,pics/oslersnodes1.jpgDyK yK ,pics/oslersnodes2.jpgDyK yK ,pics/oslersnodes3.jpgDyK yK @pics/endocarditis-rothspots.jpgDyK yK @pics/endocarditis-petechiae.jpgDyK yK .pics/dukescriteria.jpg$$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ $$If!vh5t5$ 5@ 5 #vt#v$ #v@ #v :V l'5t5$ 5@ 5 4ayt{ DyK !antibioticprophylaxisbonesurgeryDyK  F pharm.docpharm.doc gentamicinDyK postpartumcardiomyopathyyDyK  thalassemiagDyK asyDyK  bradycardiawDyK  heartblockkDyK lbbbkDyK rbbbwDyK  hemiblocksoDyK atrialkDyK afib}DyK atrialflutteriDyK svtiDyK matyDyK  ventriculargDyK vtgDyK qtsDyK  torsadesDyK avconductiondelayDyK localizationofinfarct{DyK  hyperkalemiayDyK  hypokalemiaDyK  F pharm.doc digitalisDyK sicksinussyndromewDyK  pacemakerssDyK  torsadesDyK sinustachycardiaiDyK mat}DyK atrialflutterkDyK afibiDyK wpwmDyK avnrtkDyK npjtDyK  F pharm.docpharm.doc digitalisDyK hyperthyroidismiDyK pat}DyK atrialfluttergDyK vtDyK yK fhttp://content.nejm.org/cgi/content/full/356/9/935kDyK copdDyK  F pharm.docpharm.doc digitalisDyK  F pharm.docpharm.doc theophyllineyDyK  hypokalemiaDyK hypomagnesemiaDyK  F pharm.docpharm.doc procainamide$$If!vh5R5F5F555#vR#vF#v#v:V l05R5F554ayt/$$If!vh5R5F5F555#vR#vF#v#v:V l05R5F554ayt/$$If!vh5R5F5F555#vR#vF#v#v:V l05R5F554ayt/DyK yK fhttp://dermis.net/dermisroot/en/37635/diagnose.htmDyK yK &pics/ekg-jwave.jpgDyK restrictivepericarditisDyK cardiactamponadeDyK pericardialeffusionDyK acutepericarditisDyK InfectiousPericarditisDyK viralpericarditisDyK tbpericarditisuDyK  dresslersDyK uremicpericarditisiDyK slegDyK rasDyK  melanomaDyK yK 4pics/ekg-pericarditis.jpgDyK yK 2pics/pleuraleffusion.jpgDyK yK Dpics/jhid-pericardialeffusion.jpgDyK pulsusparadoxusDyK yK lhttp://content.nejm.org/cgi/content/full/343/19/1388?DyK yK jhttp://content.nejm.org/cgi/content/full/356/11/1153DyK yK >pics/infectiousmyocarditis.jpgqDyK markers{DyK  associations{DyK  tumorbiologyyDyK  tumorspreadiDyK bmtDyK neutropenicfeversDyK  leukemiasDyK  lymphomaDyK pulmonaryneoplasiaDyK liverneoplasiagDyK giDyK epidermaltumors{DyK  cnsneoplasmskDyK malewDyK  prostatecaoDyK femalesDyK  breastcamDyK ovaryDyK yK .drugs/chemotherapy.docmDyK nsgctDyK yK fhttp://dermis.net/dermisroot/en/19683/diagnose.htmDyK acanthosisnigricansiDyK hspiDyK gcaiDyK pansDyK  wegenersgDyK tsiDyK idayDyK  coloncancerDyK yK "pics/cowden1.jpgDyK yK "pics/cowden2.jpg{DyK  PeutzJeghersiDyK fapDyK paraneoplasticpemphigusDyK tumorsuppressorsyDyK  carcinogens{DyK  breastcancersDyK  fanconisDyK  F micro.docmicro.dochhv8gDyK mmDyK yK @pics/fibromusculardysplasia.jpg{DyK  renalstudiesyDyK  proteinuriauDyK  hematuriamDyK lytesiDyK arfDyK renaldrugtoxicityDyK rhabdomyolysisiDyK crfuDyK  nephritickDyK psgnDyK iganephropathykDyK rpgnkDyK ancaiDyK gbmDyK cryoglobulinemiauDyK  nephroticiDyK mcdkDyK fsgsiDyK mgnkDyK mpgn{DyK  hypertensionyDyK  amyloidosiskDyK goutsDyK  renalpan}DyK renalwegenersDyK renalscleroderma{DyK  renaltubulariDyK atniDyK rtaDyK renalthromboticsDyK  renaldiciDyK husiDyK ttpiDyK hspDyK renalendocarditisqDyK alportsDyK interstitialnephritisoDyK balkanwDyK  renalotheryDyK  renalstonesDyK renalhypertensionDyK renalarterystenosisDyK renalmalformationskDyK apkdDyK renaltransplantDyK renalneoplasmssDyK  dialysisDyK yK "pics/nephron.gifDyK  F labs.doclabs.doc creatinineyDyK  renalstonesuDyK  nephroticDyK yK >pics/tubularepithelialcell.jpgDyK yK "pics/rbccast.jpgDyK yK "pics/wbccast.jpgDyK yK *pics/hyalinecast.jpgDyK yK &pics/fattycast.jpgyDyK  sarcoidosiswDyK  prostatecauDyK  bladdercab$$If!vh55#v#v:V l554ab$$If!vh55#v#v:V l554ab$$If!vh55#v#v:V l554ab$$If!vh55#v#v:V l554ab$$If!vh55#v#v:V l554aqDyK arfaidsDyK tumorlysissyndromesDyK  dialysissDyK  burkittsiDyK allDyK rhabdomyolysisDyK  F pharm.docpharm.doc allopurinolDyK rhabdomyolysisyDyK  fatembolism{DyK  drugprerenaluDyK  drugrenal}DyK drugpostrenal{DyK  drugacidbasekDyK rta1kDyK apkdkDyK apkd{DyK  goodpasturessDyK  hcvrenalDyK complementstudiessDyK  wegeners{DyK  churgstraussiDyK mcdkDyK fsgsiDyK mgnkDyK mpgnDyK nephroticsyndromeDyK cryoglobulinemiaDyK transplantglomerulopathyDyK hydronephrosisDyK renalmechanicalDyK renalhypertensionDyK renalarterystenosissDyK  acidbaseiDyK rtaiDyK crfsDyK  diabetesDyK yK hhttp://content.nejm.org/cgi/content/full/344/12/917DyK yK 2pics/eye-amyloidosis.jpgDyK  Fddx.docddx.doc mononeuritisDyK multiplemyelomakDyK gout{DyK  endocarditisiDyK sleiDyK pansDyK  wegenersyDyK  sclerodermaDyK hypercoagulabilityDyK  Fddx.docddx.dochypercoagulabilityDyK focalthrombosisgDyK peiDyK dvtiDyK pvtyDyK  fatembolismDyK systemicthrombosissDyK  renaldicmDyK hellpiDyK ttpiDyK husiDyK hspDyK yK >pics/riskofthromboembolism.jpgDyK acutearterialocclusionDyK yK <pics/thrombophlebitis-apa.gifDyK yK bhttp://www.annals.org/cgi/content/full/146/3/211DyK yK bhttp://www.annals.org/cgi/content/full/146/3/211gDyK peDyK yK >pics/livedoreticularis-bad.jpgDyK yK fhttp://dermis.net/dermisroot/en/42784/diagnose.htmDyK yK fhttp://content.nejm.org/cgi/content/full/341/8/586DyK transfusionreactionoDyK sepsismDyK hellpDyK  F psycdrug.doc lamictalDyK yK 4pics/rbcfragments-dic.jpgDyK yK 2pics/schizocytes-dic.jpgDyK  F pharm.docpharm.docactivatedproteinc{DyK  preeclampsiaiDyK dic{DyK  appendicitisiDyK itpDyK  F micro.docmicro.docviralhepatitisDyK  F micro.docmicro.docehecDyK  F micro.docmicro.doc shigellaDyK iganephropathyDyK yK pics/hsp.jpg{DyK  hemodyalysisDyK  F pharm.docpharm.docdapsoneiDyK utiqDyK cadmiumkDyK leadoDyK copperqDyK mercurykDyK rta1iDyK rcciDyK atniDyK rtagDyK disDyK  fanconisDyK  F pharm.docpharm.docnsaidsDyK  F pharm.docpharm.docaminoglycosidesDyK rhabdomyolysisiDyK rvtsDyK  dialysisDyK multiplemyelomaDyK yK 4pics/plasmaosmolality.gifoDyK sepsisyDyK  renalstonesDyK  F pharm.docpharm.docacetazolamideDyK hypoaldosteronismkDyK ttkg{DyK  hyponatremiaDyK diabetesinsipidusyDyK  proximalrtaiDyK pidDyK diverticulitisiDyK aaa}DyK bladdercancerwDyK  leschnyhanDyK  F pharm.docpharm.doc indinavirDyK homocystinuria{DyK  hemodialysisDyK  F pharm.docpharm.doc steroidsDyK  F pharm.docpharm.doc cyclosporineDyK yK Zhttp://www.ajkd.org/cgi/content/full/35/1/58DyK yK \http://www.ajkd.org/cgi/content/full/35/1/154iDyK fuoDyK  F pharm.docpharm.docil2DyK  F pharm.docpharm.docifna{DyK  hyperkalemiaDyK renaltransplantDyK yK .pics/calciphylaxis.jpgoDyK sodiumuDyK  potassiumqDyK calciumuDyK  magnesiumuDyK  phosphate}DyK hypernatremia{DyK  hyperkalemia}DyK hypercalcemiaDyK hypermagnesemiaDyK hyperphosphatemia{DyK  hyponatremiayDyK  hypokalemia{DyK  hypocalcemiaDyK hypomagnesemiaDyK hypophosphatemia{DyK  hypoglycemiaiDyK dkaDyK yK .pics/f-hypokalemia.jpgDyK yK ,pics/ecgpotassium.gifDyK yK ,pics/ecgpotassium.gif{DyK  osteoporosisqDyK sarcoidsDyK  hyperpth{DyK  hyperthyroidoDyK pagetsgDyK mmmDyK pthrpDyK  F pharm.docpharm.doclithiumDyK  F pharm.docpharm.dochctzDyK adrenalinsufficiencywDyK  acromegaly{DyK  hemodialysisDyK hypomagnesemiakDyK afibgDyK qtmDyK siadhkDyK pftsDyK pulmonaryproceduresiDyK abgkDyK peepgDyK pe{DyK  pneumothorax{DyK  pneumothoraxqDyK abscessDyK alveolarhemorrhagekDyK ardssDyK  pleurisyDyK pleuraleffusionDyK pleuralfibrosiswDyK  bronchitisDyK bronchiectasisyDyK  atelectasisDyK lungobstructivekDyK copdoDyK asthmaiDyK raduDyK  emphysemaDyK lungrestrictiveiDyK osaiDyK csaoDyK lungcauDyK  pneumoniaDyK  F micro.docmicro.doc pneumococcusoDyK strepawDyK  hinfluenzawDyK  mycoplasmauDyK  chlamydiayDyK  psittacosiswDyK  legionellaiDyK gnriDyK pcpyDyK  compromisedoDyK postopwDyK  aspirationDyK  F micro.docmicro.docmtbDyK pneumoniaviralDyK pneumoniafungal{DyK  pneumoniahiviDyK ildiDyK ipf{DyK  desquamativeiDyK lip}DyK histiocytosismDyK rbailkDyK boopiDyK iph{DyK  occupationaluDyK  inorganicqDyK organicDyK otherchemicals{DyK  goodpasturesDyK Hypersensitivitypneumonitis{DyK  eosinophilicyDyK  aspergillusiDyK papDyK yK pics/pft.jpgkDyK dlcogDyK cfiDyK prviDyK dah}DyK thoracentesis{DyK  thoracoscopyDyK tubethoracostomy{DyK  bronchoscopykDyK pnbpkDyK ptnaDyK pleuraleffusionDyK yK 6procedurevids/yX;H,]ą'ciDyK dvtDyK hypercoagulability}DyK factorvleidenDyK yK more/dvt-pe.docDyK yK &pics/brown-PE8.jpgDyK yK pics/PE3.jpgDyK yK pics/PE1.jpgDyK yK pics/PE2.jpgDyK yK pics/PE5.jpgDyK yK pics/PE4.jpgDyK yK pics/PE7.jpgDyK yK pics/PE6.jpgDyK  F pharm.docpharm.docthrombolyticsDyK yK jhttp://content.nejm.org/cgi/content/full/356/14/1438DyK yK bhttp://www.annals.org/cgi/content/full/146/3/211DyK yK bhttp://www.annals.org/cgi/content/full/146/3/211DyK  F pharm.doclmwhDyK  F pharm.docpharm.doc coumadinDyK yK `http://www.annals.org/cgi/content/full/139/1/19DyK yK jhttp://content.nejm.org/cgi/content/full/347/15/1143DyK  F pharm.docpharm.doc alteplaseDyK yK jhttp://content.nejm.org/cgi/content/full/347/15/1131DyK yK pics/PE9.jpgqDyK hornersDyK  F pharm.docpharm.docflolanDyK childhoodpneumoniaDyK  Fddx.docddx.doc cavitaryDyK  F micro.docmicro.doc agepneumoniaDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc mpneumoniaeDyK  F micro.docmicro.doc klebsiellaDyK  F micro.docmicro.doc legionellaDyK  F micro.docmicro.doc chlamydiaDyK  F micro.docmicro.doc coxiellaiDyK rsvDyK  F micro.docmicro.doctbDyK  F micro.docmicro.doc pseudomonas$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytn$$If8!vh5f555#vf#v#v#v:V l5f5554a8ytnqDyK empyema}DyK ThoracentesisDyK pleuraleffusionDyK aspirationpneumonitisDyK  Fddx.docddx.doc cavitaryDyK  F micro.docmicro.docmaiDyK  F micro.docmicro.docmtbDyK  F micro.docmicro.doc francisellaDyK  F micro.docmicro.doc pneumocystisqDyK kaposisDyK  F micro.docmicro.docmeaslesDyK  F micro.docmicro.doc influenzaiDyK rsvDyK  F micro.docmicro.doc cryptococcusDyK  F micro.docmicro.doc histoplasmaDyK  F micro.docmicro.doc coccidioidesDyK  F micro.docmicro.doc cryptococcusDyK  F micro.docmicro.doc blastomycesDyK  F micro.docmicro.doccandidaDyK  F micro.docmicro.docvlmqDyK empyemaDyK  F micro.docmicro.doc pneumococcusDyK  F pharm.docpharm.doc pneumovaxqDyK empyemaDyK  F labs.doclabs.docasoDyK  F micro.docmicro.doc klebsiellaDyK  F micro.docmicro.doc ChlamydiaDyK  F micro.docmicro.doc chlamydiaDyK  F micro.docmicro.docrsvDyK  F micro.docmicro.dochsvDyK  F micro.docmicro.docvzvDyK  F micro.docmicro.doccmvDyK  F micro.docmicro.docpcpiDyK spnDyK yK jhttp://content.nejm.org/cgi/content/full/352/26/2714iDyK hoaDyK yK ,pics/hoa-bonescan.jpg{DyK  LambertEatonuDyK  carcinoidsDyK  pancoastDyK yK *pics/eye-horners.jpgDyK yK ,pics/eye-horners1.jpgDyK yK ,pics/eye-horners2.jpgDyK  F micro.docmicro.docmtbDyK yK Dpics/paraneoplasticantibodies.jpgDyK yK <pics/breastcancermets-mri.jpg{DyK  LambertEatonDyK yK fhttp://content.nejm.org/cgi/content/full/356/6/612DyK yK Rpics/progressivecerebellarataxia-ddx.jpguDyK  hamartomaDyK bronchogeniccarcinomaDyK yK Jpics/cavitation-consolidation-ct.jpgwDyK  asbestosisDyK yK jhttp://content.nejm.org/cgi/content/full/355/21/2226DyK  F pharm.docpharm.doc albuterolDyK  F pharm.docpharm.doc atroventDyK  F pharm.docpharm.doc cromolynDyK  F pharm.docpharm.doccorticosteroidsDyK  F pharm.docpharm.doc TheophyllineiDyK rsvDyK  F micro.docmicro.docstrongyloides{DyK  churgstrauss$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554ayt$$If!vh5 55555#v #v#v#v#v#v:V l(5 555554aytDdxih  s DA salphaalphabI Ff)nI Ff)PNG  IHDR2SbKGD#2 cmPPJCmp0712`JIDATW?M:4 Z<+ 7CQIiVbIENDB`{DyK  corpulmonaleDyK yK Zpics/emphysema-consolidation-airfluid-ct.jpgDyK  F pharm.docpharm.doc tiotropiumDdxih  s DA salphaalphabI Ff)nI Ff)PNG  IHDR2SbKGD#2 cmPPJCmp0712`JIDATW?M:4 Z<+ 7CQIiVbIENDB`DyK lungtransplantkDyK a1atDyK yK jhttp://content.nejm.org/cgi/content/full/355/20/2125DyK  F micro.docmicro.doc influenzaaDyK  F micro.docmicro.docrsvDyK  F micro.docmicro.doc mycoplasmaDyK  F micro.docmicro.doc bpertussisDyK  F micro.docmicro.doc chlamydiaDyK  F micro.doc influenzaaDyK  F pharm.docpharm.doc bleomycinDyK yK pics/lungs1.jpgDdxih  s DA salphaalphabI Ff)nI Ff)PNG  IHDR2SbKGD#2 cmPPJCmp0712`JIDATW?M:4 Z<+ 7CQIiVbIENDB`gDyK cfDdxih  s DA salphaalphabI Ff)nI Ff)PNG  IHDR2SbKGD#2 cmPPJCmp0712`JIDATW?M:4 Z<+ 7CQIiVbIENDB`Ddxih  s DA salphaalphabI Ff)nI Ff)PNG  IHDR2SbKGD#2 cmPPJCmp0712`JIDATW?M:4 Z<+ 7CQIiVbIENDB`DyK aspirationpneumonia}DyK ThoracentesisyDyK  transudatessDyK  exudatesmDyK meigsgDyK peDyK  F micro.docmicro.doctbDyK  F pharm.doctpaiDyK sleDyK  F pharm.docpharm.doc amiodarone{DyK  pancreatitiskDyK rpgnDyK yK :pics/pulmonaryhemorrhage.jpgDyK yK Fpics/pulmonaryhemorrhage-byage.jpgDyK  F micro.docmicro.docpcpyDyK  farmerslungiDyK ipfiDyK uipiDyK dipiDyK aipkDyK nsipDyK  F pharm.docpharm.doc pirfenidoneDyK  F micro.docmicro.doc cryptococcusDyK hypersensitivitypneumonitisiDyK pbciDyK ptxDyK yK hhttp://www.nejm.org/content/2001/0344/0003/0212.aspDyK yK Bpics/alveolarproteinosis-cxr.jpgsDyK  typefouruDyK  typethreeyDyK  sarcoidosis{DyK  churgstraussgDyK tbyDyK  sarcoidosisDyK hodgkinsdiseaseDyK eosinophilicgranulomaiDyK dipDyK invasiveaspergillosisuDyK  cnsinjuryiDyK cvauDyK  cnstraumaiDyK ich}DyK cnsvasculitis{DyK  cnsinfectionDyK cnsmalformations{DyK  cnsneoplasmsuDyK  headachessDyK  seizuressDyK  dementiaDyK  Fddx.docddx.doc deliriumiDyK icpiDyK nphyDyK  pseudotumor{DyK  neuropathies{DyK  neurologicalwDyK  alzheimersmDyK picksyDyK  huntingtonswDyK  parkinsonsiDyK msamDyK motoriDyK alsqDyK werdniguDyK  kugelberg}DyK demyelinatinggDyK mskDyK ademkDyK ahemiDyK gbsDyK demyelinatingsystemiciDyK pmlsDyK  myopathyDyK myopathycongenitalDyK myopathymitochondrialDyK myopathyinflammatorygDyK mg{DyK  lamberteatoniDyK pmrsDyK  muscularsDyK  duchenneqDyK beckersmDyK emeryuDyK  neuroexamDyK neuroradiologyDyK anatomicdiagnosisiDyK nphwDyK  parkinsonsiDyK alsoDyK cnsmrimDyK cnsct}DyK cnsultrasoundDyK transcranialdopplerDyK cerebralangiographyiDyK eegiDyK nsfDyK yK .pics/fn-oculomotor.jpgqDyK vertigoDyK craniopharyngiomaDyK yK jhttp://content.nejm.org/cgi/content/full/356/15/1527wDyK  alzheimersmDyK pickssDyK  lewybodywDyK  parkinsonsiDyK alsyDyK  huntingtonsiDyK cjdiDyK nphgDyK mswDyK  meningitisyDyK  hypothyroidqDyK wilsonsiDyK b12{DyK  cnsneoplasia}DyK cnsvasculitisiDyK icpsDyK  thiamineiDyK b12oDyK folateoDyK niacinDyK  F pharm.docpharm.doc lactuloseDyK  F pharm.docpharm.docflagylDyK rhabdomyolysisuDyK  serotoninsDyK  dementiaDyK hypothyroidismiDyK b12iDyK nphDyK  F pharm.docpharm.docariceptDyK  F pharm.docpharm.doc risperidoneDyK  www.alz.orgyK (http://www.alz.org/wDyK  shydragersDyK  F pharm.docpharm.docsynemetiDyK nmsDyK yK thttp://content.nejm.org/cgi/content/full/344/22/1688?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1688&journalcode=nejmDyK  F pharm.docpharm.doc RiluzoleDyK yK @http://www.utmed.com/psychiatryDyK  F pharm.docpharm.doc pramipexolegDyK mggDyK mskDyK cidpiDyK alsDyK  F micro.docmicro.docpoliouDyK  porphyriaDyK  F micro.docmicro.doc botulismiDyK emg}DyK opticneuritisDyK yK 6pics/multiplesclerosis.gifDyK yK pics/msddx.gifyDyK  stiffpersonDyK  F pharm.docpharm.doc amantadineDyK  F pharm.docpharm.doc pemolineyDyK  marchiafavaDyK  F micro.docmicro.docjcgDyK dmsDyK  SjogrensDyK myopathycongenitalsDyK  muscularsDyK  duchenneqDyK beckersmDyK emerysDyK  mcardlesDyK myopathymitochondrialDyK myopathyinflammatoryDyK polymyositismusclegDyK mgiDyK ibmiDyK emfDyK rhabdomyolysis}DyK myopathyothermDyK connssDyK  _werdnigsDyK  mcardles{DyK  polymyositisDyK yK &pics/pmr-hands.jpgiDyK gcaDyK hypothyroidismDyK hyperthyroidismsDyK  hyperpthmDyK connswDyK  acromegalyDyK  F micro.docmicro.doc botulismDyK  F pharm.docpharm.docstatinsDyK  F pharm.docpharm.docp450{DyK  hypocalcemiaDyK rhabdomyolysisiDyK dvtDyK  F pharm.docpharm.docbromocriptineDyK  F pharm.docpharm.doc dantroleneDyK  F pharm.docpharm.doc levodopaDyK  F pharm.docpharm.doc clonidineDyK  Fpathology.docectiDyK cvaiDyK ichDyK venoussinusthrombosis}DyK cnsvasculitisDyK carotidstenosisDyK lymphomatoidgranulomatosisyDyK  fatembolism{DyK  cvasyndromesDyK  F pharm.docpharm.doc thrombolysisDyK yK ,pics/eye-cn3palsy.jpgDyK yK ,pics/eye-cn6palsy.jpgwDyK  meningitisiDyK icpqDyK absenceoDyK statusDyK febrileseizuresDyK alcoholicseizuresDyK  F pharm.docpharm.docseizureDyK  F pharm.docpharm.doc dilantinDyK  F pharm.docpharm.doc tegretolDyK  F pharm.docpharm.doc ethosuximideDyK  F pharm.docpharm.docvpawDyK  meningitisiDyK cvaiDyK ichsDyK  glaucomaDyK  F psycdrug.docvpaDyK  F pharm.docpharm.docnsaidsDyK  F pharm.docpharm.docssriwDyK  alzheimerswDyK  parkinsonsDyK  F pharm.docpharm.docsynemetsDyK  vitaminaDyK yK fhttp://content.nejm.org/cgi/content/full/356/2/166DyK yK >pics/concussion-management.jpgDyK yK (pics/concussion.jpgDyK yK @pics/postconcussionsyndrome.jpggDyK msDyK acousticneuromaDyK  F pharm.doc temozolomideDyK yK 8pics/eye-conjunctivitis.jpgDyK yK :pics/eye-conjunctivitis1.jpgDyK yK Bpics/eye-viralconjunctivitis.jpgDyK yK Jpics/eye-bacterialconjunctivitis.jpgDyK yK Lpics/eye-bacterialconjunctivitis1.jpgDyK yK :pics/eye-endophthalmitis.jpgDyK yK $pics/hypopyon.gifDyK yK 6pics/eye-keratitis-hsv.jpgDyK yK Dpics/eye-keratitis-adenovirus.jpgDyK yK Fpics/eye-keratitis-aspergillus.jpgDyK yK 4pics/eye-cmvretinitis.jpgDyK  F micro.docmicro.doccandidaDyK yK <pics/eye-candidaretinitis.jpgDyK  F path.docpath.docbehcetsDyK yK <pics/eye-hypopyon-uveitis.jpgDyK  F pharm.docpharm.doc BevacizumabDyK yK >pics/retinalveinocclusion1.jpgDyK yK $pics/eye-crvo.jpgDyK yK &pics/eye-crvo1.jpgDyK yK &pics/eye-cvro2.jpgDyK yK $pics/eye-crao.jpgDyK yK &pics/eye-crao1.jpgDyK yK &pics/eye-crao2.jpggDyK msDyK yK .pics/eye-rothspots.jpgDyK yK <pics/eye-actinickeratosis.jpgDyK yK 8pics/eye-arcusjunenilis.jpgDyK yK .pics/eye-chalazion.jpgDyK yK 0pics/eye-chalazion1.jpgDyK yK 0pics/eye-chalazion2.jpgDyK yK *pics/eye-dermoid.jpgDyK yK 0pics/eye-gerontoxon.jpgDyK  F pharm.docpharm.doc pilocarpineDyK  F pharm.docpharm.docdiamoxDyK yK .pics/eye-hordeolum.jpgDyK yK 0pics/eye-hordeolum1.jpgDyK yK .pics/eye-hyperemia.jpgDyK yK .pics/eye-pterygium.jpgDyK yK 0pics/eye-pterygium1.jpgh$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4ayth$$If!vh5 5\ #v #v\ :V l5 5\ 4aytDyK  Fddx.docddx.docpostmenopausalbleedingDyK  Fddx.docddx.doc amenorrheawDyK  obstetricsDyK femaleinfectiongDyK bviDyK pidoDyK breastsDyK  breastcaDyK breastcancerscreeningmDyK vulvaoDyK vaginaoDyK cervixiDyK cinwDyK  cervicalcayDyK  endometriumDyK endometriumfxn}DyK endometriosisDyK endometrialneoplasiaDyK endometriummesenchymalDyK _gestationalca}DyK fallopiantubemDyK ovaryDyK follicularcystskDyK pcosuDyK  ovariancaDyK ovarianepithelialDyK ovariangermcellyDyK  femaleother{DyK  incontinenceDyK femalehealthmaintenanceuDyK  menopausekDyK pmof{DyK  prolactinomaDyK  Fddx.docddx.doc amenorrheaDyK  Fddx.docddx.docoligomenorrheaDyK  F pharm.docpharm.docspironolactoneDyK  F pharm.docpharm.doc metforminDyK arrhenoblastomaiDyK cahuDyK  chancroidiDyK lgvDyK  F micro.docmicro.doc molluscumDyK  F micro.docmicro.docscabiesDyK yK *pics/condylomata.jpgDyK yK fhttp://dermis.net/dermisroot/en/14295/diagnose.htmiDyK bccDyK yK &pics/cluecells.jpgDyK  F micro.doc ngonorrheaDyK  F micro.doc trichomonasDyK  Fddx.docddx.docpostmenopausalbleeding}DyK ovariantumorsDyK  F pharm.docpharm.docmtxDyK  Fddx.docddx.doc amenorrheawDyK  krukenbergDyK  F labs.docca125DyK  F labs.docafpDyK  F labs.dochcgDyK ovarianepithelialDyK ovariangermcellDyK ovarianstromalDyK ovarianmetastaticDyK testicularcancer{DyK  klinefeltersoDyK pagetsDyK yK bhttp://www.annals.org/cgi/content/full/122/7/539DyK yK fhttp://dermis.net/dermisroot/en/17409/diagnose.htmDyK  F pharm.docpharm.doc TamoxifenDyK  F pharm.docpharm.doc exemestane{DyK  osteoporosisDyK  F pharm.docpharm.doc oxybutyninDyK  F pharm.docpharm.doc tolterodineDyK yK jhttp://content.nejm.org/cgi/content/full/355/22/2338DyK  F pharm.docpharm.doc teratogensqDyK ectopicmDyK hellpDyK  F pharm.doc teratogensDyK yK jhttp://content.nejm.org/cgi/content/full/355/21/2237sDyK  cushingsDyK  F pharm.doc metyraponemDyK penissDyK  prostateiDyK bphwDyK  prostatecaoDyK testesDyK testicularinfectionDyK testicularcancerDyK  F micro.docmicro.doc syphilisDyK  F micro.docmicro.dochsvDyK  F micro.docmicro.doc ctrachomatisDyK yK 2pics/verrucavulgaris.jpgDyK yK fhttp://dermis.net/dermisroot/en/14003/diagnose.htmyDyK  accuminatumDyK yK pics/bowens.jpgDyK yK fhttp://dermis.net/dermisroot/en/14781/diagnose.htmDyK  F pharm.docpharm.docalpha1blockersDyK  F pharm.docpharm.doc finasterideDyK  F pharm.docpharm.doc flutamideDyK  Fddx.docddx.doc smalltestes{DyK  SeminomatoussDyK  seminomaDyK spermatocyticseminomamDyK nsgctDyK embryonalcarcinomaDyK yolksactumormaleDyK choriocarcinomasDyK  teratomaDyK leydigcelltumorDyK sertolicelltumorDyK testicularlymphomaDyK  F labs.doclabs.dochcgDyK  F labs.doclabs.docafpDyK  F pharm.docpharm.doc cisplatinDyK  F pharm.docpharm.doc etoposideDyK yK 6mailto:pharm.doc#bleomycinDyK yK fhttp://content.nejm.org/cgi/content/full/356/8/842DyK  F pharm.docpharm.docmtxsDyK  teratomaDyK  F pharm.docBCGuDyK  childhoodsDyK  vaccineswDyK  metabolism}DyK teratogenesissDyK  maternal}DyK morphogenesisuDyK  disruptedDyK pedrespiratoryDyK lungmalformations}DyK pediatrichemeuDyK  bilirubiniDyK abo}DyK pedintestinalDyK pediatricliversDyK  pedheartoDyK stills}DyK pediatricskinoDyK atopicwDyK  seborrheicDyK pediatricneurouDyK  pedtumorsqDyK geneticmDyK downsqDyK turnersuDyK  metabolicwDyK  aminoacidsDyK otherenzymedeficienciesDyK lysosomalstorageDyK MucopolysaccharidosesDyK glycogenstorageDyK hepatichypoglycemiaDyK muscleenergydisordersDyK developmentimmuneDyK  F pharm.docpharm.doc teratogenswDyK  surfactantwDyK  surfactantiDyK bpdwDyK  surfactantuDyK  pneumoniaiDyK bpdDyK  F pharm.docpharm.docphenobarbitalDyK transfusionmedicineDyK yK dhttp://en.wikipedia.org/wiki/Kleihauer-Betke_testDyK  F micro.docmicro.doc cdifficilemDyK liverDyK livertransplantiDyK asdiDyK vsdiDyK tof}DyK transpositionDyK avvalvemalformations}DyK _patentductusyDyK  coarctationmDyK downsqDyK turnersqDyK edwardsqDyK marfansyDyK  praderwilliiDyK jlnsDyK  williamsiDyK vsdkDyK tof1DyK  F psycdrug.doclithiumsDyK  leukemia{DyK  pedcnstumorssDyK  hodgkins}DyK histiocytoses}DyK pedtumorrenal}DyK pedtumorother}DyK neuroblastomaDyK yK fhttp://dermis.net/dermisroot/en/12300/diagnose.htmiDyK men~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmsDyK  gilbertsiDyK fapsDyK  gardners{DyK  peutzjeghersDyK juvenilepolyposisqDyK a1lungsDyK HemochromatosisqDyK wilsons~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmkDyK apkd~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmiDyK men~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmiDyK vwfDyK Dysfibrinogenemia~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmiDyK cmtyDyK  huntingtonsDyK myotonicdystrophy~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmqDyK marfanskDyK hocmiDyK nf1DyK hereditaryangioedemaDyK cysticfibrosis~$$If!vh5t55\#vt#v#v\:V l+5t55\4ayt|BmiDyK amlDyK yK fhttp://dermis.net/dermisroot/en/10038/diagnose.htmqDyK alportsDyK yK 0pics/lir-metabolism.jpgDyK yK 0pics/lir-glycolysis.jpgDyK clottingcascadeDyK yK 0pics/lir-metabolism.jpgiDyK b12DyK yK .pics/lir-porphyria.jpgDyK yK fhttp://dermis.net/dermisroot/en/24078/diagnose.htmsDyK  dialysisqDyK criglersDyK  gauchersDyK yK bhttp://www.annals.org/cgi/content/full/146/6/425DyK yK dhttp://content.nejm.org/cgi/content/full/345/1/55DyK hepaticadenomauDyK  pituitaryDyK pituitaryadenoma}DyK hypopituitaryDyK diabetesinsipidusmDyK siadhqDyK thyroidDyK hyperthyroidismDyK hypothyroidismyDyK  thyroiditisDyK thyroidneoplasmsDyK thyroidmalformationsyDyK  parathyroidsDyK  hyperpthqDyK hypopth}DyK pseudohypopthDyK parathyroidhyperplasiaDyK parathyroidneoplasmsiDyK menqDyK adrenalsDyK  cushingsDyK adrenalhyperplasiaDyK adrenaladenomaDyK adrenallymphomasDyK  addisonsmDyK connsiDyK cahoDyK mccuneDyK adrenalmedullaDyK pheochromocytoma}DyK paraganglioma}DyK neuroblastomasDyK  diabetesDyK  F labs.doc cortisolDyK  F labs.doc prolactinDyK  F labs.docfshkDyK pcosDyK acanthosisnigricansDyK yK 2pics/diabetes-yellow.jpgDyK yK *pics/necrobiosis.gifDyK yK fhttp://dermis.net/dermisroot/en/37833/diagnose.htmDyK  F pharm.docpharm.doc diabetesDyK yK http://content.nejm.org/cgi/content/short/347/17/1342?query=TOCDyK hyperlipidemiaDyK cardiacenzymessDyK  aniongapDyK yK jhttp://content.nejm.org/cgi/content/full/355/24/2558DyK  F pharm.docpharm.doc octreotideDyK craniopharyngioma}DyK nephrogenicdiDyK  F pharm.docpharm.doc desmopressinsDyK  siadhddxDyK thyroidmalformationsDyK hyperthyroidismDyK hypothyroidismyDyK  thyroiditisDyK thyroidneoplasmsDyK  F pharm.docpharm.doclevothyroxineb$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.b$$If.!vh55#v#v:V l554a.oDyK graves{DyK  thyroidstormDyK thyroidinfectiousDyK hypothyroidismoDyK graveswDyK  hashimotosiDyK hoaoDyK celiacDyK yK 4pics/eye-exophthalmos.jpgDyK  F pharm.docpharm.docptuDyK  F pharm.docpharm.doc methimazoleDyK  F pharm.docpharm.doci131DyK  F pharm.docpharm.doci131DyK thyroidneoplasmsDyK HypothyroidismofpregnancyDyK  F pharm.docpharm.doc amiodaroneiDyK men}DyK hypercalcemiaqDyK sarcoidiDyK menqDyK wilsonsDyK corticotrophicadenomaDyK adrenaladenomaDyK adrenalcarcinomaDyK yK fhttp://content.nejm.org/cgi/content/full/356/6/601{DyK  secondaryhtnoDyK mccunewDyK  acanthosisDyK  F labs.doclabs.docreninDyK  F labs.doclabs.doc AldosteroneDyK  F labs.doclabs.doc CortisolDyK  F labs.doclabs.docrenin$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoS$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoS$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoS$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoS$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoS$$If!vh5D 5T558#vD #vT#v#v8:V l05D 5T558/ aytoSiDyK meniDyK nf1oDyK sturgeoDyK mccune}DyK neuroblastomaDyK yK fhttp://content.nejm.org/cgi/content/full/356/6/601oDyK sepsisqDyK primaryiDyK utiDyK pyelonephritisuDyK  pneumoniawDyK  meningitiswDyK  cellulitisDyK infectiousarthritis}DyK osteomyelitisDyK peritonealinfectioniDyK pid{DyK  endocarditisoDyK sexualDyK  F micro.docmicro.dochivDyK  F micro.docmicro.doc hepatitisDyK  F micro.docmicro.doc chlamydiaDyK  F micro.docmicro.dochsvyDyK  hematologic}DyK opportunisticoDyK exoticDyK  F micro.docmicro.doc parasitologyDyK  F micro.docmicro.docfungusDyK  Fddx.docddx.doc diarrheauDyK  childhoodDyK F micro.docmicro.doc}DyK yK bugs/DyK yK http://www.hopkins-id.edu/education/id_caserounds/index_case.htmlDyK osteomyelitiswbcscanuDyK  pedsepsisDyK yK jhttp://content.nejm.org/cgi/content/full/355/16/1643DyK  F micro.doc cdifficileDyK yK Dpics/lir-anaerobicglycolysis1.jpgDyK yK Dpics/lir-anaerobicglycolysis2.jpg{DyK  childhoodutiDyK  F pharm.docpharm.docanticholinergicDyK pyelonephritisoDyK sepsisuDyK  pneumoniaDyK childhoodpneumoniaDyK peritonealinfectionuDyK  fasciitis}DyK osteomyelitisDyK yK fhttp://dermis.net/dermisroot/en/10777/diagnose.htmuDyK  lemmieresyDyK  pharyngitisDyK yK fhttp://content.nejm.org/cgi/content/full/344/3/205DyK  F micro.docmicro.docstrepaDyK  F micro.docmicro.docstrepcDyK osteomyelitisrxDyK osteomyelitismechanismsDyK _osteomyelitishematogenousDyK osteomyelitiscontiguousDyK osteomyelitisvertebralDyK osteomyelitisvascularDyK osteomyelitischronich$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSh$$If!vh5 5#v #v:V l5 54aytoSDyK epiduralabscessDyK yK jhttp://content.nejm.org/cgi/content/full/355/19/2012DyK yK 2pics/epiduralabscess.jpgDyK yK :pics/epiduralabscess-mri.jpgDyK viralmeningitisDyK bacterialmeningitisDyK chronicmeningitisDyK  F micro.docmicro.doc cryptococcusDyK  F micro.docmicro.doctoxoplasmosis}DyK cnsamoebiasisDyK  F micro.docmicro.doc enterovirusgDyK lpDyK  F micro.docmicro.dochsv1DyK  F micro.docmicro.doccmvDyK  F micro.docmicro.docmumpsDyK  F micro.docmicro.doc syphilisDyK  F micro.docmicro.doclcv}DyK agemeningitisDyK meningitisorganismsDyK  F micro.docmicro.docstrepbDyK  F micro.docmicro.docecoliDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc nmeningitisDyK  F micro.docmicro.doc hinfluenzaDyK  F micro.docmicro.doc listeriaDyK viralmeningitisiDyK sahDyK  F pharm.docpharm.docbactrimDyK  F pharm.docpharm.docnsaidsDyK  F pharm.docpharm.docinhgDyK lpDyK  F pharm.docpharm.docdiamoxDyK  F pharm.docpharm.doc rifampinDyK  F pharm.docpharm.docciproDyK  F pharm.docpharm.docbacteriocidalDyK yK 6procedurevids/yX;H,]ą'cDyK latexagglutinationpanel$$IfX!vh5558585#v#v#v8#v:V l055585/ 4aXytoS$$IfX!vh5558585#v#v#v8#v:V l055585/ 4aXytoS$$IfX!vh5558585#v#v#v8#v:V l055585/ 4aXytoS$$IfX!vh5558585#v#v#v8#v:V l055585/ 4aXytoS$$IfX!vh5558585#v#v#v8#v:V l055585/ 4aXytoS$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.docstrepbDyK  F micro.docmicro.doc neisseriaDyK  F micro.docmicro.doc pneumococcus$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.docecoliDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc pneumococcus$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.doc enterovirusDyK  F micro.docmicro.doc neisseria$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.doc listeriaDyK  F micro.docmicro.doc hinfluenzaDyK  F micro.docmicro.doc listeria$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBf$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.doc listeria$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBf$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBfDyK  F micro.docmicro.docherpes$$If!vh55p5p5T#v#vp#vT:V l55p5T4aytBf$$If!vh55T5p5b#v#vT#vp#vb:V l55T5p5b4aytBfDyK  F micro.docmicro.doc listeria$$If!vh55T5p5b#v#vT#vp#vb:V l55T5p5b4aytBf$$If!vh55T5p5b#v#vT#vp#vb:V l55T5p5b4aytBf$$If!vh55T5p5b#v#vT#vp#vb:V l55T5p5b4aytBfh$$If!vh55T#v#vT:V l55T4aytBfh$$If!vh55T#v#vT:V l55T4aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfDyK  F micro.docmicro.doc cryptococcush$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfxDyK hsv1h$$If!vh5 5#v #v:V l(5 54aytBfh$$If!vh5 5#v #v:V l(5 54aytBfsDyK  whipplesDyK  F micro.docmicro.doc bartonella}DyK toxoplasmosisDyK  F micro.docmicro.docebvDyK  F micro.docmicro.doc LeishmaniaDyK  F micro.docmicro.docmalariaDyK  F micro.docmicro.doc parvovirusDyK  F micro.docmicro.dochivDyK  F micro.docmicro.dochsvDyK  F micro.docmicro.doc chlamydiaiDyK lgvDyK  F micro.docmicro.doc ngonorrheaDyK  F micro.docmicro.doc trichomonasuDyK  chancroidDyK  F micro.docmicro.dochpvDyK  F micro.docmicro.doc syphilisDyK  F micro.docmicro.doc hepatitisDyK  F micro.doclymemDyK heentDyK pedsconjunctivitisoDyK otitisyDyK  pharyngitis{DyK  epiglottitisuDyK  pertussismDyK croupiDyK ebv}DyK bronchiolitis}DyK bronchiolitisDyK  F micro.docmicro.doc adenovirusDyK  F micro.docmicro.doc enterovirusDyK childhoodpneumoniaDyK  F micro.docmicro.docsaureusDyK  F micro.docmicro.docstrepaDyK  F micro.docmicro.docstrepbDyK  F micro.docmicro.doc listeriaDyK  F micro.docmicro.doc chlamydiaDyK viralmeningitisDyK bacterialmeningitis{DyK  childhoodutisDyK  diarrheauDyK  pedsepsisDyK  F micro.docmicro.doc rotavirusDyK  F micro.docmicro.docnorwalkDyK  F micro.docmicro.doc salmonellaDyK  F micro.docmicro.doc shigellaDyK  F micro.docmicro.docecoliDyK  F micro.docmicro.docvibrioDyK  F micro.docmicro.doc yersiniaDyK  F micro.docmicro.docgiardia{DyK  endocarditisDyK  F micro.docmicro.docrmsfuDyK  pedimmuneDyK congenitalinfectionsDyK  F micro.docmicro.docsyphiliscongenitaliDyK hsvkDyK skinDyK  F micro.docmicro.doc pneumococcusDyK ConjunctivitisDyK  F micro.docmicro.dochsvDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc hinfluenzaDyK  F micro.docmicro.doc moraxellaDyK  F micro.docmicro.docsaureusDyK  F micro.docmicro.doc pseudomonasDyK  F pharm.docpharm.doc augmentinDyK  F pharm.docpharm.doccephalosporinDyK  F pharm.docpharm.doc macrolidekDyK gerdDyK yK 2pics/herpangina-lips.jpgDyK yK 2pics/herpangina-hand.jpgDyK yK 2pics/herpangina-foot.jpgDyK  F micro.docmicro.doc enterovirusDyK yK fhttp://dermis.net/dermisroot/en/10181/diagnose.htmDyK  F micro.docmicro.doc mycoplasmaiDyK ebvDyK rheumaticfeverkDyK psgniDyK ebvDyK  F micro.docmicro.doc hinfluenzaDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.docstrepamDyK croupDyK  F pharm.docpharm.doc cefuroximeDyK  F micro.docmicro.doc influenzaDyK  F micro.docmicro.docparainfluenzaDyK  F micro.docmicro.doc rhinovirusDyK  F micro.docmicro.docparainfluenzaDyK  F micro.docmicro.docparainfluenzawDyK  tracheitisDyK  F pharm.docpharm.doc ribavirinDyK yK 8more/endoscopy/mi_tr_01.htmDyK  F micro.docmicro.doc pertussisDyK  F pharm.docpharm.doc erythromycinkDyK dtapDyK  F micro.docmicro.doc agepneumoniaDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc mpneumoniaeDyK  F micro.docmicro.doc chlamydiaDyK  F micro.docmicro.doc trachomatisDyK  F pharm.docpharm.doc cefuroximeDyK  F pharm.docpharm.doc macrolidesDyK  F pharm.docpharm.doc erythromycinwDyK  meningitisDyK  F micro.docmicro.doc nmeningitisDyK  F micro.docmicro.doc nmeningitisDyK yK 4pics/purpurafulminans.gifDyK  F micro.docmicro.docstrepbDyK  F micro.docmicro.docecoliDyK  F micro.docmicro.doc listeriaDyK  F micro.docmicro.doc pneumococcusDyK  F micro.docmicro.doc hinfluenzaDyK  F micro.docmicro.doc nmeningitisDyK  F micro.docmicro.doc toxoplasmaDyK  F micro.docmicro.doc exanthemsDyK  F micro.docmicro.docmeaslesDyK  F micro.docmicro.dochhv6DyK  F micro.docmicro.doc hepatitisDyK  F micro.docmicro.docmtbDyK  F pharm.docpharm.dochrzeDyK  F micro.docmicro.docpcpDyK  F micro.docmicro.doctoxoplasmosisDyK  F micro.docmicro.doc cryptococcusDyK  F micro.docmicro.doccmvDyK  F micro.docmicro.docmaiDyK  F micro.docmicro.dochbvDyK  F pharm.docpharm.dochbvDyK  F micro.docmicro.doccandidaiDyK pnhDyK  F micro.docmicro.docdf2DyK  Fddx.docddx.docabdominalpainsDyK  diarrheaDyK  Fddx.docddx.docgibleedkDyK oralsDyK  salivaryuDyK  esophagusuDyK  givaricesqDyK zenkersDyK esophagealwebsDyK esophagealringsqDyK herniasDyK esophagealinjurykDyK gerduDyK  achalasiaDyK transferdysphagiakDyK sdesDyK sclerodermaesophagusDyK esophagealcancerqDyK stomachiDyK pudDyK gastricvaricesDyK gastriccarcinomaDyK gastriclymphomasDyK  pancreasmDyK liveryDyK  gallbladdersDyK  appendixwDyK  peritoneumuDyK  intestine}DyK pedintestinalDyK intestinevascularqDyK varicesDyK mesentericischemia}DyK avmintestinalDyK diverticulitissDyK  diarrheaiDyK ibdiDyK ibdoDyK crohnsgDyK uc}DyK malabsorptionyDyK  celiacspruesDyK  whipples{DyK  obstructionsDyK intestinetumorqDyK coloncaiDyK fapDyK carcinoidtumorswDyK  gilymphomaDyK yK :pics/paracolicabscess-ct.jpgDyK yK ,pics/normal-colon.jpgDyK  Fddx.docddx.doc diarrheaDyK stoolosmolalityiDyK b12sDyK  vitaminKsDyK  vitamindDyK  F labs.doclabs.docinrDyK  F labs.doclabs.docalkalinephosphataseDyK  F labs.doclabs.docalbuminDyK  F pharm.docopioidwithdrawalDyK yK 2pics/oralcandidiasis.jpgDyK yK <pics/oralhairyleukoplakia.jpgqDyK behcetsqDyK reitersiDyK sle{DyK  peutzjeghersDyK yK (pics/glossitis1.jpgDyK yK (pics/glossitis2.jpgqDyK plummersDyK  barrettsDyK  F pharm.docpharm.docppiDyK  F pharm.docpharm.docreglanyDyK  sclerodermayDyK  celiacsprueDyK yK "pics/stomach.gifwDyK  perniciousqDyK hpyloriDyK gastriclymphomaiDyK nntDyK portalgastropathyDyK portalgastropathyDyK yK fhttp://content.nejm.org/cgi/content/full/356/8/820qDyK hpyloriDyK yK fhttp://content.nejm.org/cgi/content/full/345/9/669DyK yK 2pics/ischemiccolitis.jpgDyK  F micro.docmicro.doc rotavirusDyK  F micro.docmicro.docnorwalkDyK  F micro.docmicro.doc adenovirusDyK  F micro.docmicro.doc astrovirusDyK  F micro.docmicro.doc calicivirusDyK yK 6pics/infectiouscolitis.jpgDyK  F micro.docmicro.docsaureusDyK  F micro.docmicro.doc difficileDyK  F micro.doc cdifficileDyK  F micro.docmicro.docehecDyK  F micro.docmicro.doc shigellaDyK  F micro.docmicro.doc salmonellaDyK  F micro.docmicro.doccampylobacterDyK  F micro.docmicro.doc yersiniaDyK  F micro.docmicro.docgiardiaDyK  F micro.docmicro.doccryptosporidiumkDyK gvhdgDyK b6DyK yK Hpics/radiation-stenosis-jejunum.jpgDyK  F labs.doc fecalfatDyK yK fhttp://content.nejm.org/cgi/content/full/344/7/510DyK dermatitisherpetiformisDyK yK .pics/celiacdisease.jpgDyK dermatitisherpetiformisqDyK meckelsDyK esophagealcanceriDyK b12DyK yK dhttp://content.nejm.org/cgi/content/full/356/1/55DyK yK rhttp://www.google.com/search?hl=en&q=whipple%27s+diseaseDyK yK ,pics/whipples-mri.jpgDyK yK *pics/sf-whipples.jpgoDyK crohnsgDyK ucyDyK  renalstonesDyK ankylosingspondylitis{DyK  ibdtreatmentiDyK pscDyK ankylosingspondylitisDyK  Fddx.docddx.docerythemanodosumDyK erythemamultiformeiDyK pscDyK yK 6pics/ulcerativecolitis.jpgDyK  F pharm.docpharm.docsulfasalazineDyK yK jhttp://content.nejm.org/cgi/content/full/344/24/1846DyK yK Hpics/radiation-stenosis-jejunum.jpgDyK yK <pics/radiationproctopathy.jpgDyK yK :pics/paracolicabscess-ct.jpgDyK yK 8more/endoscopy/mi_gs_01.htmDyK yK 2pics/intussusception.jpgiDyK nhlDyK yK ,pics/peutzjeghers.jpgmDyK ovaryDyK yK jhttp://content.nejm.org/cgi/content/full/355/22/2349DyK yK 6pics/carcinoidsyndrome.jpgDyK  Fpathology.docshortboweldeficiencyDyK  F pharm.docpharm.doc5fuDyK  F pharm.docpharm.doc IrinotecanDyK yK \http://content.nejm.org/cgi/video/355/19/e21/DyK chronicpancreatitiswDyK  gallstonesDyK  F pharm.docpharm.doc didanosineDyK yK jhttp://content.nejm.org/cgi/content/full/355/25/2670DyK yK Fpics/autoimmunepancreatitis-ct.jpgDyK  F pharm.docpharm.doc streptozocinDyK  F labs.doclabs.docgastrinyDyK  cholangitiskDyK mrcpDyK  F pharm.docpharm.docvaccinekDyK #itpDyK  F micro.docmicro.doc#ebvuDyK  liverlabsuDyK  hepatitisDyK  F micro.docmicro.doc hepatitisDyK  F micro.docmicro.doc hepatitisaDyK  F micro.docmicro.doc hepatitisbDyK  F micro.docmicro.doc hepatitiscDyK  F micro.docmicro.docviralhepatitislabsDyK alcoholichepatitisDyK autoimmunehepatitiskDyK nashyDyK  gallbladderDyK cholelithiasis}DyK cholecystitisyDyK  cholangitisqDyK biliaryyDyK  alpha1liverqDyK wilsonsDyK hemochromatosisqDyK ascitesiDyK sbpDyK portalcirrhosisyDyK  pncirrhosis{DyK  portalvenousDyK liverneoplasiaDyK livertransplantiDyK fnhiDyK hcaiDyK hcc{DyK  pedbilirubinDyK  F micro.docmicro.docviralhepatitislabsDyK yK pics/hbv1.jpgDyK yK pics/hbv2.jpgiDyK hcc{DyK  yolksactumorDyK  Fddx.docddx.docascitesDyK hepaticencephalopathyDyK yK pics/portal.jpgDyK  F micro.docmicro.doc hepatitisyDyK  alpha1liverqDyK wilsonsDyK hemochromatosisDyK  F labs.doclabs.docamaDyK  F labs.doclabs.docamaDyK  F labs.doclabs.docalkphosDyK yK hhttp://content.nejm.org/cgi/content/full/332/14/924yDyK  cholangitisDyK yK pics/n-psc1.gifDyK yK pics/n-psc2.gifDyK  F pharm.docpharm.doc ursodiolqDyK a1lungsDyK yK jhttp://content.nejm.org/cgi/content/full/350/23/2383iDyK hccDyK  F labs.doclabs.doc ferritingDyK a2DyK  F labs.doclabs.doclapDyK  F pharm.docpharm.docpenicillamineDyK  F pharm.docpharm.docmetronidazoleDyK  F micro.dochcvDyK  F labs.docafpDyK yK jhttp://content.nejm.org/cgi/content/full/356/15/1545sDyK  oncologyDyK transfusionmedicineoDyK anemia{DyK  anemiaworkupuDyK  anemiaddxDyK hemolyticanemiamDyK hellpDyK aplasticanemiaDyK hemoglobinopathywDyK  sicklecellyDyK  thalassemiaDyK thrombocytopeniaDyK  Fddx.docddx.docthrombocytopeniaiDyK hitiDyK ttpiDyK itpiDyK apayDyK  coagulationwDyK  hemophiliaDyK vonwillebrandsDyK hypercoagulabilityiDyK apaiDyK apcyDyK  prothrombinDyK renalthromboticsDyK  renaldicmDyK hellpiDyK ttpiDyK husiDyK hspsDyK  leukemiaiDyK alliDyK alliDyK amliDyK clluDyK  hairycellDyK myeloproliferativeiDyK cml}DyK myelofibrosisDyK thrombocythemiaiDyK prvuDyK  leukemoidwDyK  plasmacellDyK multiplemyelomagDyK wmwDyK  heavychainwDyK  monoclonal}DyK histiocytosessDyK  lymphomasDyK  hodgkinsiDyK nhluDyK  lymphomabDyK smalllymphocyticyDyK  cleavedcellDyK largecelllymphomasDyK  burkittsuDyK  lymphomatwDyK  adulttcell}DyK lymphoblasticoDyK sezaryDyK yK 6pics/h-clottingcascade.jpgDyK yK 6pics/f-clottingcascade.jpgDyK yK ,pics2/hematology.htmlDyK coldagglutininsuDyK  anemiaddxDyK yK ,pics/pallor-nails.jpgDyK reticulocytecountDyK peripheralsmearwDyK  bonemarrowDyK aplasticanemiaDyK hemolyticanemiaiDyK idayDyK  thalassemiauDyK  porphyria}DyK spherocytosis}DyK myelofibrosisDyK yK ,pics/schistocytes.jpgiDyK mdsDyK yK hhttp://www.nejm.org/content/1999/0341/0026/1986.aspDyK yK Rpics/microcytic-irondeficiencyanemia.jpgDyK  F pharm.docpharm.docinhDyK yK 4pics/microcyticanemia.jpgDyK  F micro.docb19DyK yK `pics/hypersegmentedneutrophil-b12deficiency.jpgDyK yK hhttp://www.nejm.org/content/1997/0337/0020/1441.aspiDyK diciDyK ttpDyK yK Tpics/microspherocytes-hemolyticanemia.jpgDyK  F pharm.docpharm.doc methyldopaDyK  F micro.docmicro.doc mpneumoniaeDyK  F micro.docmicro.docbrownreclusespiderDyK hypophosphatemiaDyK  Fddx.docddx.docthrombocytopeniaDyK  F labs.doclabs.doclapDyK  Fddx.docddx.doc splenomegalyyDyK  splenectomyDyK yK *pics/eye-icterus.jpgDyK yK ,pics/sickledcells.jpgDyK yK 2pics/sicklecellsmear.jpgDyK  F pharm.docpharm.doc pneumovaxiDyK ffpDyK cryoprecipitatekDyK iviguDyK  plateletsDyK hemolyticanemiaiDyK itpDyK  F micro.docmicro.doctsstiDyK vwdDyK  Fddx.docddx.docthrombocytopeniaiDyK hitiDyK ttpiDyK itpiDyK apaiDyK dicDyK yK jhttp://content.nejm.org/cgi/content/full/355/16/1699DyK  Fddx.docddx.docthrombocytopeniaDyK  F pharm.docpharm.docivigDyK  F pharm.docpharm.doc lepirudinDyK  F pharm.docpharm.doc argatrobanDyK HypercoagulabilityDyK yK 6pics/h-clottingcascade.jpgDyK yK $pics/thrombin.gifDyK  F pharm.docpharm.doclovenoxDyK  F pharm.docpharm.dochepariniDyK diciDyK ffpDyK cryoprecipitateDyK  F pharm.docpharm.docddavpDyK yK fhttp://dermis.net/dermisroot/en/25652/diagnose.htmDyK yK 6pics/h-clottingcascade.jpgDyK yK Hpics/hypercoagulable-prevalance.jpgiDyK apcyDyK  prothrombinDyK homocystinuriaDyK DysfibrinogenemiaiDyK pnhiDyK sleqDyK behcetssDyK  buergersiDyK prvDyK thrombocythemiaiDyK ttpiDyK dicDyK diabeteshypercoagulableDyK antiphospholipidsDyK  proteincsDyK  proteins{DyK  antithrombinDyK  F pharm.docpharm.doc warfarinDyK yK jhttp://content.nejm.org/cgi/content/full/348/15/1425iDyK sleiDyK tmaDyK yK 6pics/h-clottingcascade.jpgDyK  F pharm.docpharm.docheparinDyK yK 6pics/livedoreticularis.jpgDyK yK 0pics/livedoracemosa.jpgDyK yK &pics/proteinc1.jpgDyK yK &pics/proteinc2.jpgDyK homocystinuriaDyK yK (pics/cll-bcells.jpgDyK yK pics/cll.jpgDyK yK dpics/hairycellleukemia-cytoplasmicprojections.jpgDyK yK ,pics/aml-auerrods.jpgDyK yK &pics/chloroma1.gifDyK yK &pics/chloroma2.gifDyK yK &pics/chloroma3.gifiDyK dicmDyK downsDyK yK 4pics/cml-granulocytes.jpgDyK  F labs.doclabs.doclapDyK  F pharm.docpharm.doc imatinibDyK  F pharm.docpharm.doc hydroxyureaaDyK yK http://content.nejm.org/cgi/content/full/342/17/1255?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&titleabstract=myelofibrosis&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jouDyK yK jhttp://content.nejm.org/cgi/content/full/355/26/2765DyK yK *pics/mgus-workup.jpgDyK yK 4pics/mgus-comparisons.jpgyDyK  amyloidosisDyK yK Jpics/multiplemyeloma-plasmacells.jpgDyK  F labs.doclabs.docspepDyK  F labs.doclabs.docupepDyK  F labs.doclabs.docalkalinephosphataseDyK  F pharm.docpharm.doc BortezomibDyK  Fddx.docddx.dochyperviscocityyDyK  amyloidosisDyK  F labs.doclabs.docspepDyK  F pharm.docpharm.doc rituximabDyK  F micro.docmicro.dochivDyK  F micro.docmicro.dochhv8DyK  F micro.docmicro.docebvDyK  F pharm.docpharm.docmoppDyK yK Fpics/hodgkins-nodularsclerosis.jpgDyK yK 6pics/reedsternbergcell.jpgDyK tumorlysissyndromeDyK yK fhttp://content.nejm.org/cgi/content/full/356/5/504DyK yK Hpics/lymphomatoidgranulomatosis.jpgDyK yK pics/all-l3.jpgDyK yK Hpics/burkittslymphoma-starrysky.jpgDyK yK &pics/htlvlungs.jpgDyK yK pics/htlv1.jpgsDyK  mycosis1DyK yK fhttp://dermis.net/dermisroot/en/19924/diagnose.htmyDyK  orthopedicsDyK bonemalformationswDyK  bonecancer{DyK  osteoporosiskDyK kneeyDyK  lowbackpainuDyK  fracturesDyK bonemalformationsDyK yK bhttp://www.annals.org/cgi/content/full/139/7/575DyK inflammatoryjointdiseasegDyK oaDyK yK ,pics/kneeexam-aim.jpg}DyK OsteomyelitisDyK  F pharm.docpharm.docbisphosphonatesDyK yK bhttp://www.annals.org/cgi/content/full/137/6/529oDyK pagetsDyK  F pharm.docpharm.doc alendronate}DyK osteomyelitisuDyK  skindrugswDyK  eczematousoDyK atopicwDyK  seborrheicDyK contactdermatitiswDyK  skinfungalDyK papulosquamousuDyK  psoriasis{DyK  lichenplanus}DyK lichensimplexwDyK  pityriasisDyK epidermaltumorsDyK epidermalbenignDyK epidermalpremalignantDyK epidermalmalignant{DyK  dermaltumorsDyK dermaltumorsbenignyDyK  hemangiomasqDyK kaposisyDyK  melanocyticDyK melanocyticbenignDyK melanocyticpremalignantsDyK  melanomakDyK acneDyK vesiculobullousDyK intraepidermal{DyK  subepidermaluDyK  pemphiguswDyK  pemphigoidDyK herpesgestationisDyK epidermolysisbullosaDyK erythemamultiformeDyK dermatitisherpertiformisDyK leukocytoclasticDyK skincongenital}DyK pediatricskinDyK yK ^http://dermis.net/dermisroot/en/home/index.htmDyK yK 0http://www.dermnet.com/DyK  F pharm.docpharm.docataraxDyK  F pharm.docpharm.docdoxepinDyK yK fhttp://dermis.net/dermisroot/en/30437/diagnose.htmDyK  Fddx.docddx.docenDyK yK &pics/vitiligo1.jpgDyK yK fhttp://dermis.net/dermisroot/en/37282/diagnose.htmyDyK  sarcoidosisDyK  F micro.docmicro.doclepraDyK yK Dpics/pseudoxanthomaelasticum1.gifDyK yK Dpics/pseudoxanthomaelasticum2.gifDyK yK fhttp://dermis.net/dermisroot/en/42210/diagnose.htmDyK yK <pics/foreignbodygranuloma.jpgDyK yK fhttp://dermis.net/dermisroot/en/41156/diagnose.htmDyK yK dhttp://www.dermnet.com/moduleIndex.cfm?moduleID=8DyK yK <pics/acanthosisnigricans1.jpgDyK yK 8pics/acanthosis-benign1.jpgDyK yK 8pics/acanthosis-benign2.jpgDyK yK 8pics/acanthosis-benign3.jpgDyK yK >pics/acanthosis-malignant1.jpgDyK yK 0pics/eczema-fingers.jpgDyK yK pics/eczema.jpgDyK yK fhttp://dermis.net/dermisroot/en/27284/diagnose.htmDyK yK 4pics/atopicdermatitis.jpgDyK yK dhttp://www.dermnet.com/moduleIndex.cfm?moduleID=2DyK  F pharm.docpharm.doc cyclosporineDyK  F pharm.docpharm.doc tacrolimusDyK yK >pics/seborrhoeicdermatitis.jpgDyK yK @pics/seborrhoeicdermatitis1.jpgDyK yK @pics/seborrhoeicdermatitis2.jpgDyK yK @pics/seborrhoeicdermatitis3.jpgDyK yK @pics/seborrhoeicdermatitis4.jpgDyK yK @pics/seborrhoeicdermatitis5.jpgDyK yK fhttp://dermis.net/dermisroot/en/14554/diagnose.htmDyK yK 6pics/contactdermatitis.jpgDyK yK fhttp://dermis.net/dermisroot/en/14607/diagnose.htmDyK  F micro.docmicro.doctineaDyK  F micro.docmicro.doccandidaDyK  F micro.docmicro.doc malasseziaqDyK mycosisDyK yK fhttp://dermis.net/dermisroot/en/19720/diagnose.htmuDyK  psoriaticDyK yK |http://dermis.multimedica.de/dermisroot/en/31346/diagnose.htmDyK yK 0pics/psoriasis-back.jpgDyK yK 2pics/psoriasis-knees.jpgDyK yK &pics/psoriasis.jpgDyK yK 0pics/psoriasishands.jpgDyK  Fpathology.doc vitaminaDyK  F pharm.docpharm.docmtxDyK yK |http://dermis.multimedica.de/dermisroot/en/32882/diagnose.htmDyK yK ,pics/lichenplanus.jpgDyK yK fhttp://dermis.net/dermisroot/en/32551/diagnose.htmDyK yK |http://dermis.multimedica.de/dermisroot/en/33781/diagnose.htmDyK yK |http://dermis.multimedica.de/dermisroot/en/32735/diagnose.htmDyK  F micro.docmicro.doc syphilisDyK yK 8more/endoscopy/mi_sy_01.htm{DyK  dermaltumorsyDyK  melanocyticDyK tumorsyndromesDyK yK |http://dermis.multimedica.de/dermisroot/en/21934/diagnose.htmDyK yK 4pics/sebaceousadenoma.jpgDyK yK |http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htmDyK yK |http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htmDyK yK 0pics/epidermoidcyst.jpgDyK yK |http://dermis.multimedica.de/dermisroot/en/36857/diagnose.htmDyK yK @pics/actinickeratosis-hands.jpgDyK yK fhttp://dermis.net/dermisroot/en/35352/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/23246/diagnose.htmDyK yK 8pics/sebaceouscarcinoma.jpgDyK yK fhttp://dermis.net/dermisroot/en/18406/diagnose.htmDyK yK pics/bcc.jpgDyK yK fhttp://dermis.net/dermisroot/en/18406/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/19297/diagnose.htmDyK yK .pics/majolinsulcer.jpgDyK yK "pics/scc-lip.jpgDyK yK (pics/scc-tongue.jpgDyK yK fhttp://dermis.net/dermisroot/en/23404/diagnose.htmiDyK nf1DyK yK 0pics/dermatofibroma.jpgDyK yK fhttp://dermis.net/dermisroot/en/22350/diagnose.htmDyK yK pics/keloid.jpgDyK yK *pics/acrochordon.jpgDyK yK fhttp://dermis.net/dermisroot/en/37036/diagnose.htmDyK yK (pics/hemangioma.jpgDyK yK fhttp://dermis.net/dermisroot/en/22725/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/40613/diagnose.htmDyK yK .pics/spiderangioma.jpgDyK yK fhttp://dermis.net/dermisroot/en/21601/diagnose.htmDyK yK 6pics/pyogenicgranuloma.jpgDyK yK fhttp://dermis.net/dermisroot/en/27156/diagnose.htmDyK yK <pics/kaposissarcoma-mouth.jpgDyK yK pics/sweets.jpgDyK yK fhttp://dermis.net/dermisroot/en/31053/diagnose.htmDyK yK <pics/pyodermagangrenosum1.jpgDyK yK <pics/pyodermagangrenosum2.jpgDyK yK <pics/pyodermagangrenosum3.jpgDyK yK :pics/pyodermagangrenosum.jpgDyK yK fhttp://dermis.net/dermisroot/en/25427/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/19487/diagnose.htmDyK yK ,pics/acquirednevi.jpgDyK yK 4pics/melanocyticnevus.jpgDyK yK fhttp://dermis.net/dermisroot/en/37575/diagnose.htmDyK neurofibromatosisDyK yK fhttp://dermis.net/dermisroot/en/21179/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/20986/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/37428/diagnose.htmDyK yK 4pics/dysplasticnevus1.jpgDyK yK 4pics/dysplasticnevus2.jpgDyK yK 4pics/dysplasticnevus3.jpgDyK yK Bpics/dysplasticnevussyndrome.jpgDyK yK 6pics/malignantmelanoma.jpgDyK yK fhttp://dermis.net/dermisroot/en/18195/diagnose.htmDyK yK &pics/melanoma1.jpgDyK yK &pics/melanoma2.jpgDyK yK 8pics/amelanoticmelanoma.jpgDyK  F pharm.docpharm.docifnDyK yK fhttp://dermis.net/dermisroot/en/18065/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/17570/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/18014/diagnose.htmDyK yK &pics/melanoma3.jpgDyK yK fhttp://dermis.net/dermisroot/en/36249/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/30526/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/30730/diagnose.htmDyK  F pharm.docpharm.doc erythromycinDyK yK fhttp://dermis.net/dermisroot/en/36097/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/36097/diagnose.htmDyK  F micro.docmicro.doc PseudomonasiDyK slewDyK  pemphigoidwDyK  cellulitisDyK contactdermatitisDyK dermatitisherpetiformisoDyK eczemaDyK epidermolysisbullosaDyK erythemamultiformesDyK  impetigo{DyK  lichenplanusuDyK  pemphigusiDyK pctDyK  F micro.docscabiesiDyK tenDyK  F micro.docmicro.docvzvDyK yK fhttp://dermis.net/dermisroot/en/36070/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/36070/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/11499/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/29476/diagnose.htmDyK  F micro.docmicro.doccapitisDyK  F micro.docmicro.doc scaldedskinwDyK  cellulitisqDyK typeoneqDyK typetwoDyK yK fhttp://dermis.net/dermisroot/en/29511/diagnose.htmDyK yK &pics/pemphigus.jpgDyK  F pharm.docpharm.doccorticosteroidsDyK yK $pics/pps1oral.jpgDyK yK Bpics/paraneoplasticpemphigus.jpgDyK yK 2pics/pps2scaldedskin.jpgDyK yK 0pics/conjunctivitis.jpgDyK yK pics/pps4em.jpgDyK yK fhttp://dermis.net/dermisroot/en/29664/diagnose.htmDyK yK (pics/pemphigoid.jpgDyK yK 6pics/bullouspemphigoid.jpgDyK yK fhttp://dermis.net/dermisroot/en/29935/diagnose.htmDyK  F pharm.docpharm.doc tetracyclineDyK yK fhttp://dermis.net/dermisroot/en/26713/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/40853/diagnose.htmDyK  F pharm.docpharm.docerythropoetinDyK yK fhttp://dermis.net/dermisroot/en/29366/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/30140/diagnose.htmuDyK  typethreeDyK yK fhttp://dermis.net/dermisroot/en/43431/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/30218/diagnose.htmDyK yK :pics/erythemamultiforme2.jpgDyK yK :pics/erythemamultiforme1.jpgDyK yK :pics/erythemamultiforme3.jpgDyK yK Fpics/erythemamultiformetarget1.jpgDyK yK Fpics/erythemamultiformetarget2.jpgDyK yK Fpics/erythemamultiformetarget3.jpgDyK yK $pics/emmajor1.jpgDyK yK Dpics/erythemamultiformemajor1.jpgDyK yK 0pics/stevensjohnson.jpgDyK yK fhttp://dermis.net/dermisroot/en/30254/diagnose.htmDyK yK pics/ten1.jpgiDyK hspDyK yK fhttp://dermis.net/dermisroot/en/13645/diagnose.htmDyK yK .pics/drugbleomycin.jpgDyK yK "pics/argyria.jpgDyK yK 0pics/drugamiodarone.jpgDyK yK 6pics/drug-morbilliform.jpgDyK yK 4pics/drugmorbilliform.jpgDyK yK 6pics/drugmorbilliform2.jpgDyK yK 2pics/drug-urticaria1.jpgDyK yK 2pics/drug-urticaria2.jpgDyK yK &pics/lichenoid.jpgDyK yK ,pics/drugpustular.jpgDyK  F pharm.docpharm.doc phenytoinDyK yK 0pics/drug-dilantin2.jpgDyK yK 0pics/drug-dilantin1.jpgDyK  F pharm.docpharm.doc tegretolDyK  F pharm.docpharm.doc lamictalDyK yK 0pics/drug-lamictal1.jpgDyK yK 0pics/drug-lamictal2.jpgiDyK dicDyK  F pharm.docpharm.doc warfarinDyK yK .pics/drugwarfarin1.jpgDyK yK .pics/drugwarfarin2.jpgoDyK ehlersiDyK nf1gDyK tsoDyK sturgeiDyK ktwDyK yK fhttp://dermis.net/dermisroot/en/39866/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/23420/diagnose.htmkDyK cafeDyK yK 6pics/neurofibromatosis.jpg{DyK  neurofibromaDyK yK fhttp://dermis.net/dermisroot/en/42574/diagnose.htmDyK yK fhttp://dermis.net/dermisroot/en/42531/diagnose.htmiDyK pvd}DyK calciphylaxissDyK  fanconisDyK yK .pics/lir-porphyria.jpgDyK yK :pics/chronicerythroderma.jpgDyK yK 4pics/aldrichmeeslines.jpgDyK methemoglobinemiaiDyK idaDyK yK Fhttp://www.acponline.org/bioterro/DyK  F micro.docmicro.docanthraxDyK  F micro.docmicro.doc smallpoxDyK  F micro.docmicro.dochemorrhagicfeversDyK  F micro.docmicro.doclassaDyK  F micro.docmicro.docebolaDyK yK @more/acuteradiationsyndrome.pdfDyK yK `http://www.acponline.org/bioterro/nerve_gas.htmDyK yK vhttp://pier.acponline.org/physicians/public/d890/d890.htmlDyK organophosphatesDyK  F pharm.docpharm.doc drugsofabusesDyK  thiaminewDyK  riboflavinoDyK niacinyDyK  _pyridoxineiDyK b12oDyK folatesDyK  vitamincsDyK  vitaminasDyK  vitamindsDyK  vitaminesDyK  vitaminkuDyK  WernickesoDyK PagetsDyK yK $pics/pellagra.jpgDyK yK 0pics/pellagra-hands.jpgDyK  F pharm.docniacinDyK yK $pics/hartnups.jpgDyK yK Hhttp://en.wikipedia.org/wiki/LegumeDyK megaloblasticanemiauDyK  psoriasiskDyK acneDyK  F pharm.docpharm.doc accutanesDyK  leukemiayDyK  pseudotumorsDyK  vitamindDyK hemolyticanemia}DdZ  s 6A uarrbU,tnIP%ydžnU,tnIP%yPNG  IHDR~tRNSbKGD#2 cmPPJCmp0712Om%IDATcb 0 dG}^D,hIENDB`DyK yK fhttp://dermis.net/dermisroot/en/34987/diagnose.htmzDdZ  s 6A darrb'Yfhj͔R3On'Yfhj͔R3OPNG  IHDR~tRNSbKGD#2 cmPPJCmp0712Om"IDATc~*`d#>'4(aIENDB`qDyK WilsonszDdZ   s 6A  darrb'Yfhj͔R3On'Yfhj͔R3OPNG  IHDR~tRNSbKGD#2 cmPPJCmp0712Om"IDATc~*`d#>'4(aIENDB`zDdZ   s 6A  darr b'Yfhj͔R3On'Yfhj͔R3OPNG  IHDR~tRNSbKGD#2 cmPPJCmp0712Om"IDATc~*`d#>'4(aIENDB`oDyK traumawDyK  transplantDyK yK 6pics/cardiacpreop-acp1.jpgDyK yK 6pics/cardiacpreop-acp2.jpgDyK endocarditisprophylaxisDyK yK >pics/prevertebralemphysema.jpgDyK yK 6procedurevids/yX;H,]ą'cDyK yK 6procedurevids/yX;H,]ą'cDyK livertransplantDyK lungtransplantDyK renaltransplantDyK hearttransplantkDyK gvhdDyK yK 6pics/bmt-complications.gifDyK  F micro.docmicro.docstaphDyK  F micro.docmicro.docstaphepidermidisDyK  F pharm.docpharm.doczosynDyK  F pharm.docpharm.doc cefepimeDyK  F pharm.docpharm.docamphobDyK  F pharm.docpharm.docgcsfDyK  F pharm.docpharm.docepoDyK methemoglobinemia}DyK environmental%8@8 Normal_HmH sH tH :@: Heading 1$5CJF@F Heading 2$0^`0CJN@2N Heading 3dd@&[$\$5CJ\aJX@BX Heading 4dd@&[$\$5B*CJ\aJphD@D Heading 5$ & F@&>*CJN@bN Heading 6dd@&[$\$5CJ\aJL@L Heading 7$ & F@&^>*CJN@N Heading 8$ & F@&^ 5CJ\F @F Heading 9 $ & F@& 5CJ\DA@D Default Paragraph FontVi@V  Table Normal :V 44 la (k(No List 4 @4 Footer  !.)@. Page Number4@4 Header  !@O"@ Body Text 21 ^CJTR@2T Body Text Indent 2`^``CJFP@BF Body Text 20^`0CJ:B@R: Body Text  CJTS@bT Body Text Indent 3p^p`CJ0U@q0 Hyperlink>*B*@V@@ FollowedHyperlink>*B* RYR  Document Map-D M OJQJ^JJ^@J Normal (Web)dd[$\$CJaJ.X@. Emphasis6]*W@* Strong5\HOH Definition TermCJhtH uHC@H Body Text Indent ^CJLOL colfeaturehd )d\$ <CJaJBQ@B Body Text 3 & F5CJFOF critbody!dd[$\$ OJQJ^J:0@": s List Bullet " & Fe@2 3/HTML Preformatted7# 2( Px 4 #\'*.25@9 OJ QJ ^J j@Cj ff Table Grid7:V$0$t#9:OPtustuZh?   W F G ~ 9 : z Gu%&GHaxE#zwMNS !"56\]klZ/AYX [!!!""""T#[#\##R$S$$$%%%%]&&&&C'(N((((()I*J*v*L+ , ,0,,,,---W////[000122333444455J6K6r6*7+7k77777|8}88899C9q9r99999 : :: :9:R:S:Y::::: ; ; ;";E;F;G;Y;[;;;;;;;;;<<$<p<q<r<<<<<<<<=<=S=q======= >>>(>G>^>>>>>> ?!?"?#?$?B???????@5@x@@BBBBC'CUCCCCC8D{DD3F4FFFGG4H5HMHHHlIIII,J}JJJJKxKKKK'M(M2MMMMNNN O OOOOOOQQQdRRRSS6U7UUU=V>V^V_VgVhVVVVV?WWWWWWlXXXXXXY YYYYYY0ZKZLZTZ^ZZZZZZZ;[<[V[W[k[[|\}\\\\4]]]](^)^=^z^^^^^^_y_z__"`#`2`3`?`~``'a2aMaaaaaab7bbcvc>ddzeee>fJggXhhTijjjj*j3jCjRjSjXjjjjjjjkkk/k0k6kkkkkkkkkk lCl_l|lllll'mUVWjz#'>mnoXY !"$"m$$Q%R%g%4&&'2'3'>'s'{((((()8)f){)))))****V++++++++++,,-,?,@,T,m,,,,,,,,,---A-B-R-S-T-U-1.s.t.|...../\//900_111112I3r3B4c4o445667777 8k8~88994:G:::;<<<==Y>>>>>??T?m?n?@@@AOAA6BBCC,DDDWEEE5FFHGPHQHHHHHHHHHHHHHHIII IHIRIUIXIYI]IkIIIIIIIIIIIIIIIIIJJJJJ%J&J'J(J)JJ KKLLLMM(M5MBM\M]MMMMMYNNOPPsQR/RPRRRSSShTTTTU(U=VVVTW`WW)Y*YUY|YZQZhZZZZZ[\\\\+]]k^^2__```aaaaabMbNbvbbb>ccpdqdrd{d|ddddddeeeffffigjgxgggg h hhThUhhhhhh5iAiiiiijjj-j`jajpjjjjll6llllmXm?nbnnnn|oooopppp$q!r"r5rsisjssssstdt}B}C}D}E}F}G}S}\}]}^}_}`}a}i}r}s}t}u}v}w}x}y}z}{}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}~~ ~ ~ ~~~~~~'~(~)~*~+~E~F~G~H~I~R~S~T~U~V~Y~Z~[~\~]~f~g~h~i~j~t~u~v~w~x~|~}~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~"#$%&-./01<=>?@IJ2ǂai01ˆÈ&' !"56~  ڋۋ9 NOSijoȍɍ͍̍΍эҍӍ׍%&*+,-?Pb  ӏ$őܑؑݑĒ!"iݓ >Rst֔./0A,\QHIyzӛ, ɝʝם؝Xu'(1Rǟȟן؟.uѢҢ.TU]./>̤إۥ\^1Dا;Xmns  8gxԩ/P[\nKLT¬-KZϮ9gگۯ -PQEyI  KƵ^ U"#+9:ĺMƻǻ@v\]ƽ56NOlҾ*+TUorsBDOctu!"56no?]{HIjk%1*LZjkqr;>?(#$u5ij()6:;Z[E{|<_)-1?P\j=>^|}Bfg)wx:;Nz 56G!"757|89GHTUd'BaQ  YZ4`qr~ 7Rd"#.^+f67_UVF(WijP  Axy 01Jw+] !CDEFP)*+<=QRvL~pbGDm (   G  -    , - F }     MN;st  %&<UVjyzxyLirw  '47TW~LM#(+GczE'()KM[6u%]     0!`!!:";"L""## $_$`$$m%&&X'Y'{''''(((0)1)X))))*+0+1+9+++,.,t,,,J-----...N/00%0&0J0v00.1Z11112222223S33333335464i4444+5596k6l6m6z66666 7K77777778898:8E88889X9Y9Z9h999999:):Y:Z:s:t::::F;;;<<<<:=h=i=r====>>)>>>>??"?g???u@v@@@@oAAABBCCCCDD^E`EQFRFZFFF!G$GGGCHDHjHwHHHHI^IIIII0JJJJJKcKdKKKKKLL*L+LLL$MvMMMMMN;N_NNNLOMOdOeOOOOOOx}xxxy y6yMyyyyyMzzzP{{{$||||}C}}}P~~v|Dɀ%D߁Mƃǃ΃>Xcфp$l&\ =ш&>IBmn~ <T(8d;GpΎV֐'M TPBCX!ݘ/ٙ: kɛS #QuΠ%ɡ8M#$45L̩JΪ(bTbf٭\O/?@gSƲг|}  1<4e¹||F7b:X>`| '4>RV`n '()EF} (3456CLMNOP#$~ Z\A}(f459LMd~ 9:;cd|k4!FG-.Nz4)*efmDFOop|}BC3dDN !Z[\hi<=@Alm]xjk0P1Rs,-zFx=%&HI[\#Yh+:G_q|}(-st :bcdvw~&'6bc.! @K!5Hw6lP<P]^y-.Q:;m5Cu?@e.#p8W[2   g  y  \     kl./Oo-.Z3j!z{|k"WX_%&[  !%)*.7BHMSTU\01@klv*S !`!!!""""##,#s######&$'$($\$]$%%*%+%%%%%%%H&I&&&]''''''(3(B(b(((((( ))-)))*A*s**++---.{000O2z2{2222733*4445G5H5[5555R666d78S8T8h88 9V9999999:V::];<"<<<"=W==== >>>[????@@AB-CbCCCjDkDDDELEXEEEE_G`GlGH`H2IITJUJnJoJpJJJJJJJJLLLqLrLsLLLTMVMWMXMaMbM}N~NNNOOdPePPPPPPPQQQQpQQQQQQQ]RRRSSS(SXSYSbSSSSTUTVTiTjTTTTTlUnUUU V VV;W=WWWWW-X.XXXXYY$YRYSYdYYYZZZZ [L[M[X[[[[\\\/\K\g\s\\\\\\\\]]Z]8^e^^^^^^_r____c`d`}`~``` auavaaaabobrbbbcc,c-cNcccccdaddddZe[eeeeffhfif@gAgYgZggggggh5h6hRhh'iXiiijkkkkmlnlllBmmmnnZnnnnnn|o}o~ooooZpp#q_qqrrkstu"vvw3xxxxxxx;ylm$STq$bcޒ%{” klvw&BCXϗЗїdefw˜٘567B ?Y؛WX pCDW/>g0Cߠ |)*.<=ĤŤ2\s\iʧ˧KfgqŨ45@ک,-A)@!.>tHůƯ}±9@Wn  MN͵@eٶڶjr:fѸҸ߹!".st c bc-()9op45Rjk[\!#45j+,HJ fmCtY7gS5!Ns89TMRDp "Zz{Q!"35Sq)N'O'=KdE:qrItu.VWX=>uNLw?n34U<Wlm!cq^_mno|}/0Guv=>yzkPijk(JHIBtuBK L     P   ' (       Y Z  DEIhiLij23A B3~ST,8b{    !"Y#### $C$$$U%%%&,&f&&'V(`)l)))*8*r****++/+ , ,*,,,--..1///D0j0k0011 22e223/334444,55556k66677%777778K999::5::::;];;;;<.</<R<<<<======T>U>s>>?@@@@A+A;AHA`AxAyA3B4B5BJBKBLBWBXBBBBBB)CjCCCCCDkDD#E0EFErEEEFF(F7FGFHFIFFFFFFFFcGdGGGGGAHBHPHQHHHHHfp{|/0]^GH'(WXYij9xyǍ<=͎Ύ>~ʑdsߓ ǔՔ/I• C˖ݖ%WƗٗ-Br~˙ٙ 9Śܚ%QgǛ5@N]ozМ{ҝ>?NOqsՠ֠ޠhTuˢXʣߣ]ڤ+ئ1Ekoy5QlǨ3q6A34h9*DERS[{&;y T",|Wa޴ C\e ƸǸٸڸ)3@Exuvû_μϼSپ*+3Iÿ +>Ubq$}E`+7PZ8Kp4i .D [\jks U|()78D0e at-<T}  2 !"k;c7zpCDKLbctu"YZt238u JK Y.,-QWXpq=IJ&klq9 !"#8912qEF)*Q?exy 7 6(j <=Mx.  !!!""F#G#Z#[#8$$%%&r'?(r*)+%,\,D-..0334J66a89O;<<>j>k>>>>;??;@{@@A7ASATAdAAA0BkB,C-CsCtCCDoDDDEjEEE F F3FFFF G!GGGaHHIfIqIIJ7KLL,M-M6M>MDMHMIMOMZMdMnMoMzMMMMMMMMMMMMMMMMMMMMMMMMNNENN]OOO PP-Q7QQ RyR+STTTU:UUUUV W/W0WKWLWpWWWWXAXXXeXsXXXXXY Y}YYYYYY5ZZZZ8[[[[3\4\E\F\\\]h]]]@^q^^^^h_i_~__`J``````aaaaab(bdbbbbcceee.fffgeggik!mcmmmmnnnn9ooHpqQqrsttthuuvivvwwwxNyyzB{C{O{{c||||c}~`<={|3VcduvIمPz{5ЋދCMQl:>ڎ'(Mb_`Ґ/0Yԓ%&NӔ !?st!";_./?ؗ*GfoxŘƘԘ՘LNe}~QR˝Ɵǟ*+XYlYqrϤ(٥/Xz{%۪Ol<=ǭحc5xڱK>d8"nVQk{(¼üʼF{R|2w&e#$3qJ56X TUtuMu > #,8BCDEbdix{|  !*/9:UW\ahmn| 5CPUZ`ef|s`3qN>Iu/Wc#*p12A0q'IB]35>?P"Ey=F!>2o[\xwx7ATUstkl{|()5kHPU5%jk  . I U s           r8Yr6A2=/8!9!i!%"Q"{""""##"######=$$%B%N%%%&&&L&w&&&'(4(5(B(()))*<+$,,,-4-?--$///u0011133<66/888999::;;;;);R;u;v;O<<<<====3>4>q>r>>>P????????@:@;@?@@@SATAAABIBJBBBBBJCKCSCTCCCC D DWDDD+EEEE.F'GpGqGGRHHHHHBIII+J,JKJVKWKwKxKKKKKKKL/LbL-M.M9M^M_MpMMMMMMM)N*N6NrNsNNNNNNNNNNNNNNN6OOO P2QQQjRRRRRS8SpSS7T8TBTQTTTUVVVVWW9W:WW7X YsYtYYYYZ[e[[[H\I\`\\\]9^^^^_r____`abbbcc"ccc ddd8e9eLee'f(fAfff1g`gggggAhhiiijujjjjj.kkkkmmmm/nanbnsnn ooooppppppWqXq]r^rurrrrrrr s`tIvwwwx&xHxxxxxxxx yKyy{zzQ{{{|||Q}R}}7~n~~~~&8mC{ہ܁  Ԃu nŇƇ+,wS΋w̌NÍՎ֎cΒϒVWb/(MÙݙVd\& !/0DϟNwx'kbcz8ܬ*+,LMv~ͳ<=`ֵ>߷nùl8 s~WXD<wx=yD^  5{fvCbTUk$%= c3$6C p.oqr76ecu  G:`5 h0J~*kbcuy#,_b'n<:     g  d (     RGHe-.E ,mn WzGr7SzAB   !!!!z""##$$$$%C%%&!&=&&&&''5'?'@'((1(Q(o((()7)8)D)E)`)m)))))))**+++++t++++,,,,3,B,C,G,x,,,,,-#.$.b.c.w.2/3/K/////0;0W0000001111222V3h3i3y3z3345Z5m6n666t7u777%8&858~88888889+9q9r9999::;;;;k<<==c=d=x=y=====1>v>>>?5?Y?Z?g?????N@O@\@@@@@AA2A@AlAAAAAAAA*B+BjBkBC'D[E\EdEeEnEEMFFFG&HHHHHI@IbIII5JtJJJ=K>KPKKKK L!LTLUL`L M"M.McMdMMMMNVNWNNNNNN9O:OOOOOPPPPPQQQQiiiii.k/kCkkllllmllllYmmn/nnnnn-o.oUooooooo!p"p:ppppppqqrLrrrOsss@t:uyuzuuvvvvvvowwwww)xx1y2ynyyUzWztzzzzz/{x{y{{5|||||}}}}}}}9]^ÃքV  !9V֊Ћ<5vJ_׎ 9cw7;^͓̓ݓ%&CCD}~ߕpqrOPƗǗȗЗї'L٘#LZ Z[oȜ<=Bfg{| ^_}՞֞/1>ӟנ]/ݣ-.Ԥ()<zΥϥإ٥&'TU]^DE45KߨefufghqrLĬ>Sdyî߮ɯʯ;<Xef~ΰ12`%&w˲̲DEde{|Գe|}6̶DEF^_xɷշַfgyܸ?KnU:e  "JþſYZk !3} K-|KLt X;O@ 67lMNk|)no"#e  >?*+BCu4#e8.?'89PIJj 7>ij}t%&GM:Rq+nk!.X 4ab6.Hhl#. \56H4"#$>?JMUVdefg      L M N p q     $ % B b        5 {   S   67Bqr?@P>?L G ^,-E[ey o E6YZq    !!@!u!v!!J"K"Z""""###o$p$$$$-%%%&&*&R&S&T&o&p&&&&/''''(N)**!***** +9+f++++ ,Y,Z,|,-+-q-r------ ..#.$.;.<.S......-/.///9/:/A0B0Q0p0q0|0000(1)1011112 2Q2R223444G5}666677788}8~88899t99;;; <0<M<[<<<<Q=R===&>'>9>:>x>>O?P?\?'B(B:B_BBBDDDDEfFgFwFFFFFFGHGIGoGGG>HTHHHII{IIII JJJJJKKMKNKrKKKgLLL?Kcdt\]ߓmn!kט5ٙΚǛț5jŜX؝ٝbc&QRߠ13I~ϡ"#QMNϣУfn2ET_"ŪeM'Lѱ_`uв4QԳճ8CDW !mɵʵеѵ`a}ڷ۷`a2gֹ׹|Ӻnovx!"fg}&'s:[ (?VM7=rtr WXG`0   cd4'l" !JSTo`T#&.PQ*+:"{;<f#`am>?S!MN_`pW W]N^, 23BC;EP ezBhbxqr$IW1]^Mkl k       d e    1 E          Y u       : ; ^       & " # Q n   ? @ Q  C o ? @ O P j     O P s  / 0 ? h i v      - W X l     + , 9    ?    Y w x          # $ I       C D |    H      ( n o  w x         B a | }      i   / F    E      K        ! h! ! ! ! ! ! ! " M" " " " # ## ;# N# c# q# # # # $ S$ $ $ $ $ & & ' ' a' ' ' ,( -( M( N( ( &) ') ) ) T* U* V* r* s* * * * I+ c+ + 1, 2, =, 1- 2- ?- . ). "/ M/ ~/ / / / \0 0 1 1 1 2 O2 P2 [2 \2 2 2 2 2 3 <3 d3 3 3 3 3 3 3 3 3 3 4 +4 \4 4 4 4 4 5 a5 b5 y5 6 6 6 ?8 @8 8 39 9 9 9 ": #: 3: H: y: z: {: |: : : : : 5; ; ; ; ; 0< 1< ?< < < = ?= @= K= = = = > > > > > ? "? #? a? ? ? ? ? ? @ @ FA A A A "B }B B C LC C D D "D AD D D D VE vE E E E E tF uF F F F G jG G G G G .H mH nH H H H H I I y oy z z { ?{ i{ { { n| | } } } ~ V~ ~ ~ 2      U V Ā  , W y   r  < = l ؃  } ~ ( K х  M ц    % L z {  Y E F k ͉ K L b c ϊ W   ; < ` r = Q R p q } ͍  s T  < ߒ    S ֓ ד  z Д , - < = J K \ 8 9 T Ȗ ɖ _ H I ~ ҙ ә . | 7 8 \ ݛ ޛ P Q d e z ќ ՝   4 e Þ # H W ߠ S 9 w   - | 9 : W X  ؤ ݥ ޥ T ٦ ڦ  # $ n ( Z [    Y     9 v  $ % L 3 4 > i j y ۭ ܭ   6 u v f | s  ' ( J _  Z z     B V 1 2 E r ܶ D ˸ N O o | } T | } F  c d S T s 5 V W c Ͽ п I J f  = > o  # $ o   } - 9   U V r s  X j W  O k S   7 j k   , ^ _ z " O  S T f   > ? k \ | B C U   b c   : F k l ; R S d e o p ! J s X Y g h ' ( 3 W X z P Q l   0 Z N 0   % Y Z  A B \ = t  ' ( i j  h i | o p q   +      / C D G o 0 l    # J h ! [ \ o  F  T a D i j h i @ A N      h      h    Q R                  Q R d      4 C D Z n    p q { |  q ;       k   A B T   7 Q       n     N O X   "  % ~     S T       / 0      e      5   % & A B T  4 5 W ?! @! L! ! # L# N# j# # # # $ $ 0$ $ $ $ $ % _% % % % & .& /& &' '' D' ( ( ( |) }) ) .+ /+ + , , , - - - . . . . / / / / 0 0 =0 0 0 0 0 0 0 1 1 1 2 2 2 2 $2 2 2 2 73 83 F3 y3 z3 3 3 3 3 3 .4 4 4 P5 Q5 t5 6 66 76 I6 7 *7 g7 h7 p7 7 7 7 "8 8 8 8 8 8 9 R9 S9 \9 9 9 9 9 9 M: x: y: : : : +; ,; ?; S; T; ; ; ; ; ; < !< +< -< %= &= a> b> ? ? @ lA mA =B >B nB oB pB zB {B B B B B B B B #C @C gC hC qC rC 4D dD eD uD E YE E E E E E F 3G 4G qG G H H SI TI eI I I I J eJ J J J J J J K K K iK K FL {L L L L L "M #M WM M M N HN IN N N N >O pO O O YP P Q R R R ,S qS S S T T T T T T T 0U SU u ou pu u u Qv v Lw jw kw w w w w w 7x 8x x x /y ay ~y y y y =z z z ^{ | V} W} X} `} a} e~ f~ l~ ~ ~ 2 M h      r  ; P y N ڃ ۃ    1 2 N Y Z r Ą ń       ; r s ˅ ̅ ؅ ӆ  K o Ƈ J K Ո ֈ  r s | ʉ / 0 > ? J NJ ̋ ͋  / > t nj  ݍ ލ @ 3 ~ ̏ + 8 [ \ ? @ G Փ  ' ( 8 ؔ ו 1 " Z u 6 Ĝ Ŝ , - ) * 8 9 ˠ . q  N + Z ֧ @ A P ب ) n ѩ  L $  3 K ˬ  P a  3 s t z [ د  V p ְ  ] i S 0 1   ޵ + , 6 | ȶ ?    o [ \ y ػ ٻ ּ ׼ ؽ W Ѿ   " *  e  % 2 \ k l ( n # ` a 8 m n o  P h i u ` . y z 5 / a C #   ) 2 = x M N d . / q r  V W | " p q   & X Y r 7 .  j v A  4 5 G   6  [ f ,  2 3 X Y }  C q r x y B    Y  * i j , W X    $ % 7 > B I J K L \ ]   ` n R ] 7 g   > 1 2 u v  3 M           L z          < = N O    J K <   = 9 o p  Z ) U  G H g        L                          $ m  :     F j /! 0! C! ! " " " " " F# # # *$ Z$ [$ h$ $ $ $ % % % % & & & & k' %( d( ( ( ) ) J) ) 9* :* D* r* s* * * * * * * * * * * * * * + + + 3+ 4+ @+ A+ z+ {+ + + + + + + + + l, , 4. . */ x/ / :0 }0 !1 "1 C1 1 1 2 2 2 &3 {3 3 3 3 4 h4 4 4 5 C5 5 5 5 5 E6 k6 7 7 %8 W8 8 8 8 9 9 6: 7: O: : #; ; ; ; ; "< H< T< < = J= K= U= V= h= = = > 8> > > ;? ? "@ e@ f@ {@ A B C C C CD `D D D E bG H ?H @H KH LH H H H H I I ^I _I }I I I J J J K K K K K K /L kL L L hM iM M M 4N N N N N O O 4O P AP P P P Q Q Q Q HR qR R S MS NS S S S nT oT sT T T T T JU U U U U U U UV VV eV V ;W W W W W X X X Y -Y .Y QY RY `Y Y Y Y Y Y Z Z Z ([ Z\ \ \ \ \ e] ] ] Z^ r^ s^ |^ ^ ^ <_ J_ _ _ _ q` 0a fa a Hb eb nb b b b b c 4c jc c c d #d [d 7e e e 3f 4f If lg g g g g (h @h (i Ci i i tj j k k l l Ym am n n o o To Uo p Qq vq q q q q q q q q r r r r r (r ů Ư ӯ ] a ɲ & ' A a I ~  ɸ " ! k  P = > a b  l  } 5 M l   ` A * / # e s t U T X  n 8 k l r J h  > Q  \  ? @ y # 6 7 O 6 7 G  % [ 1 8 T i c  | g h i z {   b  . Z  D r A C P Q h i u : ; N ? s t  +   - . e    H     A u  , - 3 4 A K p   A O P x y K > @ E   J i K p   k       } ~    # S    J t   = E z      f g s t        $   Y Z   A B T    - . ? t u     ] ^ y    & ' 7 8 F              C D h    b c p q    ` a w    ' (       F G     ( *    K L X   + D E V        i t  y ! ! " # e# 5$ 6$ B$ }$ $ k% % .& e& ' &' {' ' ' #( ( ( ( ( ) ) ) ) * * * :+ + + {, |, , - a- }- - - - . . z0 .1 1 2 2 E3 F3 x3 y3 3 3 3 3 3 j4 k4 v4 w4 4 4 4 4 5 J5 K5 U5 V5 f5 5 5 5 6 6 6 6 7 7 7 7 7 8 L8 M8 8 8 8 8 E9 F9 _9 `9 9 9 9 9 G: : : ; q< r< < < < < (= O= P= e= = = = > > n? @ ]@ @ @ B DB `B }B BC C C C D E E dF F -G .G =G G G G G H H H H xI I J K L gL hL L L M M M M M N N N :O ;O O O O O O P }Q R S U U U !U "U 1U U U U V V 9W W X ;X X X fY gY ,Z -Z Z Z Z Z Z [ _[ [ [ [ [ [ \ \ ] ]^ ^^ s^ ^ ^ ^ _ _ w_ x_ _ _ R` ` ` ` ` 7a ka a a c c e me e f f Bf f f g (g \g g g g Zh 6i i i $j %j Fj j j j k k +k ,k k +l Gl l l l l l m _m m m Gn Hn Zn n n n n o o o o o o o 9p ;p p p p p p p ;q q q q 'r (r hr r r r s s s s fs gs s s t :t ;t [t t u u +u ,u bu cu u u v v v v v v v Bw Cw w w !x "x x x x Ny Oy y y y y y y y z ^z {z z z z z z z H{ }{ | `| | | H} |} } ~ 5    n  K ͂ ل   @ ؇  A a  3 ލ w x  Z   % ِ ڐ ޑ ߑ Ԓ Ւ ) * G ۓ g h ̔ z {  [   ; B #  ^   ̠ 0  / ͤ . > . s k ¨ = 4 x { |   D E ^ y ͭ έ s t Į  2 K L  # $ 8 9 g h ; dz ճ  ش -   Ӹ Ը j v 5 v ¼ 1 2 N ս ! " 4 5 \ ¾ þ Ǿ ׾ 8 I p y Ͽ  T U < = V W a   1 2 z {  >  b c d v w  ( t  u  o p D E  d e 4 G * n o 7 . / C   0 Z  `  } ) * V  ]  - } ~  t u G H U V x B C   ~ 0   $ ' E F b M N  C D ~ X o y * }   5 6 D  Q R S \ ] p  A   4 N e  / J K V W d   ( P p Q   / r s  O P Y Z e r   4  @ &  * O   n   [     j t  < q     / Q   K W ( Q x y H I v A B           + 7   H ; <   N   _   .     8 ~    Z    q     s           w x   J y ! P! Q! t! u! ! ! $" %" O" n" " " " " " " # # # # 0# o# p# # # # # # %$ $ $ % % % &% '% 8% 9% B% C% P% % % % Z& [& x& & ' ' ' ' i( ( ( n) o) ) ) * * F* * * * * * + P+ Q+ b+ + + + + }, ~, , , _- i- - - -. E. . / / <0 0 0 0 D1 y1 1 1 1 1 2 2 P3 3 3 3 X4 4 4 4 5 5 5 \7 ]7 7 7 8 8 8 8 8 8 9 9 9 .9 e9 9 ]: ^: z: ; ; O; P; b; c; 4< 5< w< x< y< < < < = +> i> > > > y? ? \@ ]@ @ \A ]A A A -B _B `B aB B B B B B D D D D SE TE gE E F !F 4F F F F aG bG G H H H H 9H | } ? @ \ ֦ " # 7 T U Z Ƨ    ;   ? @ ] ^ Ī B n ګ  [ \ ~ G H X  I W l ʰ ˰  G q ȱ ɱ W f t u IJ  4 5 g   ) * 5 6 f ̴ ? @ ڵ ۵  G { ̶  7 | . }   B \ ĺ ` X Y ¼ - 6 { ֽ *  E ; < T  S  T o p K _ ` x A X Y ^ A J i + \ ] C K  U ; ' ( ) D 4 5 e 1 2 > ? N   ( T  S 6 7 C  $ ]  6 M Q  0 = D   E F P > a c  @  9 : ; V  #   U V k $ % < _ ` t = Y Z u 3 ) 8 j S < q ! 5 > E 4  P  p 6 _ L v *+@Aj|c23C%&34av i; < b     _ z    + g          ;    ./}~EFjkFGbcu? aUVdn&1Q1  z!{!!!7"}""#a#b#r##$}$$%H%I%i%&&*&B&n&&&&' '<'{'''''((3(4((((()n+o+++,,---..y.z....4//203000M1111-2@222\3]3}333H4I4U4'5(52566677_8`8999::*;;;;I<<<<<=">>??b@@AAAA?B\BKCCEEEFFFeGGGGIIIII+J{JJJJKdLL)M*MPGPHPPPPQQ7QoQRRSS,SSSTTTTUUUWWX\XXXXNYYZ\[][[[[\"\\]^^6^7^W^^_x__``````aaaaaabbEbFbdbbbbcHdeAfffNgg.hi'i(i\iijJkylzllmmmnznnnoKpLp_ppppPr{rrsatbttTuuuFvwwyyz{{{{ ||}||}}~Hx\ۂ܂JCS]eQɈ.M6fsv~68wxab~ڍۍOŽQGmnv4k2vwcdxʚ˚^_NOfGHƠX3ʣ:b4k٪78_ϫѬҬHMϮa78mӱ  #ijų.ݵ  #v̷^7ֹ1QRpռ)5\ӽԽlmuv9:JK  bd=qChi.]  3(9DEnK$`9:]>yz?@S@opTUklpX[&'@WXfhu0mo!" !LMNcdncd%&OP*+5N d,-+IDijst-.RSZ7p\ OCCjku89"d'IJ`      ( N O - 5 ]      ^  Bs  ]Z\S;BC 6734mnu  * k l  """"T####m$$f%%%&&Z&&&4'5'''''((p(A)B))y*z**++,r,s,,,9-Y......j/////d0e00111"2o22213A55555A6[7\7j7k7r7s778899 : ::::;;;;<< = ===h>>>??8@t@@AAAAABdBBpCCCDOE9FFGGtGGGGHH=HTHUHhHiHpHqHIIJJEJFJJJ^KKLhLLMMMMMNYNpNqNVPWPP9QQRSSXTTTTTU'U(U[U;VVVWWWIX^X6Y7YYYYZqZrZZ?[@[[[c\d\\\]]]J]^]]]^C^^^f_g__1`I`J`^`_``a;bcccc3dddddd e2eeeeefffj?j\jjjWkkk l1lll!mZm[mqmrmmmmnennnnnZoopxppsqqqsBsCsvsttuuu>vvvdwwwy`yyyDzjzkzz{{}||}m~n~~tR{|҅Ӆo-LYЋыL׌B~&'`ʏ!z{M <=Emn}ה3ߕ ҖӖ5DE&lbHCDhܞ;[gXѡM*n.ɥѥ23CD]_Ѧ i̧#(@OͨѨ)>O`xʩ˩ͩΩϩЩ(ƪ9"P®#$1S]`aj9ҵ4QLIJRù%QRnyQսik˾׾?3QR[\l.^stK&\]k6'(wy  U2yz23P% !BCQyz  hstF} !]^VWg*KLX+"78HN45JA 0?z-.8.5}~PQlm`aO23()CcJKi7]ABde012?@GHQ[gh89Np !6k?'\"#)*BT$%46yz{@YZvwM);<Nablm78    7 x      - r  3  g i t  O !z2*+()4 KLN[\]uv8b0009090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909 09 09 09 0909090909090909090909090909090909090909090909090909090909090909090909090909090909 0909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090030303030303030300K60K60K60K60K60K60K60K60K6h0K60}80}80}80}80}80}80}80}80}80}80}80}80}80}80}8 0}8 0}8 0}8 0}80}8 0}8 0}8 0}80}8 0}8 0}8 0}80}8 0}8 0}80}8 0}80}8 0}8 0}8 0}80}8 0}8 0}8 0}8 0}8 0}8 0}8 0}8 0}800r<0r<0r< 0r< 0r< 0r<0r<0r< 0r<0r<0r<0r<0r<0r< 0r< 0r< 0r<0r< 0r< 0r<0r<0r<0r<0r< 0r<0r<0r<0r<0r< 0r< 0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<!0r<!0r<!0r<!0r<!0r<!0r<!0r<0r<0r<!0r<!0r<!0 r<0r<0r<0r<0r<0r<0r< 0r<0r<005H05H05H05H05H05H05H05H05H05H05H05H05H05H05H05H05H05H00(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M 0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M0(M00>V0>V0_V0_V0_V00V0V0V00W0W00W0W00X0X00X0X0X000Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y00<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[0<[ 0<[0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#` 0#` 0a#` 0a#` 0a#` 0a#`] 0#`] 0#`] 0#`] 0#`] 0#`] 0#`] 0#`0#` 0#` 0#`0#`0#`0#`0#`0#`0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#` 0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#`0#` 0#` 0#` 0#`0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#`0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#`0#`0#`0#`0#`0#` 0#` 0#`0#`0#` 0#` 0#` 0#` 0#` 0#` 0#`4 0#`4 0#` 0#`3 0#`3 0#`3 0#` 0#` 0#`0#` 0#` 0#`0#` 0#` 0#` 0#` 0#` 0#` 0#`!0#`!0#`!0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#` 0#`0#` 0 0 00 00 000 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00000000 0 0 0 0000000000 00000000 0 0 0 00 0000 0 0 0 0 00 0 0 0 0 00 0 0 000 0 0 000000000000 0 0 0000000000000000000000000000000000000и0и0и0и0и0и0и0и0и0и0и0и0и0и0и0и0и000000 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 00 0 00 0 000000000000000000000000000000000000000000000Z!0Z!0Z!0Z!00[!0[!0[!0[!0[!00\!0\!000000000000000000000000000000000000000000000 000 0000000000000000000~!0~!0~!0~!000000000\ 00000\ 000\ 0000000000000001 01 009 02 00000000000000000000000002 00000002 0002 02 02 02 02 02 00000000 0 0 00 00 00!0!0!0!0!0!0!00o!0x 0x 0x 006 05 05 05 0000000000000000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0 0  0 0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 !0 !0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0  0  0  0  0  0  0  0  0  0  0  0 0 0 0  0  0  0  0 0  0 0  0  0  0 0 0  0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0 0 0  0  0 , 0 , 0 , 0 , 0 0 0 0  0 0 0  0  0  0  0  0  0  0  0  0  0 0 0  0  0  0  0  0  0  0  0  0  0  0  0 !0 !0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 00|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d0|d00Uhx 0Uh0h0h0h0h0h0hh 0Uh0i0i0i0i0i0i0i0i0i0i0i0i0i00l0l0l00l0l0l0l0l0l0l0l0l0l0l0l0l0l0l0l0l00"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"r0"rH 0"r0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w0"w0"w0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 0"w 00000 00000000000000 0 0 0 0 00H00"0"0"0"0"( 0"0"0"0"0"0"0"0"0"0"0" 0"0"0" 0"0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0" 0"0"0"0"0"0"0"0"0"0" 0"0"0"0"0" 0"0"0"0"0"0" 0"0"0"0"0"0"0"0"0"0"0"0"0" 0" 0" 0" 0" 0" 0" 0" 0"0"0"0" 0" 0" 0" 0" 0" 0" 0" 0" 0"0"0"0"0"" 0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0" 0" 0" 0"0"0"0" 0" 0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0" 0"0" 0"0"0"0"0"0" 0" 0" 0" 0"0"0"0"0"0"0"0"0"0" 0"0"0"0"0"0"0"0"0"0"0"0"0"0" 0"0"0" 0"0"0"0"0" 0"0"0"0"0"0" 0L" 0L" 0L" 0L" 0L" 0L" 0L"0" 0" 0" 0" 0"0"0"0"0" 0g" 0" 0" 0"0" 0" 0Q" 0Q" 0Q" 0Q" 0Q" 0Q"0" 0"0" 0"0"y!0"y!0"0"0"0"0"0"0" 0" 0" 0" 0" 0" 0"0" 0" 0#" 0#"0"0"0"0"0"0"0"0"0"0"0"0"B 0"B 0"B 0"0"0"0"0" 0#" 0]" 0]" 0]"0"0"0"D 0"0"0"0"0"0"0"0"D 0"0"C 0"C 0U"C 0U"C 0U"0"K 0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"0"!0"!0"0"0"0"0"0"0"000000000000000000000000000000000000000000000000000000K 00K 000000 0 0 0 0 0000000000C 0|C 0|C 0|0|F 0|0|C 0|C 0|C 0|0|0|!0|!0|!0|!0|!0|!0?|!0|!0\|!0|!0|!0|!0|0|0|0|0|0|0|0|0|0|0|C 0|C 0|C 0|C 0|!0|0|0|0|0|0|C 0|C 0|0|0|0|0|$ 0|$ 0|0|0|# 0|# 0|0|0|0|0|# 0|# 0|# 0|0|0|0|0|% 0|% 0|% 0|0|0|% 0|& 0|0|0|0|0|0|% 0|% 0|0|0|0|0|0|0|0|0|0|0|0| 0| 0|C 0 C 0 C 0 C 0 C 0 C 00000000000000000000000000000000000000000000000000000000000000000000000000000000000000 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 0 00 0 00000 0 0 0 0 0 0 00H0|0000000000000z!0z!0z!0z!0000|!0|!0|!000{!000000000H0|0 0 0 0 0  0  0  0  0  0  0 0 0 h0 0t0t0t0t0t0t0t0th0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0 0 0 0  0 0  0 0 0 0 0 0 0 0  0  0 0 0 0 0 0  0  0  0  0  0 00'0'00(0(0(0(0(0(0(0(0(0(0(0(0( 0( 0( 0( 0( 0(0(0(0(0(0(0(0(0(0(0(0(000000000000000000000000000000000000000000000000000 00 0000 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00H000Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z: 0Z: 0Z: 0Z: 0Z: 0Z:0Z:0Z:* 0Z:0Z:0Z:0Z:0Z:0Z: 0Z:0Z:+ 0Z:0Z: 0Z: 0Z: 0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:+ 0Z:+ 0Z:+ 0Z:0Z: 0Z: 0Z: 0Z: 0Z: 0Z: 0Z:0Z:0Z:+ 0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:+ 0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:0Z:+ 0Z:+ 0Z:+ 0Z:+ 0 Z:+ 0 Z:+ 0 Z:+ 0 Z:0Z: 0 0Q0Q0Q0Q 0Q0Q0Q0Q 0Q 0Q 04S04S 04S 04S04S 04SH 0Q 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T0T0T 0T 0T 0T 0T 0T 0T 0T 0T 0T0T 0T0T 0T 0T 0T 0T 0T 0T0T 0T 0T0T 0T 0T0T 0T 0T 0T 0T 0T 0T 0T 0T0T0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T0T0T 0T 0T 0T 0T 0T 0T0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T0T 0T 0T 0T 0T 0T 0T0T 0T 0T0T0T!0T!0T!0T!0T!0T 0T 0T 0T 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o0o 0o 0o 0o 0o 0o 0o 0P{o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o`!0o`!0o`!0o 0o 0o 0o 0o 0o 0T 0 0 0 0 000000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0T 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n 0n 0n0n 0n 0n 0n 0n> 0n> 0n 0n 0n 0n 0n 0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n0n 0n 0n 0n0n0n 0n 0n 0n 0n 0n 0n 0n 0 n 0 n 0 n 0 n 0 n 0n 0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n0n0n0n0n0n0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n 0n0n0n 0n 0n 0n0n0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n 0n 0n0n 0n 0n 0n 0n 0n 0n0n0n0n 0n 0n0n0n0n0n0n0n0n 01n 01n0n 0n 0n 0n 0n0n+ 0 n+ 0n0n0n0n0n0n0n0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n0n0n0n 0n 0n 0n 0n 0n 0n 0n0n0n0n0n 0n 0n 0n 0n 0n0n0n 0n0n0n 0n 0n0n0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n0n0n 0n 0n 0n 0n 0n0n 0n 0n 0n0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n0n0n0n0n0n0n0n0n 0T00000000000000000000000000000000000 0 0 0 0 0 0R!0 0R!0 0 0 0 0 0 0 0 0 0000000Q!0Q!000000 0H 0Q0000000000000 000 0 0S!0S!0S!0000 000 0000\ 0\H 0\0000000000000000 0 0 0 0 0 0; 0; 0; 0 0 0< 0< 0< 0 000 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0000000000000000000 0 0 0 0 0 0 0 0 00000 0 0 0 0 0 0 0 0 0 0 00:T!0:T!0:T!0:T!0:0:0: 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 00 00 08 08000 0 00 0 0 0 0 0 0 0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 !0 !0 !0  0 0 0X 0X0X0X0X0X0X0X0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X0X0X0X 0X 0 0 0 0 0 0 0 0000000000000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0!0000!0!0 0 00H 0H 0 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%0% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0%w!0%w!0%0%x!0%x!0% 0% 0%00%0% 0% 0% 0% 0% 0% 0%) 0%) 0% 0% 0% 0%0%0%0% 0% 0% 0% 0% 0%0%0%0%0%0%0% 0%0%0%0%0%0%0%00909090909 09 09 09 09 09090900=0=0=0=0= 0=0=0= 0=0=0= 0= 0=0=0=0=0=0=0=0=0=0=0=0=0=0=0= 0= 0;G= 0= 0= 0=0=0=0=0=0=0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=0=0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=0=0= 0=0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=!0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=d 0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=!0=!0=!0=!0=!0=!0=!0i=!0=0=0=0=0= 0=!0=!0=!0=0=0=0=0=0=0=0=0=0=0=0=0=0=0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=0= 0= 0= 0= 0= 0= 0= 0= 0=0=0= 0=0=0=0=0=0=0=0=0=d 0M`=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=0=d 0M`=0=0=0=d 0M`=0=0=d 0M`=0=0=0=0=0=0=0= 0=0[ 0[ 0[ 0[ 00[ 0[ 0[ 000 0 0 0 0 0 0 00 0 0 0 0 00 0 0 00 0 0 0 0 00000000000000 0 0 0 0 0000000000000000000 00 0 00 00 0 0 000 0 0 00 0 0 0 0 00 0 0 0 0 0 0000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 00000000000000 0 0000 0 000000 0 000000000000000000000000000000 0 0 0 0 0 0 0 0000000000!0!0!000000 0 0 0000000000]!000000000000000000000000000000000000000000000000000000000000000000000000000000000 !0 0 !000000 !00 !000000000 !0 !0 !0 !00 !0 !0 !0 !0 !0  !0  !0  !0 000 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00000000000000000000000000000000000000 0 000 0 0 0 0 0 0 0 0 000 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0? 0? 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 00 0 0 0 00000 0 0 000 0 0 0 0 0 !00 0 0m 0m 0m0m0m 0m 0m 0m 0m 0m0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m0m 0m 0m 0m 0m 0m 0\ 0 0 0 0 0 0 0 0 !0L !0L !0L !0L !0L !0L !0L 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0000000 0 0 000000000000000000000000000H00v 0v0v0vh 0v 0 0 0x 0 0x 0 0 0 0h 0v 0 0 0 !0L80 0 0 01 01 01 01000000 !00 !000 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0!0!0!0!0!0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0!0!0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 000000 0 00 0 0 0 0 0 0 00 0 0 0=0= 0= 0=0=0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=0= 0 0B 0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B !0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B 0B0B 0B 0B 0B 0B0B 0B 0B 0B 0B 0B0B 0B0B0B0B0B 0B0B0B0B0B0B 0B 0B 0B0B0B0B0B0B0B 0B 0B 0B 0B 0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B0B 0B 0B 0B 0B0B0B0B0B0B0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B0B 0B0B0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B 0B0B 0 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k0k 0k 0k 0k 0k0k 0k 0k 0k 0k 0k 0k 0k0k0k0k0k0k0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k 0k!0k!0k!0k!0k!0k0k0k!0k!0k!0k0k0k0k0k!0k0k0k 0k 0k 0k 0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k3!0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k 0k 0k 0k 0k 0k 0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k!0k0k!0k!0k!0k!0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k 0k 0k 0k0k0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k0k0k0k0k0k 0k0k0k0k0k0k0k0k0k0k0k0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k_ 0k0k0k_ 0k_ 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k 0k 0k 0k 0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k_ 0k0k0k_ 0k0k_ 0k0k0k 0k 0k 0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k 0k 0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k!0k!0k0k0k!0k!0k!0k0k0k0k0k0k0k0k0k0k0k0k !0k0k0k0k0k0k0k0k !0k !0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k!0k!0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k0k00#0#0#0#0#0#0#0#0#0#0#0#_ 0#_ 0#_ 0#_ 0 #_ 0 #_ 0 #_ 0 #_ 0 #_ 0#0#0#I 0#I 0#= 0#= 0#0#0#0#0#0#0#0#0#0#0#!0#!0#!0#0#00#A0#A0#A0#A0#A0#A0#A0#A00CC0CC{ 0CC{ 0CC{ 0CC{ 0CC{ 0CC{ 0CC{ 0CC0CC0CC0CC0CC00F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F 0F0F!0F!0F!0F!0F!0F0F0F0F 0F 0F 0F0F0F0F0Fr 0Fr 0Fr 0Fr 0Fr 0Fr 0Fr 0Fr 0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F00Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y008_08_08_08_08_w 08_w 08_w 08_w 08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_s 08_s 08_s 08_s 08_s 08_08_08_08_ 08_ 08_08_t 08_t 08_t 08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_9!08_9!08_08_08_08_08_08_08_08_:!08_:!08_:!08_08_08_;!08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_08_00]0]0];!0];!0];!0];!0];!0];!0];!0];!0];!0 ];!0 ];!0 ];!0 ]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0000000000000000000000000000000000000000000000v!0v!0v!0000 00 0 0 0 0!0!0!000000000000000000000000000000 0 0 0000000l0l0l0l0l0l0l0l0l0l0l0l0l0l0l0l0l0lq 0lq 0lq 0l0l0l0l0l0l0l0l 0l 0l 0l0l0l0l!0l!0Ŀl!0l!0l!0l!0l!0l!0l!0l!0l0l0l0l0l0l0l0l0l0l0l0l 0l 0l0l0l0l0l0l0l0l0l0l0l0l000000000$0$!0$!0$!0$0$0$!0$!0$0$0$0$0$0$0$ 0$ 0$ 0$ 0$0$ 0$0$0$ 0$ 0$ 0$ 0$ 0$ 0$0$ 0$ 0$ 0$ 0$0$0$ 0$ 0$0$ 0$ 0$ 0$ 0$ 0$0$0$ 0$0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$0$ 0$0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$0$ 0$ 0$0$ 0$0$ 0$ 0$ 0$ 0$0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$ 0$0$0$0$0$0$0$"!0$"!0$"!0$0$0$0$0$0$!!0$!!0$!!0$!!0$0$ !0$ !0$ !0$ !0$ !0$0$0$0$#!0$#!0$#!0$#!0$#!0$#!0$0$0$0$0$0$$!0$$!0$$!0$0$0$0$0$0$00,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,)!0,)!0,0,0,0,0,!0,!0,!0,!0,0,!0,!0,!0,!0s,!0s,!0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,C!0,0,C!0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,l 0,l 0,0,l 0,l 0,l 0,0,0,m 0,m 0,m 0,m 0,0,n 0,n 0,0,0,0,0,o 0,o 0,o 0,0,0,p 0,p 0,p 0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,D!0,0,D!0,0,0,0, 0, 0, 0,0,0, 0, 0, 0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,8!0,0,8!0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,0,!0,!0,0,0,0,0,0,0,0,H!0,H!0,H!0,H!0,E!0,E!0,0,0,G!0,0,0,F!0,F!0,F!0,0,0,0,0,I!0,I!0,I!0,I!0,0,K!0,J!0,0,0,H0,0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0: 0: 0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:A 0:A 0:A 0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0:0: 0: 0: 0: 0: 0:0:0:0:h 0:0R0R0R0R0R0R0Rq!0Rq!0Rq!0Rq!0R0R0R0R0R0R0R0R0RH 0RH 0RH 0R0R0R0R0R0R0R0R 0R 0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R!0R!0R!0R!0R0R0R!0R!0R!0R0R0R0R0R0R0R0R0R0RG 0RG 0R0R0R0R0R0R0R!0R!0R!0R0R0R0R0R0R0R0R0R0R0R!0R!0R!0R!0R0R0R0R0R0R0R0R!0R!0R!0R0R0R0R0R0R0R0R0R0R0R0R0R!0R!0R0R0R0R!0R!0R0R0R0R0R!0R!0R0R0R0R0R0R0R0R0R0R0R!0R!0R0R0R!0R0R!0R0R0R0R0R0R0R!0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0RI!0R!0R!0R0RI!0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0Ry 0Ry 0Ry 0R0R 0R0R0R0R0R0R 0R0RH 0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R 0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0Rb!0Ra!0R0RH 0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R0R!0R!0R!0R!0R!0R0R0R0R0000000000000000000000000000B!0B!0B!0B!0B!00B!0B!0B!0B!00000000000A!0A!0A!0A!00000000000000000N!0M!0M!0M!0O!0L!0L!0L!00!0!0!00!0!000000000000000000000000P!0P!0P!00000!0!0!0000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0z 0z 0z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00000 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00000000000000000 0 0 0 0 0 0 0 0 0 0 0 08 08 08 08 08 000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 0 0E 0E 0E 0E 0E 0E 0E 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K1!0 K1!0 K1!0 K1!0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K0 K0 K0 K 0 K 0 K 0 K 0 K 0 K 0 K 0 K!0 K 0 K 0 K 0 K 0 K 0 K 0 0n 0n 0 0Qo 0Qo 0Qo 0Qo 0Qo 0 0o 0o 0 0Pp 0Pp 0Pp 0p 0p 0p 0p 0p 0p 0p 0p/!0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p 0p0p 0p 0p 0p 0p 0p 0p 0p0p00W|0W|0W|0W| 0 0{}0{}0{}0{} 0{}H 0{} 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0S 0ɍS 0ɍS 0S 0S 0S 0S 0S 0S 0S 0S 0S 0Sx0S 0T 0T 0T 0T 0T 0Th 0S 0| 0| 0| 0| 0| 0| 0| 0| 0| 0| 0| 0| 0| 0| 0|c!0| 0| 0| 0| 0| 0| 0| 0| 0A} 0A0A 0A} 0A0A0A0A0A0A 0A 0A 0A 0A 0A 0A 0A 0A 0A 0A 0 0m 0m~ 0m~ 0m~ 0m~ 0m 0m 0m 0m 0m 0m 0m 0m 00f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f}!0f}!0f/!0f 0f 0 0. 0. 0 0{ 0{ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0/!0/!0/!0/!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0v 0v 0 0 0 0u 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 00 0 000 0 0 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 04 040404 04 04 04 04 04 04 04 04 04 04 04040404040404040404040404040404040404 04 04 04 040404 04 04 04 04 04 04 04 04 04 0404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404040404 04 04 04 04 04 04 04 04 04 04 04 04 0404040404040404 04040404 04 040404040404u 0Ů4u 0Ů4u 0Ů4u 0Ů404040404u 04u 04u 04u 0404 04040404000000000000000000000000000 000 0V 0V 0V 0V 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0| 0| 0| 0| 0| 0| 0| 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 00!00!00000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0000 0 0 0U 0U 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00000000000000000000000000000 000000000!01>!01>!010101 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01 01H 010Q 0 0 R 0 R00ER0ER0ER0ER0ER0ER0ER0ER0ER0ER7 00UX0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U7 0UU0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U0U0U0U 0U 0U 0U0U0U 0U 0U 0U 0U 0U 0U 0 0 0~o 0~o0~o0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o 0~o0~o0~o 0~o 0~o 0~o 0~o0~o0~o0~o 0~o0~o 0~o 0 0v 0v0v 0 0x0x0x0x7 0x7 0x7 0x7 0x0x0x0x0x0x 0x 0x 0 0| 0| 0|0|00J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J0J000 0 0 0 0 0 0 0 0 0 0 0 0 000Շ0Շ0Շ0Շ0Շ0Շ0Շ0Շ00_0_0_0_0_0_0_0_ 0_ 0_ 0_ 0_ 0_ 0_ 0_ 0_ 0_ 0_ 0_0_0_0_ 0_ 0_ 0_ 0_T 0_T 0_T 0_T 0_0_0_00X0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X0X0X0X0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X 0X0X0X0X0X0X0X0X0X0X0X0X0000000000000202020202020200Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0000000007 07 07 07 00000. 0. 0. 0. 00Q 0Q 0Q 00/ 0/ 0/ 0/ 000 00 00 00 0000˯0˯0˯0˯0˯00ư0ư0ư0ư0ư0ư0ư0ư0ư0ư0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ư 0ưH 0ư 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 000000 0 06 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q!0q!0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0t 0q 0 0 0 0 0%!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0000 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00H 0q0G 0G 0G 0G 0G 0G  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 0 0 0 0 0 0 0 0 0 0 0 h 0 h 0  h 0  h 0  h 0  h 0  0 0 0 0 0 0 0 0 0 0 0 0 0 g 0 0 0 0 0 0 0 0 g 0 0 0 0 0 g 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 %!0 %!0 %!0 %!0 %!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 %!0 %!0 %!0 %!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 *!0 *!0 0 0 0 0 0 0 0 0 +!0 +!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0d!0`J d!0`J d!0`J d!0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J c 0`J 0`J 0`J c 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J !0`J !0`J !0`J 0`J %!0`J %!0`J %!0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J c 0`J c 0`J c 0`J c 0`J c 0`J 0`J c 0`J c 0`J c 0 `J c 0 `J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J t!0`J t!0`J t!0`J t!0`J t!0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J s!0`J s!0`J s!0`J s!0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J 0`J  0 0>v 0>v 0>v 0>v 0>v  0 0 w 0 w 0 w 0 w 0 w 0 w 0 w 0 w 0 w 0 w  0 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 H 0w 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 L 0 L 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 @!0 ?!0 ?!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 0 0 0 0 0 0 0 0 0 0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0 0  0 0 0  0  0  0  0  0  0  0 0 0 0  0 0  0  0  0 0 0 0  0 0 0 0 0  0  0  0 0 0  0  0  0  0 0 0 0 0  0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 009 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09  09  09  09 09 09 09 09 09 09 09 09 09 ! 09 ! 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09  0 9 09  0 9 09  0 9 09  0 9 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 8 09 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02 02  0 0m8 0m8 0m8 0m8 0m8 0m8 0m8 0m8 0m8 0m8 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 J 09 J 09 J 09 J 09 09 09 09 09 09 09  0 O 9  0 O 9 09 09 09 09 09 09  09  09  09  09  09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 09 0m8 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od Y 0od Y 0od Y 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od 0od R 0od R 0;~ od R 0y~ od R 0y~ od R 0y~ od R 0od R 0od 0od 000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Z 0 Z 0 Z 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0  00 0 0 0 0 0 0 0 00j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j 0j  0 0 0  00 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  0D h 0h 0h 0h 0h 00 0 0 0 00000 0 0000000 0 0 0 0  0  0 0  0ͥ  0ͥ  0ͥ  0ͥ 0 H 0 0 00c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0c 0000 0 0 0 0 0 0 0 0 0 00* 0* 0* 0* 0* x 0* 0 0 0  0  0x 0 0 0 0 0 0  0000 0 0 0 0 0 0  0  0  0  0  0Ŷ  0 0 0 00 0> 0> 0> 0> 0> 0> 0> - 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> - 0> - 0> - 0> - 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 0> 00& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0&  0&  0&  0& 0& 0& 0& 0& 0& 0& 0& ,!0& ,!0& ,!0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& !0& !0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& !0& !0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0&  0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& u!0& u!0& u!0& u!0& u!0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& e!0& e!0& e!0& e!0& e!0& e!0& 0& 0& 0& 0& 0& 0& 0& 0& 0& &!0& &!0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& !0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0& 0&  0 0 0$  0'!0g% '!0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0g% 0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\) g!0\) f!0\) f!0\) f!0\) f!0\) f!0\) f!0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) j!0\) j!0\) j!0\) 0\) 0\) 0\) 0\) 0\) i!0\) i!0\) i!0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) h!0\) h!0\) h!0\) 0\) 0\) 0\) 0\) k!0\) k!0\) k!0\) k!0\) k!0\) k!0\) k!0\) k!0\) k!0\) k!0 \) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\)  0iK \)  0iK \) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) - 0\) - 0\) - 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) W 0\) W 0\) W 0\) W 0\) W 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) X 0\) X 0\) X 0\) X 0\) X 0\) X 0\) X 0\) X 0\) X 0\) X 0 \) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\)  0\)  0\)  0\)  0\) 0\)  0\)  0\) 0\)  0\) 0\)  0\)  0\)  0\)  0\)  0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) !0\) !0\) !0\) !0\) !0\) !0\) !0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\) 0\)  0\) 0\)  0\)  0\) 0\) 0\)  0\)  0\)  0\) 0\)  0\)  0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\) 0\) 0\) 0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\)  0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) 0\) H 0\) 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 U!0 U!0 0 U!0 U!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0` 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 h 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 0  0 0 0 0 0 0 0 0 0 0 0 h0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 - 0 0 - 0 - 0 0 0 0 0 0 - 0 0 - 0 0 0 0 - 0 0 0 0 0 H 0 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 06 H 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 - 0 - 0 - 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00= 0= O 0= O 0= N 0= N 0= 0= 0= 0=  0=  0= 0= 0= 0= 0= 0= 0= 0= 0= 0=  0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= H 0= 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T ` 0T ` 0T ` 0T ` 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T - 0T - 0T - 0T - 0T 0T 0T 0T !0T !0T 0T !0T !0T 0T 0T !0T !0T !0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T !0T 0T !0T 0T !0T 0T 0T 0T 0T 0T 0T  00v  0 0 0 0 0 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w !0w !0w !0w !0w !0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w  00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0q 0q 0q  0 0 0 0 00o 0o 007 07 00 0 0 0 P 0 P 0 P 0 0 0 0 0 0 0 0 !0 !0 !0 !0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 0 0 0 !0 0 0 !0 0 !0 0 !0 0 !0 0 0 !0 0 0 0 !0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 M 0 M 0 M 0 M 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0   0  0 0 a 0 a 0  a 0 a 0 0 0 0 0 0  0   0   0   0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 b 0 b 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  00*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*& 0*&  0 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M, 0M,  003 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 03 008 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 08 H 08 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B  00B  00B  00B  00B  00B  00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B 00B l!00B l!00B 00B 00B 00B 00B  0 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n !0n !0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n .!0n .!0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n 0n -!0n 0n !0n !0n !0n 0n 0n 0n 0n 0n 0n 0n  0 0r 0r 0r 0r 0r  0 0 0 0 0 0 H 0 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ V!0\ 0\ 0\ 0\ 0\ 0\  0 0) 0) 0) 0) 0) 0) 0) 0) 0)  0z )  0z )  0z )  0z )  0z ) 0)  0 )  0 )  0 )  0 )  0 )  0 ) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) 0) x 0) @ 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0_ 0_ 0_0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 00000000000000000 0000 00 000000000000000000000000000000m!000 0 0 0 0 0 0: 0: 0: 0: 0 0 00000000000 00 0@ 0@ 0@ 0@ 0@ 0@ 000S 0S 0S 0S 0S 0S 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0000 0 0 0 0 0 0 0 0 0 0 0 000000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0< 0< 0< 0< 0< 0< 0<: 0<: 0<: 0<: 0<: 0<: 0< 0< 0< 0< 0< 0<0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<0< 0< 0< 0< 0< 0< 0< 0< 0<!0<!0<0< 0< 0< 0< 0< 0< 0< 0< 0<f 0<f 0<e 0<e 0<e 0<e 0< 0<0<0<0<0<0< 0< 0< 0< 0< 0< 0<H 0<0] 0] 0] 0] 0] 0] 0]0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0]0] 0] 0]0]0]' 0]' 0]' 0]' 0]' 0]0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0]p!0]p!0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0] 0]0 01t 01t 01t 01t 01t01t 01t 01t 0 0 0 0z 0z 0z 0z0z0z 0z 0z 0z0z0z 0z2!0z2!0z2!0z2!0z2!0z 0z 0z 0z 0z 0z 0z 0z 0z 0z 0z^ 0z^ 0z^ 0z^ 0z^ 0z^ 0z^ 0z^ 0z 0z 0z 0z 0zr!0zr!0zr!0zr!0zr!0z 0z 0z 0z 0z 0z 0z 0z 0z 0z 0z 0z0z0z0z0z0z 0z0z0z00=0=0=0=0=0=0=0=0=0=0=0=0= 0= 0= 0= 0= 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 0 0(!0(!00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 00 0000000 0 0 0 0 0 0 0 0 00 0 0 0 0 00 0 0 0 00 0 0 0 0 0 00 0 0 00 0000000 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0000ٿ0ٿ0ٿ0ٿ0ٿ0ٿ 0ٿ 0ٿ 0ٿ 0 0 00 0 0 0 0 00 0 0 0 00 !0 !0 !0 !0 !0 0 0 00 0 00 0 0 00 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0000 00 0 0 0 0 0 0 0 0 00w0w0w 0w 0w 0w 0w 0w0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w!0w 0w!0w0w!0w0w0w0w0w 0w0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w 0w0w 0w 0w0w 0w 0w0w 0w 0w0w 0w 0w 0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w 0w 0w0wH0w0_0_0_0_0_00000000:0: 0: 0:0:0:0:0: 0:0U 0U 0U 0U 0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U 0U 0U 0U 0U 0U0U0U!0U!0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0UH0:00000000000000000005!04!0000000 00000000000000000000000000000000000000000000000000000 00+70+70+70+70+70+70+70+70+700909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909!09!09!09!090909090909090909090909090909090909090909090909090909090909 0909 0909 0909 0909 090909090909090909090909094!094!0909090909090909090909090909 090e0e0e00 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f0 f 0 f0 f0 f0 fH0 f0i0i0i0i0i0i0i0i0i0i0i0i0i0i0i0i0i0iH0 f0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*mn!0*m0*m 0*m 0*m 0*m 0*m 0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m0*m_!0*m0 f0000000000000000000000000000000000000000000000000000000000000000000000000000!0000000000000000000 0 0 0 0 0 000000000000000000000000000000000000000000000000000000000000000000000007!07!00000000006!0!0ؕ!0ؕ0000000000!0ؕ000000000000000000000000000W!0W!0W!0W!00000000000000!0ؕ!0ؕ!0ؕ!0ؕ0000000000000000000000000000000X!0X!000000000000000000000000000000000000000Y!0Y!0Y!0000000000000000000000000000000000000000 0 0 0 0 0 0 0000000000000 00000^!0^!0^!0000000000000H00N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N0N 0N 0N 0N 0N 0N!0N 0NH00w0w!0w0w0w!0w!0w!0w!0w0w!0w0w0w0w0w!0w!0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w 0w 0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w 0w 0w 0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w0w 0w 0w 0w 0w 0w 0w0w0w 0 w 0C wi 0wi 0wi 0wi 0wi 0w0w0wk 0wk 0w000000000000000000000000000000000j 0j 0000000@000@000@000@000@0@0@0@0@0@0@0@0@0@0@0@0@0@0009:OPtustuZh?   W F G ~ 9 : z Gu%&GHaxE#zwMNS !"56\]klZ/AYX [!!!""""T#[#\##R$S$$$%%%%]&&&&C'(N((((()I*J*v*L+ , ,0,,,,---W////[000122333444455J6K6r6*7+7k77777|8}88899C9q9r99999 : :: :9:R:S:Y::::: ; ; ;";E;F;G;Y;[;;;;;;;;;<<$<p<q<r<<<<<<<<=<=S=q======= >>>(>G>^>>>>>> ?!?"?#?$?B???????@5@x@@BBBBC'CUCCCCC8D{DD3F4FFFGG4H5HMHHHlIIII,J}JJJJKxKKKK'M(M2MMMMNNN O OOOOOOQQQdRRRSS6U7UUU=V>V^V_VgVhVVVVV?WWWWWWlXXXXXXY YYYYYY0ZKZLZTZ^ZZZZZZZ;[<[V[W[k[[|\}\\\\4]]]](^)^=^z^^^^^^_y_z__"`#`2`3`?`~``'a2aMaaaaaab7bbcvc>ddzeee>fJggXhhTijjjj*j3jCjRjSjXjjjjjjjkkk/k0k6kkkkkkkkkk lCl_l|lllll'mUVWjz#'>mnoXY !"$"m$$Q%R%g%4&&'2'3'>'s'{((((()8)f){)))))****V++++++++++,,-,?,@,T,m,,,,,,,,,---A-B-R-S-T-U-1.s.t.|...../\//900_111112I3r3B4c4o445667777 8k8~88994:G:::;<<<==Y>>>>>??T?m?n?@@@AOAA6BBCC,DDDWEEE5FFHGPHQHHHHHHHHHHHHHHIII IHIRIUIXIYI]IkIIIIIIIIIIIIIIIIIJJJJJ%J&J'J(J)JJ KKLLLMM(M5MBM\M]MMMMMYNNOPPsQR/RPRRRSSShTTTTU(U=VVVTW`WW)Y*YUY|YZQZhZZZZZ[\\\\+]]k^^2__```aaaaabMbNbvbbb>ccpdqdrd{d|ddddddeeeffffigjgxgggg h hhThUhhhhhh5iAiiiiijjj-j`jajpjjjjll6llllmXm?nbnnnn|oooopppp$q!r"r5rsisjssssstdt}B}C}D}E}F}G}S}\}]}^}_}`}a}i}r}s}t}u}v}w}x}y}z}{}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}~~ ~ ~ ~~~~~~'~(~)~*~+~E~F~G~H~I~R~S~T~U~V~Y~Z~[~\~]~f~g~h~i~j~t~u~v~w~x~|~}~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~"#$%&-./01<=>?@IJ2ǂai01ˆÈ&' !"56~  ڋۋ9 NOSijoȍɍ͍̍΍эҍӍ׍%&*+,-?Pb  ӏ$őܑؑݑĒ!"iݓ >Rst֔./0A,\QHIyzӛ, ɝʝם؝Xu'(1Rǟȟן؟.uѢҢ.TU]./>̤إۥ\^1Dا;Xmns  8gxԩ/P[\nKLT¬-KZϮ9gگۯ -PQEyI  KƵ^ U"#+9:ĺMƻǻ@v\]ƽ56NOlҾ*+TUorsBDOctu!"56no?]{HIjk%1*LZjkqr;>?(#$u5ij()6:;Z[E{|<_)-1?P\j=>^|}Bfg)wx:;Nz 56G!"757|89GHTUd'BaQ  YZ4`qr~ 7Rd"#.^+f67_UVF(WijP  Axy 01Jw+] !CDEFP)*+<=QRvL~pbGDm (   G  -    , - F }     MN;st  %&<UVjyzxyLirw  '47TW~LM#(+GczE'()KM[6u%]     0!`!!:";"L""## $_$`$$m%&&X'Y'{''''(((0)1)X))))*+0+1+9+++,.,t,,,J-----...N/00%0&0J0v00.1Z11112222223S33333335464i4444+5596k6l6m6z66666 7K77777778898:8E88889X9Y9Z9h999999:):Y:Z:s:t::::F;;;<<<<:=h=i=r====>>)>>>>??"?g???u@v@@@@oAAABBCCCCDD^E`EQFRFZFFF!G$GGGCHDHjHwHHHHI^IIIII0JJJJJKcKdKKKKKLL*L+LLL$MvMMMMMN;N_NNNLOMOdOeOOOOOOx}xxxy y6yMyyyyyMzzzP{{{$||||}C}}}P~~v|Dɀ%D߁Mƃǃ΃>Xcфp$l&\ =ш&>IBmn~ <T(8d;GpΎV֐'M TPBCX!ݘ/ٙ: kɛS #QuΠ%ɡ8M#$45L̩JΪ(bTbf٭\O/?@gSƲг|}  1<4e¹||F7b:X>`| '4>RV`n '()EF} (3456CLMNOP#$~ Z\A}(f459LMd~ 9:;cd|k4!FG-.Nz4)*efmDFOop|}BC3dDN !Z[\hi<=@Alm]xjk0P1Rs,-zFx=%&HI[\#Yh+:G_q|}(-st :bcdvw~&'6bc.! @K!5Hw6lP<P]^y-.Q:;m5Cu?@e.#p8W[2   g  y  \     kl./Oo-.Z3j!z{|k"WX_%&[  !%)*.7BHMSTU\01@klv*S !`!!!""""##,#s######&$'$($\$]$%%*%+%%%%%%%H&I&&&]''''''(3(B(b(((((( ))-)))*A*s**++---.{000O2z2{2222733*4445G5H5[5555R666d78S8T8h88 9V9999999:V::];<"<<<"=W==== >>>[????@@AB-CbCCCjDkDDDELEXEEEE_G`GlGH`H2IITJUJnJoJpJJJJJJJJLLLqLrLsLLLTMVMWMXMaMbM}N~NNNOOdPePPPPPPPQQQQpQQQQQQQ]RRRSSS(SXSYSbSSSSTUTVTiTjTTTTTlUnUUU V VV;W=WWWWW-X.XXXXYY$YRYSYdYYYZZZZ [L[M[X[[[[\\\/\K\g\s\\\\\\\\]]Z]8^e^^^^^^_r____c`d`}`~``` auavaaaabobrbbbcc,c-cNcccccdaddddZe[eeeeffhfif@gAgYgZggggggh5h6hRhh'iXiiijkkkkmlnlllBmmmnnZnnnnnn|o}o~ooooZpp#q_qqrrkstu"vvw3xxxxxxx;ylm$STq$bcޒ%{” klvw&BCXϗЗїdefw˜٘567B ?Y؛WX pCDW/>g0Cߠ |)*.<=ĤŤ2\s\iʧ˧KfgqŨ45@ک,-A)@!.>tHůƯ}±9@Wn  MN͵@eٶڶjr:fѸҸ߹!".st c bc-()9op45Rjk[\!#45j+,HJ fmCtY7gS5!Ns89TMRDp "Zz{Q!"35Sq)N'O'=KdE:qrItu.VWX=>uNLw?n34U<Wlm!cq^_mno|}/0Guv=>yzkPijk(JHIBtuBK L     P   ' (       Y Z  DEIhiLij23A B3~ST,8b{    !"Y#### $C$$$U%%%&,&f&&'V(`)l)))*8*r****++/+ , ,*,,,--..1///D0j0k0011 22e223/334444,55556k66677%777778K999::5::::;];;;;<.</<R<<<<======T>U>s>>?@@@@A+A;AHA`AxAyA3B4B5BJBKBLBWBXBBBBBB)CjCCCCCDkDD#E0EFErEEEFF(F7FGFHFIFFFFFFFFcGdGGGGGAHBHPHQHHHHHfp{|/0]^GH'(WXYij9xyǍ<=͎Ύ>~ʑdsߓ ǔՔ/I• C˖ݖ%WƗٗ-Br~˙ٙ 9Śܚ%QgǛ5@N]ozМ{ҝ>?NOqsՠ֠ޠhTuˢXʣߣ]ڤ+ئ1Ekoy5QlǨ3q6A34h9*DERS[{&;y T",|Wa޴ C\e ƸǸٸڸ)3@Exuvû_μϼSپ*+3Iÿ +>Ubq$}E`+7PZ8Kp4i .D [\jks U|()78D0e at-<T}  2 !"k;c7zpCDKLbctu"YZt238u JK Y.,-QWXpq=IJ&klq9 !"#8912qEF)*Q?exy 7 6(j <=Mx.  !!!""F#G#Z#[#8$$%%&r'?(r*)+%,\,D-..0334J66a89O;<<>j>k>>>>;??;@{@@A7ASATAdAAA0BkB,C-CsCtCCDoDDDEjEEE F F3FFFF G!GGGaHHIfIqIIJ7KLL,M-M6M>MDMHMIMOMZMdMnMoMzMMMMMMMMMMMMMMMMMMMMMMMMNNENN]OOO PP-Q7QQ RyR+STTTU:UUUUV W/W0WKWLWpWWWWXAXXXeXsXXXXXY Y}YYYYYY5ZZZZ8[[[[3\4\E\F\\\]h]]]@^q^^^^h_i_~__`J``````aaaaab(bdbbbbcceee.fffgeggik!mcmmmmnnnn9ooHpqQqrsttthuuvivvwwwxNyyzB{C{O{{c||||c}~`<={|3VcduvIمPz{5ЋދCMQl:>ڎ'(Mb_`Ґ/0Yԓ%&NӔ !?st!";_./?ؗ*GfoxŘƘԘ՘LNe}~QR˝Ɵǟ*+XYlYqrϤ(٥/Xz{%۪Ol<=ǭحc5xڱK>d8"nVQk{(¼üʼF{R|2w&e#$3qJ56X TUtuMu > #,8BCDEbdix{|  !*/9:UW\ahmn| 5CPUZ`ef|s`3qN>Iu/Wc#*p12A0q'IB]35>?P"Ey=F!>2o[\xwx7ATUstkl{|()5kHPU5%jk  . I U s           r8Yr6A2=/8!9!i!%"Q"{""""##"######=$$%B%N%%%&&&L&w&&&'(4(5(B(()))*<+$,,,-4-?--$///u0011133<66/888999::;;;;);R;u;v;O<<<<====3>4>q>r>>>P????????@:@;@?@@@SATAAABIBJBBBBBJCKCSCTCCCC D DWDDD+EEEE.F'GpGqGGRHHHHHBIII+J,JKJVKWKwKxKKKKKKKL/LbL-M.M9M^M_MpMMMMMMM)N*N6NrNsNNNNNNNNNNNNNNN6OOO P2QQQjRRRRRS8SpSS7T8TBTQTTTUVVVVWW9W:WW7X YsYtYYYYZ[e[[[H\I\`\\\]9^^^^_r____`abbbcc"ccc ddd8e9eLee'f(fAfff1g`gggggAhhiiijujjjjj.kkkkmmmm/nanbnsnn ooooppppppWqXq]r^rurrrrrrr s`tIvwwwx&xHxxxxxxxx yKyy{zzQ{{{|||Q}R}}7~n~~~~&8mC{ہ܁  Ԃu nŇƇ+,wS΋w̌NÍՎ֎cΒϒVWb/(MÙݙVd\& !/0DϟNwx'kbcz8ܬ*+,LMv~ͳ<=`ֵ>߷nùl8 s~WXD<wx=yD^  5{fvCbTUk$%= c3$6C p.oqr76ecu  G:`5 h0J~*kbcuy#,_b'n<:     g  d (     RGHe-.E ,mn WzGr7SzAB   !!!!z""##$$$$%C%%&!&=&&&&''5'?'@'((1(Q(o((()7)8)D)E)`)m)))))))**+++++t++++,,,,3,B,C,G,x,,,,,-#.$.b.c.w.2/3/K/////0;0W0000001111222V3h3i3y3z3345Z5m6n666t7u777%8&858~88888889+9q9r9999::;;;;k<<==c=d=x=y=====1>v>>>?5?Y?Z?g?????N@O@\@@@@@AA2A@AlAAAAAAAA*B+BjBkBC'D[E\EdEeEnEEMFFFG&HHHHHI@IbIII5JtJJJ=K>KPKKKK L!LTLUL`L M"M.McMdMMMMNVNWNNNNNN9O:OOOOOPPPPPQQQQiiiii.k/kCkkllllmllllYmmn/nnnnn-o.oUooooooo!p"p:ppppppqqrLrrrOsss@t:uyuzuuvvvvvvowwwww)xx1y2ynyyUzWztzzzzz/{x{y{{5|||||}}}}}}}9]^ÃքV  !9V֊Ћ<5vJ_׎ 9cw7;^͓̓ݓ%&CCD}~ߕpqrOPƗǗȗЗї'L٘#LZ Z[oȜ<=Bfg{| ^_}՞֞/1>ӟנ]/ݣ-.Ԥ()<zΥϥإ٥&'TU]^DE45KߨefufghqrLĬ>Sdyî߮ɯʯ;<Xef~ΰ12`%&w˲̲DEde{|Գe|}6̶DEF^_xɷշַfgyܸ?KnU:e  "JþſYZk !3} K-|KLt X;O@ 67lMNk|)no"#e  >?*+BCu4#e8.?'89PIJj 7>ij}t%&GM:Rq+nk!.X 4ab6.Hhl#. \56H4"#$>?JMUVdefg      L M N p q     $ % B b        5 {   S   67Bqr?@P>?L G ^,-E[ey o E6YZq    !!@!u!v!!J"K"Z""""###o$p$$$$-%%%&&*&R&S&T&o&p&&&&/''''(N)**!***** +9+f++++ ,Y,Z,|,-+-q-r------ ..#.$.;.<.S......-/.///9/:/A0B0Q0p0q0|0000(1)1011112 2Q2R223444G5}666677788}8~88899t99;;; <0<M<[<<<<Q=R===&>'>9>:>x>>O?P?\?'B(B:B_BBBDDDDEfFgFwFFFFFFGHGIGoGGG>HTHHHII{IIII JJJJJKKMKNKrKKKgLLL?Kcdt\]ߓmn!kט5ٙΚǛț5jŜX؝ٝbc&QRߠ13I~ϡ"#QMNϣУfn2ET_"ŪeM'Lѱ_`uв4QԳճ8CDW !mɵʵеѵ`a}ڷ۷`a2gֹ׹|Ӻnovx!"fg}&'s:[ (?VM7=rtr WXG`0   cd4'l" !JSTo`T#&.PQ*+:"{;<f#`am>?S!MN_`pW W]N^, 23BC;EP ezBhbxqr$IW1]^Mkl k       d e    1 E          Y u       : ; ^       & " # Q n   ? @ Q  C o ? @ O P j     O P s  / 0 ? h i v      - W X l     + , 9    ?    Y w x          # $ I       C D |    H      ( n o  w x         B a | }      i   / F    E      K        ! h! ! ! ! ! ! ! " M" " " " # ## ;# N# c# q# # # # $ S$ $ $ $ $ & & ' ' a' ' ' ,( -( M( N( ( &) ') ) ) T* U* V* r* s* * * * I+ c+ + 1, 2, =, 1- 2- ?- . ). "/ M/ ~/ / / / \0 0 1 1 1 2 O2 P2 [2 \2 2 2 2 2 3 <3 d3 3 3 3 3 3 3 3 3 3 4 +4 \4 4 4 4 4 5 a5 b5 y5 6 6 6 ?8 @8 8 39 9 9 9 ": #: 3: H: y: z: {: |: : : : : 5; ; ; ; ; 0< 1< ?< < < = ?= @= K= = = = > > > > > ? "? #? a? ? ? ? ? ? @ @ FA A A A "B }B B C LC C D D "D AD D D D VE vE E E E E tF uF F F F G jG G G G G .H mH nH H H H H I I y oy z z { ?{ i{ { { n| | } } } ~ V~ ~ ~ 2      U V Ā  , W y   r  < = l ؃  } ~ ( K х  M ц    % L z {  Y E F k ͉ K L b c ϊ W   ; < ` r = Q R p q } ͍  s T  < ߒ    S ֓ ד  z Д , - < = J K \ 8 9 T Ȗ ɖ _ H I ~ ҙ ә . | 7 8 \ ݛ ޛ P Q d e z ќ ՝   4 e Þ # H W ߠ S 9 w   - | 9 : W X  ؤ ݥ ޥ T ٦ ڦ  # $ n ( Z [    Y     9 v  $ % L 3 4 > i j y ۭ ܭ   6 u v f | s  ' ( J _  Z z     B V 1 2 E r ܶ D ˸ N O o | } T | } F  c d S T s 5 V W c Ͽ п I J f  = > o  # $ o   } - 9   U V r s  X j W  O k S   7 j k   , ^ _ z " O  S T f   > ? k \ | B C U   b c   : F k l ; R S d e o p ! J s X Y g h ' ( 3 W X z P Q l   0 Z N 0   % Y Z  A B \ = t  ' ( i j  h i | o p q   +      / C D G o 0 l    # J h ! [ \ o  F  T a D i j h i @ A N      h      h    Q R                  Q R d      4 C D Z n    p q { |  q ;       k   A B T   7 Q       n     N O X   "  % ~     S T       / 0      e      5   % & A B T  4 5 W ?! @! L! ! # L# N# j# # # # $ $ 0$ $ $ $ $ % _% % % % & .& /& &' '' D' ( ( ( |) }) ) .+ /+ + , , , - - - . . . . / / / / 0 0 =0 0 0 0 0 0 0 1 1 1 2 2 2 2 $2 2 2 2 73 83 F3 y3 z3 3 3 3 3 3 .4 4 4 P5 Q5 t5 6 66 76 I6 7 *7 g7 h7 p7 7 7 7 "8 8 8 8 8 8 9 R9 S9 \9 9 9 9 9 9 M: x: y: : : : +; ,; ?; S; T; ; ; ; ; ; < !< +< -< %= &= a> b> ? ? @ lA mA =B >B nB oB pB zB {B B B B B B B B #C @C gC hC qC rC 4D dD eD uD E YE E E E E E F 3G 4G qG G H H SI TI eI I I I J eJ J J J J J J K K K iK K FL {L L L L L "M #M WM M M N HN IN N N N >O pO O O YP P Q R R R ,S qS S S T T T T T T T 0U SU u ou pu u u Qv v Lw jw kw w w w w w 7x 8x x x /y ay ~y y y y =z z z ^{ | V} W} X} `} a} e~ f~ l~ ~ ~ 2 M h      r  ; P y N ڃ ۃ    1 2 N Y Z r Ą ń       ; r s ˅ ̅ ؅ ӆ  K o Ƈ J K Ո ֈ  r s | ʉ / 0 > ? J NJ ̋ ͋  / > t nj  ݍ ލ @ 3 ~ ̏ + 8 [ \ ? @ G Փ  ' ( 8 ؔ ו 1 " Z u 6 Ĝ Ŝ , - ) * 8 9 ˠ . q  N + Z ֧ @ A P ب ) n ѩ  L $  3 K ˬ  P a  3 s t z [ د  V p ְ  ] i S 0 1   ޵ + , 6 | ȶ ?    o [ \ y ػ ٻ ּ ׼ ؽ W Ѿ   " *  e  % 2 \ k l ( n # ` a 8 m n o  P h i u ` . y z 5 / a C #   ) 2 = x M N d . / q r  V W | " p q   & X Y r 7 .  j v A  4 5 G   6  [ f ,  2 3 X Y }  C q r x y B    Y  * i j , W X    $ % 7 > B I J K L \ ]   ` n R ] 7 g   > 1 2 u v  3 M           L z          < = N O    J K <   = 9 o p  Z ) U  G H g        L                          $ m  :     F j /! 0! C! ! " " " " " F# # # *$ Z$ [$ h$ $ $ $ % % % % & & & & k' %( d( ( ( ) ) J) ) 9* :* D* r* s* * * * * * * * * * * * * * + + + 3+ 4+ @+ A+ z+ {+ + + + + + + + + l, , 4. . */ x/ / :0 }0 !1 "1 C1 1 1 2 2 2 &3 {3 3 3 3 4 h4 4 4 5 C5 5 5 5 5 E6 k6 7 7 %8 W8 8 8 8 9 9 6: 7: O: : #; ; ; ; ; "< H< T< < = J= K= U= V= h= = = > 8> > > ;? ? "@ e@ f@ {@ A B C C C CD `D D D E bG H ?H @H KH LH H H H H I I ^I _I }I I I J J J K K K K K K /L kL L L hM iM M M 4N N N N N O O 4O P AP P P P Q Q Q Q HR qR R S MS NS S S S nT oT sT T T T T JU U U U U U U UV VV eV V ;W W W W W X X X Y -Y .Y QY RY `Y Y Y Y Y Y Z Z Z ([ Z\ \ \ \ \ e] ] ] Z^ r^ s^ |^ ^ ^ <_ J_ _ _ _ q` 0a fa a Hb eb nb b b b b c 4c jc c c d #d [d 7e e e 3f 4f If lg g g g g (h @h (i Ci i i tj j k k l l Ym am n n o o To Uo p Qq vq q q q q q q q q r r r r r (r ů Ư ӯ ] a ɲ & ' A a I ~  ɸ " ! k  P = > a b  l  } 5 M l   ` A * / # e s t U T X  n 8 k l r J h  > Q  \  ? @ y # 6 7 O 6 7 G  % [ 1 8 T i c  | g h i z {   b  . Z  D r A C P Q h i u : ; N ? s t  +   - . e    H     A u  , - 3 4 A K p   A O P x y K > @ E   J i K p   k       } ~    # S    J t   = E z      f g s t        $   Y Z   A B T    - . ? t u     ] ^ y    & ' 7 8 F              C D h    b c p q    ` a w    ' (       F G     ( *    K L X   + D E V        i t  y ! ! " # e# 5$ 6$ B$ }$ $ k% % .& e& ' &' {' ' ' #( ( ( ( ( ) ) ) ) * * * :+ + + {, |, , - a- }- - - - . . z0 .1 1 2 2 E3 F3 x3 y3 3 3 3 3 3 j4 k4 v4 w4 4 4 4 4 5 J5 K5 U5 V5 f5 5 5 5 6 6 6 6 7 7 7 7 7 8 L8 M8 8 8 8 8 E9 F9 _9 `9 9 9 9 9 G: : : ; q< r< < < < < (= O= P= e= = = = > > n? @ ]@ @ @ B DB `B }B BC C C C D E E dF F -G .G =G G G G G H H H H xI I J K L gL hL L L M M M M M N N N :O ;O O O O O O P }Q R S U U U !U "U 1U U U U V V 9W W X ;X X X fY gY ,Z -Z Z Z Z Z Z [ _[ [ [ [ [ [ \ \ ] ]^ ^^ s^ ^ ^ ^ _ _ w_ x_ _ _ R` ` ` ` ` 7a ka a a c c e me e f f Bf f f g (g \g g g g Zh 6i i i $j %j Fj j j j k k +k ,k k +l Gl l l l l l m _m m m Gn Hn Zn n n n n o o o o o o o 9p ;p p p p p p p ;q q q q 'r (r hr r r r s s s s fs gs s s t :t ;t [t t u u +u ,u bu cu u u v v v v v v v Bw Cw w w !x "x x x x Ny Oy y y y y y y y z ^z {z z z z z z z H{ }{ | `| | | H} |} } ~ 5    n  K ͂ ل   @ ؇  A a  3 ލ w x  Z   % ِ ڐ ޑ ߑ Ԓ Ւ ) * G ۓ g h ̔ z {  [   ; B #  ^   ̠ 0  / ͤ . > . s k ¨ = 4 x { |   D E ^ y ͭ έ s t Į  2 K L  # $ 8 9 g h ; dz ճ  ش -   Ӹ Ը j v 5 v ¼ 1 2 N ս ! " 4 5 \ ¾ þ Ǿ ׾ 8 I p y Ͽ  T U < = V W a   1 2 z {  >  b c d v w  ( t  u  o p D E  d e 4 G * n o 7 . / C   0 Z  `  } ) * V  ]  - } ~  t u G H U V x B C   ~ 0   $ ' E F b M N  C D ~ X o y * }   5 6 D  Q R S \ ] p  A   4 N e  / J K V W d   ( P p Q   / r s  O P Y Z e r   4  @ &  * O   n   [     j t  < q     / Q   K W ( Q x y H I v A B           + 7   H ; <   N   _   .     8 ~    Z    q     s           w x   J y ! P! Q! t! u! ! ! $" %" O" n" " " " " " " # # # # 0# o# p# # # # # # %$ $ $ % % % &% '% 8% 9% B% C% P% % % % Z& [& x& & ' ' ' ' i( ( ( n) o) ) ) * * F* * * * * * + P+ Q+ b+ + + + + }, ~, , , _- i- - - -. E. . / / <0 0 0 0 D1 y1 1 1 1 1 2 2 P3 3 3 3 X4 4 4 4 5 5 5 \7 ]7 7 7 8 8 8 8 8 8 9 9 9 .9 e9 9 ]: ^: z: ; ; O; P; b; c; 4< 5< w< x< y< < < < = +> i> > > > y? ? \@ ]@ @ \A ]A A A -B _B `B aB B B B B B D D D D SE TE gE E F !F 4F F F F aG bG G H H H H 9H | } ? @ \ ֦ " # 7 T U Z Ƨ    ;   ? @ ] ^ Ī B n ګ  [ \ ~ G H X  I W l ʰ ˰  G q ȱ ɱ W f t u IJ  4 5 g   ) * 5 6 f ̴ ? @ ڵ ۵  G { ̶  7 | . }   B \ ĺ ` X Y ¼ - 6 { ֽ *  E ; < T  S  T o p K _ ` x A X Y ^ A J i + \ ] C K  U ; ' ( ) D 4 5 e 1 2 > ? N   ( T  S 6 7 C  $ ]  6 M Q  0 = D   E F P > a c  @  9 : ; V  #   U V k $ % < _ ` t = Y Z u 3 ) 8 j S < q ! 5 > E 4  P  p 6 _ L v *+@Aj|c23C%&34av i; < b     _ z    + g          ;    ./}~EFjkFGbcu? aUVdn&1Q1  z!{!!!7"}""#a#b#r##$}$$%H%I%i%&&*&B&n&&&&' '<'{'''''((3(4((((()n+o+++,,---..y.z....4//203000M1111-2@222\3]3}333H4I4U4'5(52566677_8`8999::*;;;;I<<<<<=">>??b@@AAAA?B\BKCCEEEFFFeGGGGIIIII+J{JJJJKdLL)M*MPGPHPPPPQQ7QoQRRSS,SSSTTTTUUUWWX\XXXXNYYZ\[][[[[\"\\]^^6^7^W^^_x__``````aaaaaabbEbFbdbbbbcHdeAfffNgg.hi'i(i\iijJkylzllmmmnznnnoKpLp_ppppPr{rrsatbttTuuuFvwwyyz{{{{ ||}||}}~Hx\ۂ܂JCS]eQɈ.M6fsv~68wxab~ڍۍOŽQGmnv4k2vwcdxʚ˚^_NOfGHƠX3ʣ:b4k٪78_ϫѬҬHMϮa78mӱ  #ijų.ݵ  #v̷^7ֹ1QRpռ)5\ӽԽlmuv9:JK  bd=qChi.]  3(9DEnK$`9:]>yz?@S@opTUklpX[&'@WXfhu0mo!" !LMNcdncd%&OP*+5N d,-+IDijst-.RSZ7p\ OCCjku89"d'IJ`      ( N O - 5 ]      ^  Bs  ]Z\S;BC 6734mnu  * k l  """"T####m$$f%%%&&Z&&&4'5'''''((p(A)B))y*z**++,r,s,,,9-Y......j/////d0e00111"2o22213A55555A6[7\7j7k7r7s778899 : ::::;;;;<< = ===h>>>??8@t@@AAAAABdBBpCCCDOE9FFGGtGGGGHH=HTHUHhHiHpHqHIIJJEJFJJJ^KKLhLLMMMMMNYNpNqNVPWPP9QQRSSXTTTTU'U(U[U;VVVWWWIX6Y7YYYYZqZrZZ?[@[[[c\d\\\]]]J]^]]]^C^^^f_g__1`I`J`^`_``a;bcccc3dddddd e2eeeeefffj?j\jjjWkkk l1lll!mZm[mqmrmmmmnennnnnZoopxppsqqqsBsCsvsttuuu>vvvdwwwy`yyyDzjzkzz{{}||}m~n~~tR{|҅Ӆo-LYЋыL׌B~&'`ʏ!z{M <=Emn}ה3ߕ ҖӖ5DE&lbHCDhܞ;[gXѡM*n.ɥѥ23CD]_Ѧ i̧#(@OͨѨ)>O`xʩ˩ͩΩϩЩ(ƪ9"P®#$1S]`aj9ҵ4QLIJRù%QRnyQսik˾׾?3QR[\l.^stK&\]k6'(wy  U2yz23P% !BCQyz  hstF} !]^VWg*KLX+"78HN45JA 0?z-.8.5}~PQlm`aO23()CcJKi7]ABde012?@GHQ[gh89Np !6k?'\"#)*BT$%46yz{ZvwM);<Nablm78    7 x      - r  3  g i t  O !z2*+()4 KLN[\]uv8b 0 009090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909 09 09 09 0909090909090909090909090909090909090909090909090909090909090909090909090909090909 090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909 00303030303030303 00K60K60K60K60K60K60K60K60K6j0K60}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}80}8 00r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<0r<!0r<!0r<!0r<!0r<!0r<!0r<!0r<0r<0r<!0r<!0r<!0 r<0r<0r<0r<0r<0r<0r< 0r<0r< 00F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F0F 00K0K0K0K0K0K0K0K0K0K0K0K 0K0K0K0K0K0K0K0K0K0K0K0K0K0K0K 00T0T0T0T0T 00T0T0T 00U0U 00GV0GV 00V0V 00 W0 W0 W 0 00W0W0W0W0W0W0W0W0W0W0W0W0W0W0W 00Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y 0Y0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^ 0|^ 0!`|^ 0!`|^ 0!`|^ 0!`|^] 0|^] 0|^] 0|^] 0|^] 0|^] 0|^] 0|^0|^ 0|^ 0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^40|^0|^0|^0|^0|^0|^40|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^ 0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^0|^ 0|^ 0|^ 0|^0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^0|^0|^0|^0|^0|^ 0|^ 0|^0|^0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^4 0|^4 0|^ 0|^3 0|^3 0|^3 0|^ 0|^ 0|^0|^ 0|^ 0|^0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^!0|^!0|^!0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^ 0|^0|^ 0 0 00 00 000 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00000000 0 0 0 0000000000 00000000 0 0 0 00 0000 0 0 0 0 00 0 0 0 0 00 0 0 000 0 0 000000000000 0 0 00000000000000000000000000000000000 00)0)0)0)0)0)0)0)0)0)0)0)0)0)0)0)0) 00C0C0C0C0C 0C 0C 0C 0C 0C 0C 0C 0C0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C0C 0C 0C0C 0C 0C0C 0C 0C0C 0C 0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0CZ!0CZ!0CZ!0CZ!0C0C[!0C[!0C[!0C[!0C[!0C0C\!0C\!0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C 0C0C0C 0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C0C~!0C~!0C~!0C~!0C0C0C0C0C0C 00U0U\ 0U0U0U0U0U\ 0U0U0U\ 0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U1 0U1 0U0U9 0U2 0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U0U2 0U0U0U0U0U0U0U2 0U0U0U2 0U2 0U2 0U2 0U2 0U2 0U0U0U0U0U 000 0 0 00 00 00!0!0!0!0!0!0!00o!0x 0x 0x 006 05 05 05 00000000000000000 00h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  0h  0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  0h  0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  0h  0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h !0h !0h !0h !0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  0h  0h  0h  0h 0h 0h  0h  0h , 0h , 0h , 0h , 0h 0h 0h 0h  0h 0h 0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h 0h 0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h !0h !0h 0h 0h 0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h  0h 0h 0h 0h 0h  0h  0h  0h  0h  0h  0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h 0h  00b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b 00fz 0f0f0f0f0f0f0fj 0f0g0g0g0g0g0g0g0g0g0g0g0g0g 00vj0vj0vj 00Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk0Dk 00{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{p0{pJ 0{p0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u0{u 0 00[~0[~0[~ 0[~0[~0[~0[~0[~0[~0[~0[~0[~0[~0[~0[~0[~0[~ 0[~ 0[~ 0[~ 0[~ 0[~0[~J0[~0|0|0|0|0|( 0|0|0|0|0|0|0|0|0|0|0| 0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0| 0|0|0|0|0| 0|0|0|0|0|0| 0|0|0|0|0|0|0|0|0|0|0|0|0| 0| 0| 0| 0| 0| 0| 0| 0|0|0|0| 0| 0| 0| 0| 0| 0| 0| 0| 0|0|0|0|0|" 0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0| 0| 0| 0|0|0|0| 0| 0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0| 0|0| 0|0|0|0|0|0| 0| 0| 0| 0|0|0|0|0|0|0|0|0|0| 0|0|0|0|0|0|0|0|0|0|0|0|0|0| 0|0|0| 0|0|0|0|0| 0|0|0|0|0|0| 0| 0| 0| 0| 0| 0| 0|0| 0| 0a| 0a| 0a|0|0|0|0| 0| 0a| 0a| 0a|0| 0| 0| 0| 0| 0| 0| 0|0| 0l|0| 0|0|y!0|y!0|0|0|0|0|0|0| 0| 0=| 0| 0| 0| 0|0| 0| 0}| 0}|0|0|0|0|0|0|0|0|0|0|0|0|B 0|B 0|B 0|0|0|0|0| 0}| 0| 0| 0|0|0|0|D 0|0|0|0|0|0|0|0|D 0|0|C 0|C 0|C 0|C 0|0|K 0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|0|!0|!0|0|0|0|0|0|0| 000000000000000000000000000000000000000000000000000000K 00K 000 00k0k 0k 0k 0k 0k 0k0k0k0k0k0k0k0k0k 0C 0C 0C 00F 00C 0C 0C 000!0!0!0!0!0!0!0!0!0!0!0!0O0000000000C 0CC 0CC 0C 0!000000C 0C 00000$ 0$ 000# 0# 00000# 0# 0# 00000% 0% 0% 000% 07& 000000% 07% 0700000000000 0 0C 0 C 0 C 0 C 0 C 0 C 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0 0 J00000000000000z!0z!0z!0z!0000|!0|!0|!000{!000000000J00R 0R 0R 0R 0R  0R  0R  0R  0R  0R  0R 0R 0R j0R 00000000j0R 0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f 0f 0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f 0f0f0f0f0f0f0f0f0f0f0f0f 0f 0f 0f 0f0f0f0f 0f0f 0f0f0f0f0f0f0f0f 0f 0f0f0f0f0f0f 0f 0f 0f 0f 0f 009&09& 00&0&0&0&0&0&0&0&0&0&0&0&0& 0& 0& 0& 0& 0&0&0&0&0&0&0&0&0&0&0&0& 00t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t.0t. 0t. 0t.0t.0t. 0t. 0t. 0t. 0t. 0t.0t. 0t. 0t. 0t.0t. 0t. 0t. 0t. 0t. 0t.0t. 0t. 0t. 0t. 0t. 0t.0t. 0t. 0t. 0t.0t. 0t. 0t. 0t.0t. 0t. 0t.0t. 0t. 0t. 0t. 0t. 0t. 0t. 0t.J0t.080808080808080808080808080808080808080808080808080808 08 08 08 08 080808* 080808080808 0808+ 0808 08 08 08080808080808080808080808080808080808080808080808080808+ 08+ 08+ 0808 08 08 08 08 08 080808+ 080808080808080808080808080808+ 080808080808080808+ 08+ 08+ 08+ 0 8+ 0 8+ 0 8+ 0 808 0 0>P0>P0>P0>P 0>P0>P0>P0>P 0>P 0>P 0Q0Q 0Q 0Q0Q 0QJ 0>P 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS 0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS0FS 0FS 0FS 0FS 0FS 0FS0FS 0FS 0FS 0FS 0FS0FS0FS 0FS0FS 0FS 0FS 0FS 0FS0FS 0FS0FS 0FS 0FS 0FS 0FS 0FS0FS 0FS 0FS 0FS 0FS0FS 0FS0FS 0FS 0FS 0FS 0FS0FS 0FS0FS0FS0FS!0FS!0FS!0FS!0FS!0FS 0FS 0FS 0FS 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0yQn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0Qn`!0Qn`!0Qn`!0Qn 0Qn 0Qn 0Qn 0Qn 0Qn 0FS 0 0 0 0 000000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0FS 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ> 0Ȉ> 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0@Ȉ 0@Ȉ 0Ȉ 0eȈ 0eȈ 0eȈ 0eȈ 0eȈ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ+ 0 Ȉ+ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ 0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ 0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ0Ȉ 0FS00000000000000000000000000000000000 0 0 0 0 0 0R!0 0R!0 0 0 0 0 0 0 0 0 0000000Q!0Q!000000 0J 0>P0q0q0q0q0q0q0q0q0q0q0q0q0q 0q0q0q 0q 0qS!0qS!0qS!0q 000 000 0000 0J 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0 ; 0 ; 0 ; 0  0  0 < 0 < 0 < 0  0 0 0  0  0  0  0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0000T!00T!00T!00T!00000 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 00 00 0 0000 0 00 0 0 0 0 0 0 0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 !0 !0 !0  0 0 0 00000000 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0 0 0 00 0 0 0000 0 0 0 0 0 0 0 0 0000000000000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0!0000!0!0 0 00J 0J 0 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $w!0 $w!0 $0 $x!0 $x!0 $ 0 $ 0 $0 $0 $0 $ 0 $ 0 $ 0 $ 0 $ 0 $ 0 $) 0 $) 0 $ 0 $ 0 $ 0 $0 $0 $0 $ 0 $ 0 $ 0 $ 0 $ 0 $0 $0 $0 $0 $0 $0 $ 0 $0 $0 $0 $0 $0 $0 $ 00(80(80(80(80(8 0(8 0(8 0(8 0(8 0(80(80(8 00<0<0<0<0< 0<0<0< 0<0<0< 0< 0<0<0<0<0<0<0<0<0<0<0<0<0<0<0< 0< 0E< 0< 0< 0<0<0<0<0<0<0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<0<0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<0<0< 0<0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<!0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<d 0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<!0<!0<!0<!0<!0<!0<!0g<!0<0<0<0<0< 0<!0<!0<!0<0<0<0<0<0<0<0<0<0<0<0<0<0<0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0< 0<0< 0< 0< 0< 0< 0< 0< 0< 0<0<0< 0<0<0<0<0<0<0<0<0<d 0^<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<0<d 0^<0<0<0<d 0^<0<0<d 0^<0<0<0<0<0<0<0< 0<0[ 0[ 0[ 0[ 00[ 0[ 0[ 000 0 0 0 0 0 0 00 0 0 0 0 00 0 0 00 0 0 0 0 00000000000000 0 0 0 0 00000000000000000000000000000000000000000 0 0 0 0 0 0000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 00000000000000 0 0000 0 000000 0 000000000000000000000000000000 0 0 0 0 0 0 0 00 00000000!0!0!000000 0 0 0000000000]!000000000000000000000000000000000000000000000000000000000000000000000000000000000 !0 0 !000000 !00 !000000000 !0 !0 !0 !00 !0 !0 !0 !0 !0  !0  !0  !0 000 0 0b 0b 0b 0b 0b0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b0b 0b 0b0b0b 0b 0b 0b 0b 0b 0b 0b 0b 0b0b0b 0b 0b 0b0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b? 0b? 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b 0b0b 0b 0b 0b0b 0b 0b 0b 0b0b0b0b0b 0b 0b 0b0b0b 0b 0b 0b 0b 0b !0b0b 0 0 0 000 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0 !0 !0 !0 !0 !0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 00 0000000 0 0 000000000000000000000000000J00 000j 0 0j 0j 0jz 0j 0z 0j 0/ 0/ 0/j 0 0 0 0 !0:0 0U 0U 0U 0U 0U 0U0U0U0U0U0U0U !0U0U !0U0U0U 0U 0U 0U 0U 0U 0U0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U!0U!0U!0U!0U!0U 0U 0U 0U 0U 0U0U0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U!0U!0U 0U 0U0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U 0U0U0U0U0U0U 0U 0U0U 0U 0U 0U 0U 0U 0U 0U0U 0U 0U 0;0; 0; 0;0;0; 0; 0; 0; 0; 0; 0; 0; 0; 0; 0; 0; 0;0; 0U 0^@ 0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@ !0^@0^@0^@0^@0^@00^@00^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@ 0^@0^@ 0^@ 0^@ 0^@ 0^@0^@ 0^@ 0^@ 0^@ 0^@ 0^@0^@ 0^@0^@0^@0^@0^@ 0^@0^@0^@0^@0^@0^@ 0^@ 0^@ 0^@0^@0^@0^@0^@0^@0^@ 0^@ 0^@ 0^@ 0^@ 0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@0^@ 0^@ 0^@ 0^@ 0^@0^@0^@0^@0^@0^@0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@0^@ 0^@0^@0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@ 0^@0^@ 0 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j0 j 0 j 0 j 0 j 0 j0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j0 j0 j0 j0 j0 j0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j!0 j!0 j!0 j!0 j!0 j0 j0 j!0 j!0 j!0 j0 j0 j0 j0 j!0 j0 j0 j 0 j 0 j 0 j 0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j3!0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j!0 j0 j!0 j!0 j!0 j!0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j 0 j 0 j 0 j0 j0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j0 j0 j0 j0 j0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j_ 0 j0 j0 j_ 0 j_ 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j 0 j 0 j 0n j 0n j 0n j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j_ 0 j0 j0 j_ 0 j0 j_ 0 j0 j0 j 0 j 0 j 0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 0 j 0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j!0 j!0 j0 j0 j!0 j!0 j!0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j !0 j0 j0 j0 j0 j0 j0 j0 j !0 j !0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j!0 j!0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j0 j 00p!0p!0p!0p!0p!0p!0p!0p!0p!0p!0p!0p!_ 0p!_ 0p!_ 0p!_ 0 p!_ 0 p!_ 0 p!_ 0 p!_ 0 p!_ 0p!0p!0p!I 0p!I 0p!= 0p!= 0p!0p!0p!0p!0p!0p!0p!0p!0p!0p!0p!!0p!!0p!!0p!0p! 00}?0}?0}?0}?0}?0}?0}?0}? 00A0A{ 0A{ 0A{ 0A{ 0A{ 0A{ 0A{ 0A0A0A0A0A 00D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D!0D!0D!0D!0D!0D0D0D0D 0D 0D 0D0D0D0D0Dr 0Dr 0Dr 0Dr 0Dr 0Dr 0Dr 0Dr 0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D0D 00 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X0 X 00]0]0]0]0]w 0]w 0]w 0]w 0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]s 0]s 0]s 0]s 0]s 0]0]0]0] 0] 0]0]t 0]t 0]t 0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]9!0]9!0]0]0]0]0]0]0]0]:!0]:!0]:!0]0]0];!0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0]0] 0000;!0;!0;!0;!0;!0;!0;!0;!0;!0 ;!0 ;!0 ;!0 0000000000000000000000000000000000000000000000000 00X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0Xv!0Xv!0Xv!0X0X0X0X 0X0X 0X 0X 0X 0X!0X!0X!0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X0X 0X 0X 0X0X0X0X0X 00Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ưq 0Ưq 0Ưq 0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư 0Ư 0Ư 0Ư0Ư0Ư0Ư!0Ư!0Ư!0Ư!0Ư!0Ư!0Ư!0!Ư!0!Ư!0Ư!0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư 0Ư 0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư0Ư 00_0_0_0_0_0_ 00~0~!0~!0~!0~0~0~!0~!0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~0~"!0~"!0~"!0~0~0~0~0~0~!!0~!!0~!!0~!!0~0~ !0~ !0~ !0~ !0~ !0~0~0~0~#!0~#!0~#!0~#!0~#!0~#!0~0~0~0~0~0~$!0~$!0~$!0~0~0~0~0~0~ 0000000000000000000)!0)!00000!0!0!0!00!0!0!0!0!0!000000000000000C!00C!00000000000000000000000000000000000l 0l 00l 0l 0l 000m 0m 0m 0m 00n 0n 00000o 0o 0o 000p 0p 0p 000000000000000D!00D!0000 0 0 000 0 0 00000000000000008!008!000000000000000000000000000!0!00000000H!0H!0H!0H!0E!0E!000G!000F!0F!0F!00000I!0I!0I!0I!00K!0J!000J00909090909090909090909090909090909090909 09 09090909090909090909090909090909A 09A 09A 0909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909090909 09 09 09 09 09090909j 090Q0Q0Q0Q0Q0Q0Qq!0Qq!0Qq!0Qq!0Q0Q0Q0Q0Q0Q0Q0Q0QH 0QH 0QH 0Q0Q0Q0Q0Q0Q0Q0Q 0Q 0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q!0Q!0Q0Q0Q!0Q!0Q!0Q0Q0Q0Q0Q0Q0Q0Q0Q0QG 0QG 0Q0Q0Q0Q0Q0Q0Q!0Q!0Q!0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q!0Q!0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q!0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q0Q0Q0Q!0Q!0Q0Q0Q0Q0Q!0Q!0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q0Q0Q!0Q0Q!0Q0Q0Q0Q0Q0Q0Q!0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0QI!0Q!0Q!0Q0QI!0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Qy 0Qy 0Qy 0Q0Q 0Q0Q0Q0Q0Q0Q 0Q0QH 0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q 0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Qb!0Qa!0Q0QH 0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q0Q!0Q!0Q!0Q!0Q!0Q0Q0Q0Q 0000000000000000000000000000B!0B!0B!0B!0B!00B!0B!0B!0B!0000000000 0A!0YA!0YA!0YA!0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0YN!0YM!0YM!0YM!0YO!0YL!0YL!0YL!0Y0Y!0Y!0Y!0Y0Y!0Y!0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0YP!0YP!0YP!0Y0Y0Y0Y0Y!0Y!0Y!0Y0Y0Y0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0Y 0 0 0 0 0 0z 0z 0z 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00000 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00000000000000000 0 0 0 0 0 0 0 0 0 0 0 08 08 08 08 08 000000 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 0 0E 0E 0E 0E 0E 0E 0E 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI1!0gI1!0gI1!0gI1!0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI0gI0gI0gI 0gI 0gI 0gI 0gI 0gI 0gI 0gI!0gI 0gI 0gI 0gI 0gI 0gI 0 0Wm 0Wm 0 0m 0m 0m 0m 0m 0 0Kn 0Kn 0 0n 0n 0n 0o 0o 0o 0o 0o 0o 0o 0o/!0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o 0o0o 0o 0o 0o 0o 0o 0o 0o0o 00z0z0z0z 0 0{0{0{0{ 0{J 0{ 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0#} 0#} 0} 0} 0} 0} 0} 0} 0} 0} 0} 0}z0} 0 0 0 0 0 0j 0} 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑c!0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0֑ 0} 00 0} 000000 0 0 0 0 0 0 0 0 0 0 0 0ǖ 0ǖ~ 0ǖ~ 0ǖ~ 0ǖ~ 0ǖ 0ǖ 0ǖ 0ǖ 0ǖ 0ǖ 0ǖ 0ǖ 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0}!0}!0/!0 0 0 0 0 0 0՜ 0՜ 0 0 0 0 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z0Z0Z 0Z0Z0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z/!0Z/!0Z/!0Z/!0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z0Z0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Zv 0Zv 0Z 0Z 0 0 u 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0  0  0 0  0  0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 0 0 0 0 0 0 0 0 0 0000000000000000000 0 0 0 000 0 0 0 0 0 0 0 0 0 00000000000000000000000000000000000000000000000000000000000000000000000 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 00 0 0  0000 0 000000u 0u 0u 0u 00000u 0u 0u 0.u 0.0 0000 00b0b0b0b0b0b0b 00s0s0s 00I0I0I0I0I0I0I0I0I0I0I 00O0O 0O0O0O 0OV 0OV 0OV 0OV 0O 0O 0O0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O| 0O| 0O| 0 O| 0O| 0O| 0O| 0O 0O  0O  0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O0O 0O 0O 0O 0O  0O 0!0O 0!0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O  0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O0O 0O 0O 0O0O0O0O 0O 0O 0OU 0OU 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0  0  0  0  0  0  0  0  0  0  0  0  0 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  00V0V0V0V0V0V0V 0V00000000!00>!00>!000000 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00 00J 000@P 0 0eP 0eP 00P0P 0P 0P 0P 0P0P0P0P0P 7 00SZ0S0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T7 0ST0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T0T 0T 0T 0T 0T 0T 0T 0T  0T 0T 0T 0T 0T 0T0T0T0T 0T  0T  0T 0T0T 0T 0T 0T 0T 0T 0T 0 0 0m 0m0m0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m0m0m 0m 0m 0m 0m0m0m0m 0m0m 0m  0 0t 0t0t 0 0.w0.w0.w0.w7 0.w7 0.w7 0.w7 0.w0.w0.w0.w0.w0.w 0.w 0.w 0 0:{ 0:{ 0:{0:{00}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}0}00_0_ 0_  0_  0_  0_ 0_  0_  0_  0_  0_  0_  0_  0_  0_ 00/0/0/0/0/0/0/0/000000000 0  0  0  0  0  0  0  0  0 0 0000 0 0 0 0T 0T 0T 0T 00000000 00000000000000000000000000 0 0 0 0 0 0 0 0 0 0 0 000000000000000000000000000000000000000000000000000000000w0w0000007 07 07 07 00000. 0. 0. 0. 00Q 0Q 0Q 00/ 0/ 0/ 0/ 000 00 00 00 00 00%0%0%0%0%00 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0 H 0  0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0ܲ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 0 0 0 0 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P0P 0P0P0P 0P0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0P 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0!0!0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0\ 0\ 0\ 0\ 0\%!0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\ 0\0\ 0\ 0\ 0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\ 0\0\J 00 0 0 0 0  0  0 0  0  0  0  0  0  0  0 0 0 0 0 0 0 0 0 !0 0 0 0 0 0 0 0 0 0 0 0 h 0 h 0  h 0  h 0  h 0  h 0  0 0 0 0 0 0 0 0 0 0 0 0 0 g 0 0 0 0 0 0 0 0 g 0 0 0 0 0 g 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !0 !0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 %!0 %!0 %!0 %!0 %!0 0 0 0 0 0 0 0 0  0  0  0  0  0 0 0 0  0 %!0 %!0 %!0 %!0  0  0  0  0  0  0 0  0  0  0  0 0  0  0 *!0 *!0  0  0  0  0  0  0  0  0 +!0 +!0  0 0 0 0 0 0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0 0 0 0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0d!0H d!0H d!0H d!0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H 0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H c 0H 0H 0H c 0H  0H 0H 0H 0H 0H 0H 0H !0H !0H !0H 0H %!0H %!0H %!0H 0H 0H  0H  0H  0H  0H 0H 0H 0H 0H c 0H c 0H c 0H c 0H c 0H 0H c 0H c 0H c 0 H c 0 H 0H  0H  0H  0H 0H 0H 0H 0H 0H  0H  0H  0H  0H  0H 0H 0H 0H 0H 0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H 0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H 0H 0H 0H 0H 0H 0H  0H  0H 0H  0H  0H  0H  0H t!0H t!0H t!0H t!0H t!0H  0H  0H  0H  0H  0H  0H  0H 0H  0H s!0H s!0H s!0H s!0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H 0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H  0H 0H 0H 0H 0H 0H 0H 0H 0H  0H  0 0t  0t  0t  0t  0t  0 0zu  0zu  0zu  0zu  0zu  0zu  0zu  0zu  0zu  0zu  0 0Tv  0Tv 0Tv  0Tv  0Tv  0Tv  0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv  0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv 0Tv  0Tv  0Tv 08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~  08~ J 0Tv  0u  0u  0u  0u  0u  0u  0u  0u 0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u 0u  0u  0u  0u  0u 0u 0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u  0u 0u  0u  0u  0u  0u  0u  0u  0u  0 0a  0a  0a 0a  0a  0a 0a  0a  0a  0a  0a  0a  0a  0a 0a 0a 0a 0a 0a 0a  0a 0a 0a 0a 0a 0a  0a  0a 0a L 0a L 0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a 0a 0a 0a 0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a ( 0a ( 0a  0a  0a  0a @!0a ?!0a ?!0a  0a  0a  0a  0a  0a  0a 0a 0a 0a  0a  0a  0a  0a 0a 0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a  0a 0a  0 0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C !0C !0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C 0C 0C 0C 0C 0C 0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C 0C  0C  0C 0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0C  0  0  0  0  0  0  0  0  0  0  0  0  0C  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0 0 0 0 0 0 0  0 0 0 0  0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  00 0  0  0  0  0  0  0  0  0  0  0  0 (0 (0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0 0  0  0  0  0  0  0  0  0 ! 0 ! 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  07 0  07 0  07 0  07 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 : 0  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  00  0 06  06  06  06  06  06  06  06  06  06  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07 07 07  07 07 07 07 07 07 07 07 07 07 07 07 07 07  07  07  07 07 07 07 07 07 07 07 07 07 07 07 07 07 07 07 07  07  07  07 07 07 07 07 07 07 07 07 J 07 J 07 J 07 J 07 07 07 07 07  07  07  0gM 7  0gM 7  07  07  07  07  07 07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07  07 07 07 07 07  07 07 ( 07  07  07  07 07 07  07  07  07  07  07  07  07  07  07  07  07 07 07 07 07 07 07 07 07 07 07 07  06  0b  0b  0b 0b  0b  0b  0b  0b  0b  0b 0b  0b 0b  0b 0b 0b Y 0b Y 0b Y 0b 0b  0b  0b 0b 0b 0b 0b 0b  0b  0b  0b 0b 0b 0b  0b  0b  0b  0b 0b 0b  0b  0b  0b  0b 0b 0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b 0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b  0b 0b  0b  0b  0b  0b  0b  0b  0b  0b ( 0b  0b  0b  0b 0b  0b R 0b R 0| b R 0| b R 0| b R 0| b R 0b R 0b  0b  0 001~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~  01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~  01~ 01~ 01~ 01~ 01~ 01~ 01~  01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~ 01~  01~  01~ Z 01~ Z 01~ Z 01~  01~  01~  01~  01~  01~  01~  01~  01~  01~  01~  01~  00 0 0 0  00g 0g 0g 0g 0g 0g 0g 0g  00Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č  0Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č 0Č  0 0Q 0Q  00  0“  0“  0“ 0“ 0“  0“  0“ 0“  0“ 0“  0“ 0“  0 “  0“ 0“ 0“ 0“  00 0 0 0  0 0 0 00V 0V  0 0 0 0 0 0 0 0W 0W 0W  0W  0F W  0F W  0W  0' W  0' W  0' W  0' W 0W J 0W 0j  00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 0 00 0 ( 0 0  0  0  0 0 0 0  00  0 0  0  0 z 0  0ܮ  0ܮ 0ܮ ( 0ܮ ܮ  0ү ܮ 0ܮ 0ܮ  0ܮ  0ܮ  0ܮ  0ܮ  0 0 00 0 0 0 0 0 0  0  0  0  0  0   0 0 0  0 0 0  0  0  0  0  0  0 - 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0 0 0  0  0  0  0  0  0 0 0  0 0  0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 0  0  0  0  0  0  0 - 0 - 0 - 0 - 0 0  0  0  0  0  0  0 0  0 0 0 0 0  0 0 0  0 0  0  0  0 0  0  0  0  0  0  00 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0  0  0  0  0  0 ,!0 ,!0 ,!0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0  0 0 0 0  0  0 !0 !0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 0 (!0 (!0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 (0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0 ( 0 ( 0  0  0  0  0  0  0 0 0  0  0  0  0 0 0 0 0 0 u!0 u!0 u!0 u!0 u!0  0  0  0 0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 e!0 e!0 e!0 e!0 e!0 e!0  0  0  0  0  0  0  0  0 ( 0 &!0 &!0  0 ( 0 0  0  0  0  0  0  0  0 !0  0  0  0  0  0  0  0  0  0 0  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  0 ( 0 ( 0 ( 0 ( 0 0 0"  0'!0# '!0# 0#  0#  0# 0# 0# 0# 0#  0# 0# 0# 0# 0# 0# 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' g!0' f!0' f!0' f!0' f!0' f!0' f!0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' j!0' j!0' j!0' 0' 0' 0' 0' 0' i!0' i!0' i!0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' h!0' h!0' h!0' 0' 0' 0' 0' k!0' k!0' k!0' k!0' k!0' k!0' k!0' k!0' k!0' k!0 ' 0' 0' 0' 0' 0' 0' 0' (0' (0' ( 0' (0' ( 0' 0' (0' ( 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0I '  0I '  0'  0' 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0' 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0' 0' 0' 0' 0'  0'  0'  0'  0'  0'  0'  0'  0' 0'  0'  0'  0'  0'  0'  0'  0' 0' 0' 0'  0' 0'  0'  0'  0'  0'  0' 0' 0'  0'  0'  0'  0' 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0' - 0' - 0' - 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0' 0' 0' 0' 0' 0' 0' 0'  0'  0' 0' W 0' W 0' W 0' W 0' W 0' 0' 00' 0' 00' 0' 0' 0'  0' X 0' X 0' X 0' X 0' X 0' X 0' X 0' X 0' X 0' X 0 ' 0'  0'  0' 0'  0'  0'  0' 0'  0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0'  0'  0' 0' 0' 0' 0' 0' 0' !0' !0' !0' !0' !0' !0' !0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 4 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0 0' 00' 0 0' 0 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0' 0'  0'  0' 0' 0' 0' 0' 0' 0' 0'  0'  0' 0 0' 0 0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0'  0' J 0'  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T U!0T U!0T 0T U!0T U!0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T 0T  0T  0T  0T  0T  0T  0T  0T  0T 0T 0T 0T 0T 0T 0T 0T 0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T 0T  0T  0T  0T  0T  0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T  0T  0T 0T 0T 0T  0 T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T  0T  0T  0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T 0T  0T  0T  0T  0T  0T  0T  0T  0T 0T  0T  0T 0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T  0T 0T  0T  0T  0T  0T 0T 0T  0T j 0T  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d  0d 0d 0d !0d !0d 0d  0 0  0  0 0 0 0 0 0 0 0 j0 0= 0= 0= 0= 0= 0= 0=  0=  0=  0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=  0=  0=  0=  0=  0=  0=  0=  0= 0=  0=  0=  0=  0=  0=  0=  0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0= 0=  0= 0= 0= 0= 0=  0= 0=  0= - 0= 0= - 0 = - 0 = 0= 0= 0= 0= 0= - 0 = 0= - 0 = 0= 0= 0= - 0 = 0= 0= 0=  0= J 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 J 0  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0P  0 0n  0n  0n  0n  0n  0n  0n  0n  0n - 0n - 0n - 0n  0n  0n  0n  0n  0n 0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n 0n 0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n 0n 0n  0n  0n  0n 0n 0n 0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n 0n  0n  0n  0n 0n 0n 0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n  0n 0n  0n  0n  0n  0n 0n 0n  0n 0n  0n  0n 0n 0n  0n  0n  0n  0n 0n  0n  0n  0n  0n  0n  0n  0n  00 < 0 < O 0 < O 0 < N 0 < N 0 < 0 < 0 < 0 <  0 <  0 <  0 < 0 < 0 <  0 < 0 < 0 < 0 < 0 < 0 <  0 <  0 < 0 < 0 <  0 <  0 < 0 < 0 <  0 < 0 < 0 <  0 < 0 < 0 < 0 < 0 < 0 < 0 < 0 < 0 < 0 < 0 <  0 <  0 <  0 < 0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 <  0 < J 0 <  0;S 0;S  0;S  0;S 0;S  0;S  0;S 0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S 0;S 0;S 0;S 0;S 0;S 0;S 0;S 0;S  0;S 0;S  0;S  0;S  0;S  0;S 0;S ` 0;S ` 0;S ` 0;S ` 0;S  0;S 0;S  0;S  0;S  0;S 0;S  0;S  0;S  0;S 0;S  0;S  0;S  0;S  0;S  0;S  0;S - 0;S - 0;S - 0;S - 0;S  0;S 0;S 0;S !0;S !0;S  0;S !0;S !0;S  0;S  0;S !0;S !0;S !0;S  0;S  0;S  0;S 0;S  0;S  0;S 0;S  0;S  0;S  0;S  0;S 0;S 0;S 0;S 0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S 0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S 0 0;S 0 0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S 0 0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S  0;S 0;S  0;S  0;S 0;S 0;S 0;S !0;S 0;S !0;S 0;S !0;S  0;S  0;S  0;S  0;S  0;S  0;S  00u  0 0 0 0 0 0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv 0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv !0Kv !0Kv !0Kv !0Kv !0Kv 0Kv 0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv 0Kv 0Kv 0Kv 0Kv 0Kv 0Kv  0Kv  0Kv 0Kv  0Kv 0Kv  0Kv  0Kv  0Kv 0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv  0Kv 0Kv  0Kv  0Kv 0Kv  0Kv 0Kv 0Kv 0Kv 0Kv  0Kv  0Kv  0Kv  00S 0S 0S  0S  0S  0S  0S 0S 0S  0S 0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S 0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0S  0 0˭  0˭  0˭  0 0M  0M 0M  00ɮ 0ɮ  00 0  00 0 0 0 P 0 P 0 P 0 0 0  0  0  0  0  0 !0 0!0 0!0 0!0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0 0  0  0  0  0  0  0  0 0K  0K  0K  0K 0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K 0K  0K 0K  0K 0K  0K  0K 0K  0K  0K  0K  0K  0K  0K 0K  0K 0K 00K 0K 0K 0K  0K 0K 0K  0K  0K 0K  0K  0K  0K  0K 0K 0K 0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K 0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K  0K  0K 0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K  0K 0K  0K  0K  0K 0K 0K  0K  0 0q 0q 0q 0q 0q  0q  0q  0q  0q  0q  0q 0q 0q  0q  0q  0q  0q  0q  0q  0q 0q 0q 0q 0q 0q 0q 0q 0q 0q 0q !0q !0q 0q 0q 0q !0q 0q 0q !0q 0q !0q 0q !0q 0q !0q 0q 0q !0q 0q 0q 0q !0q 0q  0q  0q  0q  0q  0q  0q 0 0q  0q  0q  0q  0q 0q 0q 80q 0q  0q  0q  0q  0q  0q  0q 0q  0q 0q  0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q  0q  0q 0q  0q  0q  0q  0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q 0q 0q 0q  0q  0q  0q  0q  0q  0q M 0q M 0q M 0q M 0q  0q  0q  0q  0q  0q 0q  0q  0q  0q 0q  0q  0q  0q 0q 0q  0q  0q  0 q  0 q  0q  0q a 0q a 0` q a 0q a 0q  0q 0 0q 0 0q 0 0q 0 0q 0 0 q  0 q 0 0 q  0 q 0q  0q  0q  0q  0q 0q  0q  0q  0q 0q 0q 0q  0q  0q 0q  0q  0q  0q  0q  0q  0q  0q  0q b 0q b 0q  0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q 0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q 0q 0q 0q 0q 0q 0q 0q 0q 0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  0q  00$ 0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$  0$ 0$ 0$ 0$ 0$  0$  0$  0$  0$  0$  0$  0$  0 0*  0*  0*  0*  0* 0* 0* 0*  0* 0* 0*  0*  0* 0* 0* 0* 0* 0* 0*  0*  0*  0*  0*  0*  0*  001  01  01  01  01  01  01 01  01  01  01  01  01 01 01  01 01 01 01 01  00D7 0D7 0D7 0D7 0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7 0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7  0D7 J 0D7  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@ 0@  0@  0@  0@  0@  0@  0@ 0@  0@  0@  0@  0@  0@  0@  0@  0@ 0@  0@  0@  0@  0@  0@ 8 0@ 8 0@ 8 0@ 8 0@  0@  0@  0@  0@  0@  0@ 8 0@ 8 0@ 8 0@ 8 0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@ 8 0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@ 8 0@ 8 0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@  0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@  0@  0@  0@  0@  0@  0@  0@  0@  0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ 0@ l!0@ l!0@ 0@ 0@ 0@  0@  0 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m  0m  0m  0m  0m 0m  0m  0m 0m 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m !0m !0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m 0m 0m 0m 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m 0m 0m 0m 0m  0m  0m  0m  0m 0m 0m 0m  0m  0m 0m 0m 0m 0m 0m 0m 0m  0m  0m  0m 0m  0m  0m  0m  0m  0m  0m 0m  0m  0m  0m  0m  0m  0m 0m 0m 0m  0m 8 0m 8 0m 8 0m 8 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m 0m  0m  0m  0m  0m  0m  0m 8 0m  0m  0m 0m  0m  0m  0m  0m 8 0m  0m  0m  0m  0m 8 0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m .!0m .!0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m  0m 0m  0m  0m  0m  0m  0m  0m  0m 0m 0m 0m 0m 0m  0m  0m  0m  0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m 0m  0m 0m 0m 0m 0m  0m  0m  0m  0m  0m  0m  0m -!0m  0m !0m !0m !0m  0m  0m  0m  0m  0m  0m  0m  0 0  0  0  0  0  0 02  02  02  02  02 J 02  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 V!0 0  0  0  0  0  0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 8 0 0  0 8 0  0  0  0  0  0  0  0  0  0 0  0  0  0  0 z 0 @ 0  0  0 8 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0 8 0 8 0  0 0  0  0  0 0 0 00O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0O 0 00 0 0 0 0 0 0 0 0 0 0 0 0 00 00000000000000000 08080808 00 000000000000000000000000000000m!000 0 0 0 0 0 0  0  0  0  0 0 00000000000 00 0@ 0@ 0@ 0@ 0@ 0@ 000S 0S 0S 0S 0S 0S 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0000 0 0 0 0 0 0 0 0 0 0 0 000000 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 00 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 00 0 0 0 0 0 0 0: 0: 0: 0: 0: 0: 0:: 0:: 0:: 0:: 0:: 0:: 0: 0: 0: 0: 0: 0:0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0: 0:0: 0: 0: 0: 0: 0: 0: 0: 0:!0:!0:0: 0: 0: 0: 0: 0: 0: 0: 0:f 0:f 0:e 0:e 0:e 0:e 0: 0:0:0:0:0:0: 0: 0: 0: 0: 0: 0:J 0:0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\0A\ 0A\ 0A\0A\0A\' 0A\' 0A\' 0A\' 0A\' 0A\0A\ 0A\ 0A\ 0A\8 0A\ 0A\ 0A\ 0A\ 0A\ 0A\8 0A\ 0A\p!0A\p!0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\ 0A\8 0A\8 0A\8 0A\8 0A\8 0A\ 0A\ 0A\ 0 0Ar 0Ar 0Ar 0Ar 0Ar0Ar 0Ar 0Ar 0 0 0 0x 0x 0x 0x0x0x 0x8 0x 0x0x80x 0x82!0x82!0x82!0x2!0x2!0x 0x 0x 0x 0x 0x 0x 0x 0x 0x 0x^ 0x^ 0x^ 0x^ 0x^ 0x^ 0x^ 0x^ 0x 0x 0x 0x 0xr!0xr!0xr!0xr!0xr!0x 0x 0x 0x 0x 0x 0x 0x 0x 0x 0x 0x0x0x0x0x0x 0x0x0x 00M0M0M0M0M0M0M0M0M0M0M0M0M 0M 0M 0M 0M 0 0 0 0 0 0 0 08 0 0 0 0 0 0 0 0 0 000 0 0 0(!0(!00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 00 0000000 0 0 0 0 0 0 0 0 00 0 0 0 0 00 0 0 0 00 0 0 0 0 0 00 0 0 00 0000000 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 !00 0000000 0 0 0 0 0 00 0 0 0 0 00 0 0 0 00 !0* !0* !0* !0* !0* 0 0 00 0 00 0 0 00 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0000 00 0 0 0 0 0 0 0 0 0000 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0!0 0!00!0000808 0808 0 0 0 0 0 0 0 0 0 00 0 0 0 0 0 0 0 0 0 0 0 0 0 00 0 00 0 00 0 00 0 0 00000000000000000000000000000000000000000000008000000000000000000000000 0 00J00o0o0o0o0o 000000 00J0J 0J 0J0J0J0J0J 0J0e 0e 0e 0e 0e0e0e0e0e0e0e0e0e0e0e0e0e0e80e0e0e0e0e 0e 0e 0e 0e 0e0e0e!0e!0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0e0eJ0J0000000000808000000005!04!0000000 00000000000000000000000000000000000000000000000000000 00;50;50;50;50;50;50;50;50;5 007070707070707070707070707070707070707070707070780707070707070707070707070707070707070707070707070707070707070707070707070707070707070707070707070707070707070707070,q0@0700q01A(vz0707070707070707070707!07@0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y 0Y0Y 0Y0Y 0Y0Y 0Y0Y 0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y4!0Y4!0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y0Y 0Y03@03@03@ 00@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@0@ 0@0@0@0@J0@0D0D0D0D0D0D0D80D80D80D80D0D0D80D0D0D0D0DJ0@0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0Gn!0G0G 0G 0G 0G 0G 0G0G80G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G0G_!0G0@0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z!0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z 0Z 0Z 0Z 0Z 0Z 0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z7!0Z7!0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z6!0Z!0>pZ!0>pZ0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z!0>pZ0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0ZW!0ZW!0ZW!0ZW!0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z!0>pZ!0>pZ!0>pZ!0>pZ0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z@X!0Z@X!0Z@0Z@0Z@0Z@0Z@0Z@0Z@0Z@0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z@0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z@0ZY!0ZY!0ZY!0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z 0Z 0Z 0Z 0Z 0Z 0Z 0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z 0Z0Z0Z0Z0Z^!0Z^!0Z^!0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0Z0ZJ0Z000000000000000000000000000000 0 0 0 0!0 0J0Z00!000!0!0!0B!0B0!00000!0(!0(0000000000000000000000000000000000000 0 0000000000000000000000000 0 0 0000000000000@0@0@0@0@0@0000000000000000000000000000000000000000000000 0 0 0 0 0 000 0m 0i 0i 0i 0i 0i 000k 0k 0000000000000000000000000000000000j 0j 000000 00@0@0@0@0@0@0@0@0@0j0 0 ]0 0 X 00 )+-0^ i  l E / w !\&fH44 !#%V(l*j,/04k9V?@,G$JNOR&SW[.\\@]]H^^Y__`1aabpbbeHhilnrt?yz{|m~v{|Օ}./>-,t#TLl %!"$%g(,/7<F@UBC6FG LO RSY[s\!^`df%iltx~`iБt5H|tYtĭ/M~H U;*o;vFZ)%U%1),,R.0368:<=AENRSW0Y_emqu{vy{zn/Gÿ[ zv1B~V@-  G  d<$B%&'b)_.5H<TACbKPQRRSUKYC\m^eh2lFr2uw|~Oʀ]% ԍNyLZ/:&;G `c!= m[Ah"m*.058X=+ABC.DDFGHKNPRUYGZ(_PbͅvE=E_Qӱ`tB 8bb[^".s|  .gKTSuM$"%,4`79::];F^&ijVn(pCtz{S~ąC~U7shJiDZ;G`@=H9 }$>'`+p12@589r>;?BE+J7N4ZU^djDnJrQt@uPy݀mE3u95: xHr,H (26;+AFLL(UTY^`be7lQpqq4rrsKttZuuvwwx${Ámʈ܎3FӞϫ`d Kt1^3Qq#lC %>#'+.32364=IDALNORUY^gabglqx4~5sʨ672>~tixS*Q6nQ<D # | g   $ % ) E- 1 H: @ I 8S 8Z L^ ` b 4i n Zt y .~ Y _ X ` ז  f Ԫ * خ  | o  v 5 ! ; n ~ . )  P  0   w W   \ n ' + , . 3 ; ? CF I K N U Z _ ` =b c d g l o r v | X~ 1 W * e q P :  p . F  b " % 3 3 + ?  F   Y & s     . y# )) t/ *5 8 > A jF aO U W Z ^ ` _j k n p s t ,w Vy } ~ J f Ƃ Ў + U  ۣ h L S  9 . Z @ ~ I    T d L # y   q    :    } 0" # % X* 5, . }1 4 5 8 ; v= ? B G L ,O .T 'V W Z [ ] b "e g ii k k cl Dm :n n jo p p bq q r s uw y {| } 6 t 9  . y  - R }  &   d  ! ~& * + - "4 c8 : @ gF H L S Z ] a g "l $n p ys | k ۄ Y O D '  ݵ 6 A }   ` b P Gb ]Q}"%)@**+9,,W- ..S//0w1_233t469=L@BaDEKN4QATUY^a"fikpru |?KÅYJΧr[qк"UgQQ*&Y-+ &} f!"'*158<@BHLDOQTV[]e^cTknsu=|u2 RvrOFj&G!.̬ScVX iƾV?\YgC7(*~xK @J    =[qkt{$"&"D(")"*"L,"-"/"1"(2"3" 5"27":"m<"=" B"G"?J"N"eQ"T"5V"qY";^"e"Qj"nk"l"l"(o"q"r"s"jw"+z"{"|""̃""""""" ""R"+"۠"""a""Z")"з"h#Sk#k# "#$%&'()*,./01345789;<>?ACDKOQRSUWXYZ[\]^_`bcdefhjkmnpvwxy{|}~       C D E F G I J K L M N O P Q R S U V _ ` b c e g h k l n p r t v x z { | ~              " $ % & ' ( ) + - . 0 1 4 5 9 < = > @ B D F H J L S U V X Y Z \ ] ^ ` b d e g h i k m n o p q s t v w y { } ~                ! " # % ' * , . 0 1 3 4 6 8 9 < > @ D F I K N O P Q R S T V W X Y Z [ \ ] ^ _ b c e h i k l m n q s t u v w x y z { }                 " # % ' ) * , . 0 1 3 4 7 8 9 ; < = ? @ A C D E F G H I J K L M N P R S U W Z \ ^ a b c d f h j l n o p r t v y { ~                   # $ & ( * + - / 0 3 5 7 : < > A C E F H J L N Q S U X Z \ ] _ ` b c f g h j k m n p r s u x z | }     ")+,.023568:<>@BDFHJLNQRTVWZ[\]_fhijlmnopqrstvwyz|}~    !#$'(*+.01358:<>@BEGIKLNPRTVXY[]_acdfgiklnoqrstwyz|     "#$&(*-./1345689;<>@BCEFGHJKMNPRTUWXZ\]^`acdfghjklnoqstvxy{}~    ^`abcdfghjklmopqstvyz{|~ :E!![).5*?ABFCCDnEGH!JJSZ_^e-hkoDww!xxx}[q vv `A @qn !U$ "&')+o2:-<<9==>F8NTY0YLYYY.ZIZaZqZs]cjq>uy~ ܈όی&8Be{ƍ &6EUeuŽʎю &5@Rdp{;KO֝&:ϬQOȷ+b@zI\.TcR op]VG   q!!"#$$$v&.36W9=@`E/I}OTX;[\](^^|bekorSvx}XX};d4G֢b0M/PG]v6bv  Y #E&(,3;?BG2GIG_G|GKOQ!U]pb'g pxV}"']XC,#h0ղu1a5M }|$~+/-36`>BOJOTn[Daelxosxrz~ 4tڑ>r;2{A8n, %s"%-48D?WZgŅ3_uϓֵ4!yDUA"   $!!!"e"""$2q9?GK+OW]kcq?u!|q؞tVMxa(#3[;7FP(Uc_ipgx~ׂ4ߌ@јOͧl[swyMq?"PW@ c s%,h/42AHvN Q$UX]gbodfi2kmVtL~&/ȉڌL":/ó˷V?J8{z|0FY & + + 3 E ! Q% ) + 1 5 9 .> KE J 3M T %[ a d Ok q t ^x | r~ %  3 ߴ R | _ ( ; } 4 R  [ v    P d ;  ;% "* ^. 1 L6 r: = *@ "D H K N ?R V ([ _ a a b c Vd ve )h l o .u y ~  ? P ֦ ׳ Q J 5  d  r d R - D   ' ! % * / y6 #> A E I O nT 4W 2\ a 8i p #s as s s s t t B} Մ  Y K ڨ F  4  ~ * I h  Y r H P r    b       , ` l      $ % * Z2 : B K bR X _ d i q Bv dy |  E    r \ è K o ( * F : W T   % #/ 1 %5 i; B 8E I L R X Oa Td j Yn r xz B} N h  k ; 4 M = y O 9 o &    - !#(26z9*=@BOEINP|YC` dh1nq|L+ Briqo&+~N@ {&*_2Z9?_GKQ%X[^7c-gl_q|B=ٟҤ)Nv5Ia 8   $","1"58"@"G"]K"M"$V"]"Xc"g"k"p"tu"z"" ""%"N"v""/"X""")"h#Uk#k#!+-26:=@BEFGHIJLMNPTVagiloqrstuz                    ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B H T W X Y Z [ \ ] ^ a d f i j m o q s u w y }               ! # * , / 2 3 6 7 8 : ; ? A C E G I K M N O P Q R T W [ _ a c f j l r u x z |             $ & ( ) + - / 2 5 7 : ; = ? A B C E G H J L M U ` a d f g j o p r | ~            ! $ & ( + - / 2 5 6 : > B O Q T V X Y [ ] _ ` e g i k m q s u w x z | }          ! " % ' ) , . 1 2 4 6 8 9 ; = ? @ B D G I K M O P R T V W Y [ ^ a d e i l o q t v w y { ~    !#$%&'(*-/1479;=?ACEGIKMOPSUXY^`abcdegkux{  "%&),-/24679;=?ACDFHJMOQSUWZ\^`behjmpuvx{}~ !%')+,027:=?ADILOQSVY[_beimpruwz| _einruwx}k#+7<AC_be~(.0HMQjpt)+JORmuy#'FLPo{}.46OUWnrv"&DW[u}6?B]fh~' = ? ] h j    9 U W m p s   8 D G g | ~  $ ' C M P l v y  . 6 K o w Pt#@J$7:bx4UdfYqvyr.PuV s """# $$$j$$$&&&''( 1=1G1j111=7W7h7777888q===(>@>E>^>u>>>>?9B[BcBDEE?EVEZE]EtExE F#F(FGGGJKKO4O9OKOnz;Uu?P &LTbǕ9VaŜΝǞ@FvMls+<ǩiϪĮvϰڰ&P\̴ܴpǼͼ 4= "+!5LY]XxSty$G_d {3[_o $t!Jbo"36R[7P3Z^? d k  6 G ' > B H m         ! % 4 K O }      $;?A^il DU_Nw$(+Z^a$NY"9PY*v**+++--.//0011141711 22b22233333355556 6$6N6Q6X7o77899:;;<<<0?G?Q??@@eAAAAAAAAAB+B4BcHHHkIIIJJJ>KYK_KLLLLLLLLMNNNP3PHPSSSPU~UUU VVWWWRXtXxX{XXXXXXXY'Ycc deefffffg ghhiii&iuuuzzz`w{4FJi}ހ#&?EH_cfˁځ݁*.2ISXry|łǂ3?BZ_aۃ:ILcgiDŽʄ!$:=@`cf|܅.1HX[Æ&(Oeh͇9@CnÈ$(HWZ̉ωLo{Ҋ Sj*6Ls",8D^fۓ̘Ԙ%Ehәޙ/9=^mq͚7AEhvʠޠ GKjĢ +ȫ 8Hwa?GS۷ BgvyθҸ37Ghl_}¼ϼžϾk#%<JLlzLcg)F\0FW%)b=bzaw}q,1k;LOmxZyZ_>DIios ( Q \ p   t      $37QX\ruBI %,/9j*@S&>[jn=I)*****----...>.L.O.n.x.{......222@4`4e45"5'5@@@ePPPPP QQ2Q6QLQpQQQQQR/RݼRx~ 7chUt.1}5@C]dh$03ILPfsv<eil?bv(9 Sjuw6OalPv *E[^!.8Wcf!LY#$#$S%s%w%%% &&3&E&I&p&&&&&&&'','2'5'W'Z']'z'''''))))))***.../@/D////NBNENiN{N~NNNNNNNNNN O&O*O@OCOPOsOxOOOOOOOOOOOPPP8P?PBP[PaPePPPQQQRSRZR]RRR{SSSSSSSSTT5T?TjTTT4UKUbUUUU;VYV]V`V~VV=W]WkWnWWWWWWVXzXXXXX[[[___%`H`N`:aPaaateeeoooooopp'p/pHpUp[prpppppppq#q:qVq_q|qqqqqqqrrr r#r;r@rCrZr^rarrrrrrrrsss$s's>sBsEs]sbs{ssssssssssttt=tGtJtltttttttttttu*u?uBu^ubueu|uuuuuuuuuuuuvv"vKvbvwvvvvvvvv w*wOw\w_wwwwwwx(x-x3xVxlxxxxxxxxy0y8yBzjzuz ~,~9~րmς48eߑ 7?,A2<E\z߱?K@Jf5>@]ce׶MexVrv;P-t*:$Pj}>TWs}Ulv[~5?f           $ ( K Q T j m p             ( , / H N Q h l o         " L V x   ^e}*/Z$(K k } t!!!!!!'">"B"r"""..../ /000H1b1f1222P4v4~4 5!5)5888888899!9<9D99 ::<<<====>> > >#>&>B>L>>???G?W?g??????@-@6@AAA3G\G`GNIhIsIBJaJnJMMMNNNPPP V)V3VYYY[[[\\\\]!]$];]U]X]w]]{eeeffffg'glll^sssssst*u3u7utu}uyyy z/z4z:z]zgz|'|)|}ډ  (24Q[^׊9EHhqsƋȋ%(HUʐ7GKn|z8XevˢXr  1 2X`c֦ئԲݲ;Sg(./GLPw>KLOjwz!25Xik),DILfmn48;Uac )5A_jm,03R^a{AHKkxz,/P^p*-HUXz2JMlAXeh9Zhk2Joq <BG(^(b(Y)))))))**/,O,Y,#-=-A----....//B0\0`0000)3C3G35;5I5o777m8888889@9E9L9s9|9L:::z;;;;;;1<s<x<= > >???E6E=E-GSGgGkGGGGGGzIIII JJJDJOJRJ{JJJJJJJJJKK>K_KlKoKKKKLLVLyNNNNNNNNOP8POP:U_UkUWWWX4X8XXXX YIYMY}YYYZZZ8[`[j[[[[F\o\|\\\\]D]Q]h]]]]]]]^ ^_#_'_Jaeamabc cnnnppp*vKvUvxxy|||Jrx-O]`4V`ɉ Rimғ֖e͚њԚ*JTܣKQêΪ 6MIM >IвEO|&6  @QCE1;4nrV /?Um5:Qz'25^kn}/LP/?'%%%C>d>n>WBvB}BBBBLLLO)O3OSSSYU{UU___dddg$g.g+|C|H|o}}}}}}5W[ګYptw®Ʈɮ ,1\k#:>043;y ,/Rd 1 Z d $+.EILmxz/9;W`b~ 1EGg 6CFdpr 157Xnq*6MQSoxz5GJjx{36C`ko"""V"t"w"d#{##1(K(O(Q(j(m(o((((((()))1)5)*++7.[._.}666?9d9m9:3;8;yBBBBBBBBBBCCC6C:C=C\CiClCCCCCCCCC/DMDXDDDDDDDDDE E+E?E&HGH[HIII+LGLQLqMMMMNN_NyNNpPPPPPPS%S/SHSeSoSxYYYYZ(Z2ZIZXZ[ZrZvZZZZE[o[{[V\x\\`c~ccdee]etexeBq rrvvvz#{,{&}P}\}F\nqԂ؂ۂ%/@gp׃<]leA]c3?hsҒے̕Lhrr֫٫#&?BYu¬Ĭ#03ILOfjm5<Nht7A2RVg~8Tb\uCjsPv~  $(?ky 'MQ3KMvMi%BNsNy    ) 1 4 N a d        !$,$5$8$_$h$''''''01N1Y1d1{11111111g<<<???B@e@l@KKK+LILLL>NdNwNhOOO,SnSsSTTTTTUrUUUXXX]]]5_`_m_mmmm%n)n4nbnfnnnnnno3o]oaooooSp{pppppCrsrwrrrss-s5s8scsgsssst$u(ulxxx|B|F|I|h|l|o||||||)~H~L~O~o~s~v~~~&<?`׆8<?dhkćȇهAkwĊҊY}ʎ!$IMޒ!,0NY]“ٓݓ &47`jn͔Ԕה!@LNp,/Oik />Bgrt—ɗ˗&ADaknb%LW\ŪLo;R\̴8`j-QUXq0Yc>fp 98Yh}?J  :K+5Zj}            % /& 6& ' 5' ?' ' ( )( + 0+ G+ s. . . . . . 0 T0 Y0 y2 2 2 2 2 2 +4 D4 J4 7 7 7 X8 8 8 9 9 19 79 `9 k9 : : : : : : : ; ; ; '; 3; 5; O; V; X; ; ; ; ; ; -? T? ^? ? ? ? ? $@ :@ E !F %F (F jF qF F F F G G G G $H +H Q Q Q "R LR XR [ A[ K[ ] /] C] d d d d d d d e e -e Fe _e be e e e e e e e f f $f -f Gf jf |f f f f f f g h h h h h h ?m gm qm tm m m m m m n n n q q q q r r v Av Mv x x x x x y y )y ;y >y _y my oy y y y y y y y z z 6z @z Dz iz |z z z z z z z z { { { 9{ ={ ?{ a{ g{ i{ { { { { { { { { { | &| )| E| [| n| | | | | | } )} ;} =} V} ]} `} {} } } } } } } } ~ :~ T~ V~ z~ ~ ~ ~ ~ ~  . 2 Y n       G Q  +  0 ; m   T q { a v z ȡ ֡ ڥ ߧ % մ ϼ  @ Q     " 9 = @ a o r   4 ; > Y b e    1 ; r p   ! B H J k q / q x G ^ f G c m o  . 0 K j l   h  ! F Y   0 D F k ~   < R a  ( ,  ^ e     % ) N x    & = A    > ~  ) 2 # # # c$ $ $ ) ) ) @+ + + 4 4 4 -< J< Z< ]< < < < < < < < = = = #= &= A= I= N= q= = = = = = = = = > > !> I> _> b> > > > > > > > > > ? (? +? U? m? p? ? ? ? ? ? ? ? ? ? @ @ @ F@ Z@ ]@ @ @ @ @ @ @ @ @ @ A A "A 9A =A @A ZA jA mA A A A A A A A B B -B ;B >B ZB lB B B B B C !C @C aC eC {F F F 5K \K fK K K K K K K K ` ~` ` ` a a a a b b b Bb Fb b b b 8j ]j dj k ;k Dk Vk zk k k l !l /o Ko Qo q 4q Nq y @y Hy Py xy y y y y y y z z 3z =z Ez pz zz z z z z z { { 8{ A{ K{ t{ x{ { { { { | | 0| U| Y| | | | u ނ G a n Ɉ  v   5 \ f ъ  Nj ы O q {   % & = A : d q 8 U _ I p y ( 2 0 I O R x Ӛ ߚ    / 9 < U [ ^ u ڛ ޛ  2 \ j m ʜ ! ) , Q Y \ ĝ 4 I K i ў  & ) O W s џ ڟ ݟ  1 8 ; b k r Π  4 9 ` } ǡ  P Y x ͢ ħ Χ K k o ) T a j ѩ n ܫ  ! g  d   3 Y ] l Q " - O f  ߶   8 = 2 [ h { й ݹ ޹  s ӻ   , / V a  A K T Q o * P Z P z  &    1 > n I q    ! = G  ) ; [ ~  ! L Y \ @ i w  / 7 d $ .   8 [ ` c  > V | $ F J M q  5 9 |    1 6 : V _ b    & , / J R U y    / 4 7 _ k n   C U X {   " + . L W Z w   ; C F l     5 9 > X ` c y   D d p r    3 ?   " 9 = @ Z d g  % K p x         !  3 E Z u ~ ` \ w     &" H" _" " " # , , , 30 R0 _0 O3 m3 u3 |6 6 6 : : : A A B F F F M N N OO tO O O O O \ \ \ ` /a 4a i i i l l l l l m m ,m 7m _m m m m m m n @n Dn Zn ~n n n n n 2o [o to o p p ;p `p ip p #q .q q q q )r Nr fr gs s s s s s u v v aw ww w &z Wz [z z z { } @} E} } ~ ~ o   n m ń o - 3 7   ' 7 ; Q d E d q ̞ $ D N Š ɠ  1 H y   ߨ V t R  A F J w ȷ C m w L t x $ ; U x | 4 M S   D f u y j n  2 >  C N U      = h u <( [( g( - - - 9 ": +: z: : : : : : < < < < < < < = = != H= L= O= v= z= }= = = = = = = > )> +> R> g> j> > > > > > > ? ? ? :? H? K? j? v? y? ? ? ? ? ? @ @ &@ )@ J@ Z@ h@ @ @ @ @ @ @ @ @ @ A A A ?A ZA ]A A A A A A A A A A B +B -B DB ]B B B B lQ Q Q Q Q Q Q Q Q S T T T T Y z މ ! M [ + / [ Ú ǚ ̚   ) 0 3 S [ _ | ӛ ٛ ܛ   2 C G e q t Ŝ ֜ ٜ   # ' * A E H _ c f } Ɲ  % ' M ` c z ~ Þ ʞ ̞   " % > D G ^ b e | Ɵ ɟ  ' + . E I L i t v ɠ ͠ Р  % 5 8 O S V s   # 7 : X u w â ̢ Т    3 : = a s v ʣ ݣ   % , / M Z ] ~ פ  2 : ? c y   + < X } , = ^ |   l  9 E G d n 6 W c   ӵ ׵  w p  % )   ' d h p i q [ M ~ X y y - V c    - 1  H ]  3 7 : ] m p      Fiz #:>AX\_vz} $1TY    !!/!K!O!n!w!"##$$$U'l'y'K*b*f*i***4/X/^/F000333444E4U4l4|444444445%5`5u5y55555555555 66626J6M6b6f6i6~66666666771747P7e7h777888R999===>> >?@@D6D>DE F$FFFFHHHH IIO%O/O+UNURUSWoWsW\+]/]^^^`1`5`8`X`\`_```&a=aAadb}bbddde9e=ef gg6j^jjjx yy3|u|z|?EHLr҄6AԊߊŽ۔'INwԛݛ#&HLڡ(Z^˩EJ'Z^4QUXizݶȷĽнս .:=]jKcmp̿Ͽ[_q%(}zn)JT,>A_ux36S]`)-PWZ36Uad"03OXZr'4DZw  1MOq*1Ciq&9@Srz'GKN(/Sg,[_bR}   k          & *     EILimp0W[^(,/\`co"LPi4Zb##cjcj  7;;bf     O!r!v!""""J#Q#$c$j$'&L&V&&''1'G'g'u'y''''''(f(m():)>)S)))***++++ ,,,,,,/-6- /`/g//000Z0a00000002'3.3O4u4y444445#5777+8B8T88888/969999:::>:B:::;3;7;;;{;;<<=h======%>M>Q>>>>B?m?q?YAvAzA}AAACCDD.D2D5D`DdDgDDDDDD*GjGqG^IIIIIIJJJ%KJK\KKKK{LLL=M}MMNNNNNNNO OzOOOtPPPPPPQR R R-R1R(TQTUTTTTW?XFXtYYYZZZ[8[<[O[[[x```a1b8b-cXcecc)d0dDdddRe|eef6f:f'OYi37 {ǐAX\.7 .2@dh #:>UY]s̖Ж+2g1[_h<CxȩC_ryAko 37p\s6ft>ORv|-15>bwQm{ #'+ELPlv  &.,40Wl1NXo6'FZ*)+2/W!y{*Teii)-!Tpv 8>;C & 0 6 e t !DJ+KZIXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCtXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCXXXCXXXXXXXXXXXCXCCXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXXCXCXCCXXXXXXXXXXXXXXXXXXXXXXX"%0! !8@0(  B S  ?! _Hlt156128800 _Hlt156282114 _Hlt157055355 _Hlt157055712 _Hlt157055718 _Hlt157920706 _Hlt157920709 _Hlt158457467 _Hlt158457767 _Hlt162349402 _Hlt163116746 _Hlt164148161 _Hlt164160948 _Hlt164161873 _Hlt524950245 _Hlt524950246 _Hlt147031686 _Hlt524950635 _Hlt524950636 _parasite _Hlt467070858 _Hlt465083110 _Hlt79505386 _Hlt163634293 _Hlt519958254 _Hlt79415600 _Hlt79415601 _Hlt79428753 _Hlt79505414 _Hlt79570246 _Hlt79570638 _Hlt79570755 _Hlt145481726 _Hlt78627729 _Hlt78685784 _Hlt79149361 _Hlt79432137 _Hlt79566130 _Hlt79570304 _Hlt79571291 _Hlt79572070 _Hlt79572072 _Hlt79572091 _Hlt79572127 _Hlt79572147 _Hlt79572308 _Hlt136959626 _Hlt136959627 _Hlt145411162 _Hlt524148193 _Hlt79409865 _Hlt79510331 _Hlt79572129 _Hlt80846639 _Hlt80846651 _Hlt145479235 _Hlt145738040 _Hlt145743253 _Hlt147580460 _Hlt157058375 _Hlt157659525 _Hlt160875671 _Hlt163552878 _Hlt163621500 _Hlt163709018 _Hlt11278990 _Hlt57440393 _Hlt145568233 _Hlt145569392 _Hlt145570080 _Hlt145570081 _Hlt145654894 _Hlt145654899 _Hlt145822397 _Hlt145822428 _Hlt163708232 _Hlt163708388 _Hlt163712492 _Hlt518928810 _Hlt520444508 _Hlt10868072 _Hlt56601860 _Hlt57440110 _Hlt62818019 _Hlt57439076 _Hlt60432845 _Hlt60432881 _Hlt60433023 _Hlt77527104 _Hlt78739841 _Hlt147050329 _Hlt77046372 _Hlt77602031 _Hlt78685557 _Hlt78685558 _Hlt78685774 _Hlt78888707 _Hlt79900590 _Hlt79900986 _Hlt146946394 _Hlt147049082 _Hlt147069674 _Hlt156466898 _Hlt162599492 _Hlt78627892 _Hlt147049009 _Hlt147049102 _Hlt147049814 _Hlt147049817 _Hlt147050323 _Hlt147069429 _Hlt155715351 _Hlt533077052 _Hlt19375423 _Hlt33354405 _Hlt57438849 _Hlt57439247 _Hlt77527164 _Hlt77576385 _Hlt77576463 _Hlt78627899 _Hlt78888709 _Hlt57438830 _Hlt57438831 _Hlt77527197 _Hlt77575987 _Hlt77575988 _Hlt158525905 _Hlt158525906 _Hlt162614140 _Hlt77238167 _Hlt497723078 _Hlt23176819 _Hlt77139857 _Hlt77139858 _Hlt77170948 _Hlt78630720 _Hlt78630721 _Hlt157920713 _Hlt467071060 _Hlt469066463 _Hlt472674890 _Hlt486747959 _Hlt486748054 _Hlt77142283 _Hlt77142815 _Hlt77142829 _Hlt77168588 _Hlt77168685 _Hlt77168687 _Hlt77168689 _Hlt77168844 _Hlt77174283 _Hlt77234456 _Hlt78888044 _Hlt78972742 _Hlt79241059 _Hlt79241060 _Hlt79297253 _Hlt79297254 _Hlt145759910 _Hlt145843958 _Hlt145844010 _Hlt148350352 _Hlt467070850 _Hlt467071409 _Hlt475782402 _Hlt486748024 _Hlt492518838 _Hlt515818722 _Hlt23176756 _Hlt23176787 _Hlt56603217 _Hlt77173986 _Hlt78627751 _Hlt145987203 _Hlt147999968 _Hlt465739126 _Hlt465739127 _Hlt467070805 _Hlt467071502 _Hlt467248664 _Hlt469930303 _Hlt469930304 _Hlt474471346 _Hlt481746803 _Hlt481746804 _Hlt486747900 _Hlt521668254 _Hlt57989865 _Hlt145755330 _Hlt147999546 _Hlt155715354 _Hlt77137027 _Hlt77138012 _Hlt77138631 _Hlt145654900 _Hlt464925867 _Hlt465737139 _Hlt465737140 _Hlt465738161 _Hlt466731701 _Hlt467073538 _Hlt473003111 _Hlt492006198 _Hlt521584468 _Hlt77136038 _Hlt77136039 _Hlt77136829 _Hlt77137071 _Hlt77138474 _Hlt77593824 _Hlt77593825 _Hlt77600434 _Hlt77674433 _Hlt78628962 _Hlt78773615 _Hlt78773616 _Hlt78888814 _Hlt145654838 _Hlt145654839 _Hlt145988292 _Hlt145988348 _Hlt155715358 _Hlt156396312 _Hlt156396582 _Hlt157660096 _Hlt78368495 _Hlt78368496 _Hlt465081086 _Hlt467757145 _Hlt470024795 _Hlt481118862 _Hlt481118940 _Hlt481118942 _Hlt481118945 _Hlt481118951 _Hlt481118953 _Hlt481118954 _Hlt503702937 _Hlt519230041 _Hlt519230145 _Hlt534109436 _Hlt534109437 _Hlt34067368 _Hlt74921844 _Hlt74921845 _Hlt77135012 _Hlt78001121 _Hlt78382449 _Hlt78441693 _Hlt78442704 _Hlt78470499 _Hlt78567307 _Hlt78627907 _Hlt78648775 _Hlt78648893 _Hlt146949167 _Hlt146949190 _Hlt146950459 _Hlt147031409 _Hlt457183850 _Hlt465088721 _Hlt467756412 _Hlt467756634 _Hlt467757055 _Hlt513547716 _Hlt519435890 _Hlt58750907 _Hlt79245649 _Hlt79245701 _Hlt146990864 _Hlt154563536 _Hlt154568037 _Hlt154568038 _Hlt156283561 _Hlt156284090 _Hlt162588694 _Hlt467756486 _Hlt467756973 _Hlt20902603 _Hlt154565914 _Hlt156049343 _Hlt156879972 _Hlt467831088 _Hlt469067734 _Hlt486746974 _Hlt493089603 _Hlt493090982 _Hlt493092135 _Hlt493092353 _Hlt493146700 _Hlt23176856 _Hlt77047252 _Hlt79857131 _Hlt79857163 _Hlt457206870 _Hlt463263966 _Hlt463263967 _Hlt463264583 _Hlt465004238 _Hlt466189944 _Hlt466301499 _Hlt467140598 _Hlt467832740 _Hlt467834906 _Hlt472952442 _Hlt486747389 _Hlt486747463 _Hlt498084136 _Hlt500415091 _Hlt10867949 _Hlt60434383 _Hlt77326049 _Hlt77326877 _Hlt77327740 _Hlt78627813 _Hlt147030705 _Hlt147031560 _Hlt147031723 _Hlt153170970 _Hlt156282672 _Hlt463264154 _Hlt467831257 _Hlt469067810 _Hlt469068695 _Hlt473644120 _Hlt474494351 _Hlt490475546 _Hlt493089608 _Hlt19973395 _Hlt19973396 _Hlt60434776 _Hlt148350033 _Hlt155715259 _Hlt467758211 _Hlt466129700 _Hlt465611723 _Hlt524441037 _Hlt524442572 _Hlt60434548 _Hlt60806968 _Hlt77866095 _Hlt77927814 _Hlt78627808 _Hlt77487530 _Hlt79859151 _Hlt147210879 _Hlt77487534 _Hlt77487593 _Hlt77599198 _Hlt147203726 _Hlt148947113 _Hlt156879534 _Hlt156879544 _Hlt156879955 _Hlt157920707 _Hlt157920708 _Hlt158351320 _Hlt158351321 _Hlt164147835 _Hlt146469911 _Hlt146619707 _Hlt146622658 _Hlt146622693 _Hlt146643671 _Hlt147210727 _Hlt155844565 _Hlt155844566 _Hlt155844612 _Hlt156879984 _Hlt163625808 _Hlt136870513 _Hlt146469914 _Hlt147205465 _Hlt158349948 _Hlt158349949 _Hlt164137074 _Hlt146905606 _Hlt158350709 _Hlt158350710 _Hlt60873881 _Hlt73769135 _Hlt76890304 _Hlt76890339 _Hlt76890407 _Hlt76892019 _Hlt76892020 _Hlt76893507 _Hlt76893570 _Hlt76898872 _Hlt76921831 _Hlt76957064 _Hlt76957091 _Hlt77270866 _Hlt77578304 _Hlt78627736 _Hlt78727317 _Hlt78727318 _Hlt78888052 _Hlt79576449 _Hlt80028258 _Hlt145412186 _Hlt464810789 _Hlt9508538 _Hlt9508564 _Hlt20060627 _Hlt20060628 _Hlt57991338 _Hlt57991339 _Hlt77416362 _Hlt148118124 _Hlt153172687 _Hlt153173091 _Hlt155715364 _Hlt156997773 _Hlt155845212 _Hlt465579470 _Hlt466466786 _Hlt466467026 _Hlt491922106 _Hlt492347787 _Hlt20059846 _Hlt77578320 _Hlt145760426 _Hlt145760618 _Hlt459014496 _Hlt464268974 _Hlt465577618 _Hlt465577619 _Hlt466043530 _Hlt466044061 _Hlt466889393 _Hlt523052726 _Hlt56600055 _Hlt56600056 _Hlt57965558 _Hlt78627744 _Hlt78966237 _Hlt78966318 _Hlt145743886 _Hlt145760917 _Hlt155695736 _Hlt155695737 _Hlt486746336 _Hlt162778091 _Hlt475326967 _Hlt475768480 _Hlt475771666 _Hlt481119043 _Hlt481482913 _Hlt481660885 _Hlt482095203 _Hlt482095204 _Hlt486748998 _Hlt489958015 _Hlt481118761 _Hlt465580611 _Hlt466041680 _Hlt466043821 _Hlt466363564 _Hlt155715423 _Hlt158524977 _Hlt526173796 _Hlt77251441 _Hlt77252416 _Hlt77252420 _Hlt77252629 _Hlt77578329 _Hlt147285343 _Hlt156282632 _Hlt56602170 _Hlt56602912 _Hlt77251370 _Hlt77251491 _Hlt77252047 _Hlt77252293 _Hlt77252590 _Hlt77325115 _Hlt77396445 _Hlt77396446 _Hlt78627819 _Hlt78887620 _Hlt145988307 _Hlt145988343 _Hlt147032655 _Hlt156280557 _Hlt157834832 _Hlt157834833 _Hlt160876526 _Hlt518747394 _Hlt524869333 _Hlt526171295 _Hlt526178443 _Hlt19106111 _Hlt60432820 _Hlt78638614 _Hlt147285881 _Hlt147286064 _Hlt155959304 _Hlt155959305 _Hlt162349366 _Hlt521082609 _Hlt526171771 _Hlt526171923 _Hlt526253640 _Hlt15788922 _Hlt19106134 _Hlt60432793 _Hlt145822151 _Hlt147202248 _Hlt147202249 _Hlt155715420 _Hlt157494998 _Hlt464810242 _Hlt465090310 _Hlt465754463 _Hlt466017698 _Hlt500414694 _Hlt56600901 _Hlt56602915 _Hlt56602919 _Hlt56602969 _Hlt77248642 _Hlt78823029 _Hlt78823051 _Hlt156551944 _Hlt56601869 _Hlt56602913 _Hlt78627910 _Hlt465003794 _Hlt155715369 _Hlt524077260 _Hlt56602845 _Hlt56602910 _Hlt473441213 _Hlt56602965 _Hlt58320648 _Hlt78627934 _Hlt155715371 _Hlt466021812 _Hlt494185363 _Hlt467755938 _Hlt492347852 _Hlt58320506 _Hlt78627916 _Hlt472952428 _Hlt481118958 _Hlt77248576 _Hlt78627937 _Hlt78627928 _Hlt157494882 _Hlt472681181 _Hlt465081390 _Hlt465092132 _Hlt465413876 _Hlt465414107 _Hlt467756565 _Hlt467756868 _Hlt467757740 _Hlt467757741 _Hlt467757842 _Hlt469331988 _Hlt469852188 _Hlt476386358 _Hlt145481675 _Hlt467758393 _Hlt475334263 _Hlt475334315 _Hlt77055040 _Hlt77055041 _Hlt77424410 _Hlt77427281 _Hlt77430505 _Hlt77430506 _Hlt77431508 _Hlt77431509 _Hlt145480906 _Hlt465004111 _Hlt481746853 _Hlt77426334 _Hlt155715470 _Hlt163624918 _Hlt163624919 _Hlt163625063 _Hlt163625064 _Hlt156553805 _Hlt473003062 _Hlt480074791 _Hlt480074792 _Hlt480204683 _Hlt481120617 _Hlt481122462 _Hlt481122463 _Hlt490374697 _Hlt473608800 _Hlt473608801 _Hlt475334319 _Hlt481060980 _Hlt481061438 _Hlt481119201 _Hlt481119242 _Hlt481119365 _Hlt481120581 _Hlt481212569 _Hlt481746872 _Hlt490374197 _Hlt490374198 _Hlt490374332 _Hlt490374431 _Hlt516205074 _Hlt77486038 _Hlt77486398 _Hlt77486399 _Hlt77486400 _Hlt77486417 _Hlt79241154 _Hlt79241248 _Hlt80028248 _Hlt156551984 _Hlt156553164 _Hlt163209622 _Hlt163209623 _Hlt465740236 _Hlt475334175 _Hlt475334229 _Hlt486748248 _Hlt490374514 _Hlt490374669 _Hlt77519238 _Hlt156553094 _Hlt156553095 _Hlt162783526 _Hlt478788907 _Hlt490374551 _Hlt78627761 _Hlt77578584 _Hlt146947556 _Hlt155715373 _Hlt472584317 _Hlt472584318 _Hlt490890540 _Hlt78627800 _Hlt79031186 _Hlt465083582 _Hlt465490128 _Hlt491433264 _Hlt465600828 _Hlt466128940 _Hlt466732631 _Hlt466732632 _Hlt472583823 _Hlt490373246 _Hlt472668953 _Hlt472669142 _Hlt491400195 _Hlt465654147 _Hlt465656797 _Hlt466022088 _Hlt472681158 _Hlt472681177 _Hlt466020713 _Hlt466093387 _Hlt78712254 _Hlt78738753 _Hlt78738754 _Hlt145489627 _Hlt78739827 _Hlt78739828 _Hlt78826744 _Hlt155852447 _Hlt155852448 _Hlt156394892 _Hlt156394893 _Hlt519774760 _Hlt519774761 _Hlt57448274 _Hlt78627777 _Hlt155713939 _Hlt215032423 _Hlt521657340 _Hlt155715375 _Hlt156280077 _Hlt156280078 _Hlt158804062 _Hlt163718099 _Hlt79570259 _Hlt79572131 _Hlt147332075 _Hlt57439373 _Hlt145489865 _Hlt145489852 _Hlt490482342 _Hlt503355553 _Hlt77252821 _Hlt78627794 _Hlt155715378 _Hlt77252815 _Hlt80764131 _Hlt147332427 _Hlt155715411 _Hlt148346587 _Hlt148346573 _Hlt78627945 _Hlt78628798 _Hlt464922210 _Hlt492347692 _Hlt155715413 _Hlt469067764 _Hlt469067622 _Hlt492005446 _Hlt464922915 _Hlt465139496 _Hlt465139497 _Hlt467832686 _Hlt464920900 _Hlt464922225 _Hlt490880248 _Hlt492298835 _Hlt492298836 _Hlt77139550 _Hlt469842036 _Hlt492309912 _Hlt500414347 _Hlt533077335 _Hlt77139351 _Hlt162617277 _Hlt162617278 _Hlt490880553 _Hlt492309983 _Hlt496247019 _Hlt486747155 _Hlt490880429 _Hlt492347741 _Hlt58841634 _Hlt490475571 _Hlt492287189 _Hlt510972057 _Hlt519956564 _Hlt519956565 _Hlt79667951 _Hlt162590445 _Hlt155715381 _Hlt500415381 _Hlt155715492 _Hlt157677194 _Hlt77047398 _Hlt77252812 _Hlt78444075 _Hlt148378272 _Hlt148378812 _Hlt157830038 _Hlt157830039 _Hlt148378247 _Hlt148378248 _Hlt157835358 _Hlt158090360 _Hlt148378256 _Hlt148378257 _Hlt148378270 _Hlt148378291 _Hlt148378811 _Hlt148378813 _Hlt155715366 _Hlt157833647 _Hlt148378271 _Hlt157835296 _Hlt77136087 _Hlt490715982 _Hlt466610810 _Hlt490713659 _Hlt490713660 _Hlt157677563 _Hlt465005363 _Hlt463238738 _Hlt465409294 _Hlt154568189 _Hlt465089644 _Hlt465090797 _Hlt465082257 _Hlt465656961 _Hlt467248622 _Hlt155715416 _Hlt465176936 _Hlt472665860 _Hlt157741620 _Hlt157741621 _Hlt472665875 _Hlt474471289 _Hlt474471644 _Hlt457206204 _Hlt463269302 _Hlt461266563 _Hlt464808377 _Hlt464809564 _Hlt466955400 _Hlt465416180 _Hlt466039629 _Hlt475099977 _Hlt79247366 _Hlt464716000 _Hlt464716043 _Hlt464808520 _Hlt465414037 _Hlt465414272 _Hlt467324987 _Hlt467325034 _Hlt467325048 _Hlt79247389 _Hlt80845798 _Hlt80845799 _Hlt157835256 _Hlt157835289 _Hlt464808457 _Hlt464808570 _Hlt465416129 _Hlt476384738 _Hlt79247431 _Hlt157835379 _Hlt464920922 _Hlt62883264 _Hlt79246512 _Hlt79248202 _Hlt79249840 _Hlt145411122 _Hlt464813096 _Hlt465181341 _Hlt465181342 _Hlt521584915 _Hlt464808219 _Hlt464808352 _Hlt464809150 _Hlt465580580 _Hlt467325202 _Hlt490478049 _Hlt60432697 _Hlt157677684 _Hlt155845130 _Hlt156552729 _Hlt156552730 _Hlt162513290 _Hlt160876605 _Hlt160876803 _Hlt163625010 _Hlt164160602 _Hlt58752466 _Hlt60464734 _Hlt60464735 _Hlt501883710 _Hlt501883711 _Hlt146882561 _Hlt9348080 _Hlt9348081 _Hlt9348191 _Hlt58751316 _Hlt78913235 _Hlt146882586 immunology _Hlt462751204 _Hlt146794886 _Hlt146795030 _Hlt521080581 _Hlt146794868 _Hlt146794869 _Hlt464820606 _Hlt465083585 _Hlt465600830 _Hlt156539201 _Hlt146795269 _Hlt146795288 _Hlt491399308 _Hlt146794871 _Hlt146795313 _Hlt146795168 _Hlt145489277 _Hlt156542105 _Hlt156542109 _Hlt146795392 _Hlt511490413 _Hlt462751256 _Hlt466732633 _Hlt464268962 _Hlt466022092 _Hlt466020589 _Hlt465656799 _Hlt466020832 _Hlt472583824 _Hlt466020853 _Hlt78822997 _Hlt155855189 _Hlt145489260 _Hlt466449973 _Hlt467755451 _Hlt467755452 _Hlt497220838 _Hlt145489269 _Hlt473604034 _Hlt155855667 _Hlt158027402 _Hlt77866949 _Hlt77866952 _Hlt164502565 _Hlt462751580 _Hlt466128988 _Hlt462751681 _Hlt464268880 _Hlt464268881 _Hlt464269001 _Hlt464270206 _Hlt489504858 _Hlt462751728 _Hlt23011234 _Hlt466045001 _Hlt9348102 _Hlt492532224 _Hlt76996483 _Hlt79667602 _Hlt492532241 _Hlt77867024 _Hlt9348462 _Hlt492532250 _Hlt492532228 _Hlt78472395 _Hlt78472396 _Hlt9348437 _Hlt79667604 _Hlt9348245 _Hlt492532299 _Hlt492532447 _Hlt521587130 _Hlt77138640typeone _Hlt490893252 _Hlt490892768 _Hlt79245454 _Hlt155713836 _Hlt155713837 _Hlt78826740typetwo _Hlt490893291 _Hlt490893325 _Hlt155850355 _Hlt157945849 _Hlt157945845 _Hlt155850360 _Hlt156467989 _Hlt156467941 _Hlt472669139 _Hlt155850357 _Hlt155850373 _Hlt155850331 _Hlt155850305 _Hlt155850306 _Hlt155851671 _Hlt155850317 _Hlt155850320 _Hlt472681175 _Hlt490817021 _Hlt79667793 typethree _Hlt146470025 _Hlt146469987 _Hlt490892909 _Hlt457206213 _Hlt146946724typefourgvhd _Hlt491433443 _Hlt491433444 _Hlt76996530 _Hlt79667606immunodeficiencies _Hlt162783307 _Hlt78913745 _Hlt80022737 _Hlt156466000 _Hlt146795117tcellsdigeorgecmcbcells _Hlt146795199 igadeficiency _Hlt80763514 _Hlt163134875 _Hlt146519741cvid _Hlt146795292 _Hlt504711067 _Hlt492517235 _Hlt492517236 _Hlt153276059 _Hlt473207460 _Hlt504711048 _Hlt504711050 _Hlt146641087 _Hlt148201625brutons _Hlt146795278 _Hlt163116847 _Hlt163116744 _Hlt163116745duncansbtwiskottaldrich _Hlt156542107 _Hlt28369375ataxiatelangiectasia _Hlt521584458 _Hlt163114021scidsada _Hlt146945069 _Hlt78381453 _Hlt155844822 phagocytes _Hlt158027154cyclicneutropenia _Hlt152574454 _Hlt152574455 _Hlt162589853cd18 _alzheimers _rheumatology_atypicallymphocytes_hemochromatosis _labetalol_lungs_gca_tb_psc _diabetes_thrombocytopenia_inflammatoryjointdiseasejobs _Hlt146643674 _Hlt146640798 _Hlt146640799 _Hlt164160087 _Hlt164160088 _Hlt147124211chediakhigashi _Hlt154564754 _Hlt77578390 _Hlt490629999 _Hlt490630000 _Hlt490365841 _Hlt498000847 _Hlt498000848 _Hlt473603030 _Hlt147286065 _Hlt490365826 _Hlt156453296 complement _Hlt497997491 _Hlt497997492 _Hlt76996721 _Hlt76996847 _Hlt76996848 _Hlt76997149 _Hlt465738072 _Hlt76996869 _Hlt79667611hereditaryangioedema _Hlt79245565complementstudies _Hlt79153907 _Hlt79154369 _Hlt79154537 _Hlt163120846 _Hlt163120856c1allergy _Hlt155715374 anaphylaxis _Hlt156545083 _Hlt163634783 _Hlt215032419 _Hlt146946408 _Hlt146946392 _Hlt146946389 _Hlt146946381 _Hlt153275599 _Hlt153275600 _Hlt153275731 _Hlt156452211 _Hlt156452212 _dermatology _givarices_corticotrophicademona_hypercalcemia_men_hpylori_testicularinfection_vpa_liverpregnancy_glycogenstorage _celiacsrue drugfeverdrugrash _Hlt78995198 _Hlt146947696 serumsicknessatopy _Hlt157835354 _Hlt77578463 _Hlt157835352 _Hlt157835355 foodallergiesdustmite rheumatology _Hlt60432798 _Hlt60432828 _Hlt77252419 _Hlt155715422 _Hlt77578303 _Hlt155715464 _Hlt457206827 _Hlt78627889 _Hlt473443801 _Hlt500419025 _Hlt500418892 _Hlt157918001 _Hlt157918002 _Hlt464810341 _Hlt464810745 _Hlt77395433 _Hlt19106254 _Hlt466020321 _Hlt485466777 _Hlt464810479 _Hlt491420238 _Hlt464810440 _Hlt465754468 _Hlt497724316 _Hlt473443797 _Hlt500419216 _Hlt473609388 _Hlt500418962 _Hlt500419066 _Hlt500419159 _Hlt526253876 _Hlt56602175 _Hlt56602911 _Hlt77238182 _Hlt511569034 _Hlt526177097 _Hlt521082805 _Hlt521083024 _Hlt155959307 _Hlt163111815 _Hlt163111816 _Hlt469583217 _Hlt504795183 _Hlt521083073 _Hlt78638622 _Hlt156281033 _Hlt472681192 _Hlt473443833 _Hlt474484955 _Hlt496980387 _Hlt518745844 _Hlt518745845 _Hlt156282633 _Hlt475890499 _Hlt484064456 _Hlt162349400 _Hlt157834834 _Hlt77395446 _Hlt78823400 _Hlt502781411 _Hlt502781412 _Hlt157495002 _Hlt147032750 _Hlt19377666 _Hlt526171302 _Hlt145988044 _Hlt145988345 _Hlt147285355 _Hlt77252595 _Hlt77395124 _Hlt145822159 _Hlt147202254 _Hlt511570971 _Hlt155711991 _Hlt526253641 _Hlt526173810 _Hlt526178445 _Hlt146512314 _Hlt146512315 _Hlt22480053 _Hlt77248575 _Hlt504733448 _Hlt504733449 _Hlt491690620 _Hlt501247974 _Hlt491881152 _Hlt524869339 _Hlt77325114 _Hlt77325117 _Hlt526171928 _Hlt524869369 _Hlt526001235 _Hlt77397349 _Hlt19106242 _Hlt19294166 _Hlt77396448 _Hlt77397325 _Hlt32067211 _Hlt19106117 _Hlt60434991 _Hlt160876529 _Hlt500997798 _Hlt485031923 _Hlt485031924 _Hlt475890450 _Hlt156050151 _Hlt77252436 _Hlt77252749 _Hlt77252423 _Hlt77252637 _Hlt77395398 _Hlt77252709 _Hlt56103552 _Hlt22480149 _Hlt77252081 _Hlt146339370 _Hlt146339371 _Hlt77252735 _Hlt147286090 _Hlt77252415 _Hlt78627871 _Hlt78627891 _Hlt492532344rheumhp _Hlt147287071 _Hlt158803970raynauds _Hlt79570513 _Hlt21197624 _Hlt21197625 _Hlt79667614 _Hlt156540276 _Hlt21170537 _Hlt21170538 _Hlt145738289 _Hlt146259418 _Hlt146259419 _Hlt78473844 _Hlt147210584 _Hlt147210585 _Hlt147210586 _Hlt156057894 _Hlt155695614 _Hlt80768137 _Hlt80768138 _Hlt145752089 _Hlt80023183 _Hlt162597700 _Hlt162597729 _Hlt162598144 lowbackpain _Hlt147285128 _Hlt147285129 _Hlt146339979 _Hlt77249190 referredpain _Hlt153098001 _Hlt153098002 _Hlt78627927joint _Hlt155715372 _Hlt78627936 _Hlt56602909inflammatoryjointdisease _Hlt56602967 _Hlt500419211 _Hlt500419231 _Hlt494185366 _Hlt466024623 _Hlt466019758 _Hlt466023792 _Hlt466023777 _Hlt524077262 _Hlt56603061 _Hlt466019755 _Hlt473439980 _Hlt521082424 _Hlt466024201 _Hlt491694686 _Hlt147033438 _Hlt473609434 _Hlt466359192 _Hlt497724383 _Hlt473439859 _Hlt524446953 _Hlt28367648 _Hlt58333322 _Hlt58333323 _Hlt500211419 _Hlt473441339 _Hlt500211386 _Hlt473441239 _Hlt473441282 _Hlt473441315 _Hlt473441219 _Hlt466023411 _Hlt466019886 _Hlt473441344 _Hlt473441635 _Hlt473441318 _Hlt473441674 _Hlt500419003 _Hlt491564091 _Hlt525999976 _Hlt473439772 _Hlt473442301 _Hlt145821835 _Hlt77259200 _Hlt58320704 _Hlt78741343 _Hlt153258166 _Hlt153258167 _Hlt156059543 _Hlt156059544 _Hlt147132547 _Hlt147132548 _Hlt147132823 _Hlt145736917 _Hlt145736918 _Hlt147285187 _Hlt147285336 _Hlt466022853 _Hlt153100422 _Hlt153100423 _Hlt148089625 polyarticular _Hlt57990435 _Hlt147286923 _Hlt147286924 _Hlt78630763 _Hlt163717214 _Hlt163717208 _Hlt163717209 _Hlt156058933hoa _Hlt146622682 _Hlt526007783 _Hlt526007529 _Hlt145485892 _Hlt526006218 _Hlt526006180 _Hlt146960642 _Hlt146960643 _Hlt56602935oaosteoarthritis _Hlt153179077 _Hlt147033402 _Hlt153179113 _Hlt153179140 _Hlt526253996 _Hlt526254021 _Hlt79667619 _Hlt147032587 _Hlt153179125 _Hlt153179146 _Hlt147032814ra _Hlt473939527 _Hlt521082808 _Hlt521083025 _Hlt78822957 _Hlt154564751 _Hlt154564761 _Hlt154564799 _Hlt162349067 _Hlt162349068 _Hlt466092994 _Hlt153805378 _Hlt153805379 _Hlt163040924 _Hlt161999758 _Hlt147046315 _Hlt155694987 _Hlt155694988 _Hlt147046260 _Hlt147046261 _Hlt80763268 _Hlt80763269 _Hlt146260404 _Hlt80765603 _Hlt80765364 _Hlt80765367 _Hlt80765685 _Hlt155959372 _Hlt80765393 _Hlt80765358feltyfeltys _Hlt77578393 _Hlt490365873 _Hlt161482926 _Hlt79248099jra pediatricrastills _Hlt79417452 _Hlt78001480 _Hlt28367714 _Hlt466020945 _Hlt473602989infectiousarthritissepticarthritis _Hlt145988341infectiousmonoarthritis _Hlt77395736 _Hlt145988442 _Hlt145988776 _Hlt145988777 _Hlt146000170 _Hlt146000171 _Hlt473939605 _Hlt146000315 _Hlt156058723 _Hlt466025523 _Hlt163208942 synovialfluid _Hlt147032817 tbarthritis _Hlt466024938 _Hlt491566288 _Hlt491566289gout _Hlt78818540 _Hlt473439470 _Hlt473439614 _Hlt79247090 _Hlt79247948 _Hlt145752674 _Hlt145752571 _Hlt145752569 _Hlt145988290 _Hlt145988344 _Hlt491566136 _Hlt145999366 _Hlt145999349 pseudogoutcppd _Hlt146605959 _Hlt146605967 _Hlt473940009 _Hlt473940010 _Hlt524849296 _Hlt492867263 _Hlt473440783 _Hlt157833479hydroxyapetitecaoxcalciumoxalate Fibromyalgia _Hlt147285429relapsingpolychondritis scoliosis _Hlt156128802 _Hlt156128810 _Hlt156128798 _Hlt156128804 _Hlt77424467 _Hlt147210724 _Hlt156049936 _Hlt156463807 _Hlt162515587 _Hlt162515019 _Hlt162515585 _Hlt156280922 _Hlt466360162 _Hlt156281040 _Hlt484064331 _Hlt162349636 _Hlt466020846 _Hlt466129569sle _Hlt466129531 _Hlt469642866 _Hlt475292342 _Hlt78638619 _Hlt78638624 _Hlt80022738 _Hlt156107464 _Hlt156107465 _Hlt157762449 _Hlt157762126 _Hlt147039843 _Hlt520828164 _Hlt77272598 _Hlt498433403 _Hlt498433426 _Hlt78638735 _Hlt147039834 _Hlt473444402 _Hlt147039829 _Hlt77672478 _Hlt152575503 _Hlt163624532 _Hlt156058796 _Hlt156058797 _Hlt156466331 _Hlt163620910 _Hlt163650049 _Hlt163650143 _Hlt156281150 _Hlt457982048 _Hlt491881222siccasjogrens _Hlt468435612 _Hlt77789169 _Hlt156394951 _Hlt156394956 _Hlt457983761 polymyositis _Hlt145569376 _Hlt145569388 _Hlt145759847 _Hlt77324472 _Hlt77324502dermatomyositis _Hlt469332278 _Hlt79667631 _Hlt522269091 _Hlt522269055 _Hlt522269056 _Hlt522269057 _Hlt79667633 _Hlt524869430 _Hlt79667635 scleroderma _Hlt463264489 _Hlt463264520 _Hlt468435717 _Hlt77257667 _Hlt522269420 _Hlt77257663 _Hlt522269390 _Hlt522269405 _Hlt155849924 _Hlt155849925 sarcoidosis _Hlt77866951 _Hlt78913747sarcoid _Hlt146603960 _Hlt78823808 _Hlt78823524 _Hlt158026578 _Hlt155854901 _Hlt158026995 _Hlt158026815 _Hlt158026913 _Hlt158026876 _Hlt158026877 _Hlt158026869 _Hlt158026870 _Hlt519828174 _Hlt9348584 _Hlt9348592 _Hlt79667638 _Hlt501884438 _Hlt522273743 _Hlt158027475 _Hlt77170912 _Hlt77170935 _Hlt163621496 _Hlt469334108 _Hlt77601145 _Hlt77601190lofgrens _Hlt23011316 _Hlt23011370 vasculitides _Hlt466428910 _Hlt492347584 _Hlt500222082 _Hlt60432813 _Hlt524086471 _Hlt156466642 _Hlt524086478 _Hlt524086429 _Hlt153099249 _Hlt147393035 _Hlt147393036 _Hlt524086382 _Hlt524086523 _Hlt524086530 _Hlt32068261 _Hlt32067503 _Hlt32067311 _Hlt32067371 _Hlt147036986 _Hlt147036987 _Hlt163048575 _Hlt158809749 _Hlt158809326 _Hlt147122840 _Hlt156449472 _Hlt156449473 cnsvasculitis _Hlt78442227 _Hlt78648933 _Hlt156050285 _Hlt156465920 _Hlt77135271 _Hlt77135290 _Hlt77135297 _Hlt77135276 _Hlt79667652 _Hlt77135279 _Hlt77135283 _Hlt77137648vasculitisinfection _Hlt164148707 _Hlt164148721 giantcellgcatatemporalarteritis _Hlt19287979 _Hlt19288743 _Hlt19288739 _Hlt524086428 takayasustakayasu _Hlt481483326 _Hlt19287955_bone_werdnig_arnold-chiari_craniopharyngioma_pedintestinal_felty_streptococcus_ecoli _lysteria _hinfluenza _pneumococcus_herpes_enteric _neisseria _maltlymphoma_sle _hyperpth_hypopth_pseudohypopth _hydroxyurea_sdes_lungphysiology _thiamine _pyridoxine_ts _psoriatic_conns_hiv_homocystinuria _histoplasma_sipples _Hlt145737856 kawasakiskawasaki _Hlt464268953pan _Hlt524086477 _Hlt32068470 _Hlt490817014 _Hlt79667792 _Hlt490816994 _Hlt490816962 _Hlt466044929 _Hlt157494457 _Hlt153170966 _Hlt153275602 _Hlt490817042 _Hlt146618418 _Hlt473645473 _Hlt488161895 _Hlt488161896wegeners _Hlt490817144 _Hlt490817145 _Hlt145903639 _Hlt520563047 _Hlt520563048 _Hlt490817089 _Hlt490817090 _Hlt463264338 _Hlt145903433 _Hlt145903734 _Hlt145903491 _Hlt153098918 _Hlt524086467 _Hlt157492916 _Hlt157492917 _Hlt32067334buergersbuergersdisease _Hlt466045007 churgstrausschurgchurgstraussangiitis _Hlt156879391 _Hlt145737946 _Hlt164161871 _Hlt164161872 _Hlt524441918 _Hlt77326035behcets _Hlt157835043 _Hlt79667797 _Hlt163205550 _Hlt157835094 _Hlt157835095 _Hlt157835151 _Hlt157835291 _Hlt78685810 _Hlt78685843hlaassociations _Hlt492532375 _Hlt79667807dr4 _Hlt154420340 _Hlt154420341 _Hlt77395133rcvs _Hlt156050609 _Hlt156050610spondylarthropathies _Hlt500425360 _Hlt500425361 _Hlt500425373 _Hlt466023418 _Hlt473441227 _Hlt500425362 ankylosingankylosingspondylitis _Hlt500211403 _Hlt145822489 _Hlt145822393 _Hlt473439748 _Hlt466610525 _Hlt473441317 _Hlt473441343 psoriatic _Hlt511570969 _Hlt473443293 _Hlt155711994 _Hlt78824780 _Hlt79667822 _Hlt526253655 _Hlt526253787 _Hlt78779382 _Hlt146259720 _Hlt78824773 _Hlt79667824 _Hlt78779388 _Hlt473439495 _Hlt78824837 _Hlt78824894 _Hlt78824855 _Hlt78824880 _Hlt78824883 _Hlt473441320 _Hlt500425375 _Hlt77863131reiters _Hlt473441662 _Hlt473939523 _Hlt146512449 _Hlt473442279 _Hlt145569619 _Hlt524864973 _Hlt147031893 _Hlt147031894 _Hlt146179099 _Hlt148201275 _Hlt148201453 _Hlt146179143 _Hlt148348403 _Hlt157690684 _Hlt156125164 _Hlt156125165 _Hlt157690692steroidmyopathy _Hlt164161806 _Hlt157755491 _Hlt157755475 _Hlt157755476 _Hlt464810439 _Hlt162778583cardio _Hlt519230047 _Hlt56601863 _Hlt57440115 _Hlt79570255 _Hlt155715350 _Hlt469929772 _Hlt78627735 _Hlt524866809 _Hlt79570637 _Hlt467823939 _Hlt79417257 _Hlt490894859 _Hlt145738280 _Hlt78685792 _Hlt147633359 _Hlt493334394 _Hlt145738393 _Hlt156544351 _Hlt145738413 _Hlt145743255 _Hlt467823936 _Hlt78686033 _Hlt473602442 _Hlt78685807 _Hlt145738183 _Hlt145738229 _Hlt467823825 _Hlt78686050 _Hlt78685812 _Hlt78685817 _Hlt467823934 _Hlt78686037 _Hlt467824158 _Hlt493338191 _Hlt520444515 _Hlt30431854 _Hlt30431855 _Hlt493148104 _Hlt493176315 _Hlt79566131 _Hlt79572130 _Hlt145479213 _Hlt145569094 _Hlt145569389 _Hlt147495338 _Hlt163712495 _Hlt145569398 _Hlt467824175 _Hlt493176308 _Hlt77923657 _Hlt77924324 _Hlt503449468 _Hlt79570378 _Hlt467824332 _Hlt57990216 _Hlt79417015 _Hlt57990511 _Hlt79570316 _Hlt145738053 _Hlt145738185 _Hlt490893558 _Hlt491315498 _Hlt79572128 _Hlt145481740 _Hlt57964515 _Hlt473602571 _Hlt473602372 _Hlt490714395 _Hlt490893416 _Hlt58584397 _Hlt79417030 _Hlt57990505 _Hlt79570334 _Hlt465612322 _Hlt58584310 _Hlt145738191 _Hlt145481788 _Hlt145481768 _Hlt145420873 _Hlt490894639 _Hlt163621549 _Hlt490893787 _Hlt79417159 _Hlt79417039 _Hlt79149400 _Hlt58751768 _Hlt79570514 _Hlt490895597 _Hlt495206631 _Hlt493756559 _Hlt490207931 _Hlt491312876 _Hlt493346800 _Hlt493862596 _Hlt496842431 _Hlt493346900 _Hlt145566905 _Hlt147495061 _Hlt157659527 _Hlt62819021 _Hlt163712913 _Hlt145567761 _Hlt473625296 _Hlt472955802 _Hlt79416941 _Hlt79417151 _Hlt490708980 _Hlt79417043 _Hlt492309286 _Hlt493655016 _Hlt10868075 _Hlt79149708 _Hlt79428915 _Hlt79149883 _Hlt79432138 _Hlt490893742 _Hlt471879051 _Hlt524868024 _Hlt21799549 _Hlt79505388 _Hlt79508171 _Hlt156901062 _Hlt475774615 _Hlt524148197 _Hlt79416938 _Hlt79505415 _Hlt157055888 _Hlt469066012 _Hlt469066013 _Hlt471813967 _Hlt496859725 _Hlt79508246 _Hlt147580463 _Hlt471891485 _Hlt157055753 _Hlt163622197 _Hlt145821461 _Hlt79508259 _Hlt163621375 _Hlt80846643 _Hlt80846650 _Hlt160875674 _Hlt145821490 _Hlt145821488 _Hlt79417067 _Hlt79571294 _Hlt79417076 _Hlt79417084 _Hlt163708389 _Hlt79571313 _Hlt163708234 _Hlt467813569 _Hlt467813570 _Hlt492004275 _Hlt519958260 _Hlt79416933 _Hlt79416995 _Hlt157054767 _Hlt58751296 _Hlt466215049 _Hlt490718956 _Hlt157054820 _Hlt501884788 _Hlt79415652 _Hlt145822427 _Hlt145822402 _Hlt469929359 _Hlt469929360 _Hlt490715565 _Hlt23005788 _Hlt79504609 _Hlt490715528 _Hlt163554802 _Hlt79504632 _Hlt491311326 _Hlt491311231 _Hlt491311233 _Hlt491311259 _Hlt79572158 _Hlt466203341 _Hlt491311276 _Hlt491311305 _Hlt491311177 _Hlt79572201 _Hlt79572309 _Hlt79572066 _Hlt79572069 _Hlt147580829 _Hlt79417078 _Hlt79417112 _Hlt163717764 _Hlt491423640 _Hlt492315448 _Hlt79417114 _Hlt491313548 _Hlt493346867 _Hlt57440210 _Hlt78966021 _Hlt493759176 _Hlt62818020 _Hlt145570085 _Hlt57440171 _Hlt145654898 _Hlt492007367 _Hlt163552893 _Hlt500422163 _Hlt79417496 _Hlt157058389 _Hlt491311278 _Hlt491311188 _Hlt467813645 _Hlt499632084 _Hlt79417479 _Hlt472955683 _Hlt492287140 _Hlt79417448 _Hlt79428881 _Hlt79428813 _Hlt62818865 _Hlt79417187 _Hlt491315230 _Hlt491964038 _Hlt492555196 _Hlt493763904 _Hlt494027915 _Hlt79417181 _Hlt79428754 _Hlt79429015 _Hlt79504131 _Hlt11278992 _Hlt79429304 _Hlt466044925 _Hlt466044932 _Hlt472955335 _Hlt79417456 _Hlt161915906 _Hlt156544458 _Hlt236325545 _Hlt163712804 _Hlt156282112 _Hlt156282113 _Hlt472955801 _Hlt156282588 _Hlt472955555 _Hlt164148200 _Hlt493752640 _Hlt156282116 _Hlt490818339 _Hlt465093635 _Hlt490818208 _Hlt490880693 _Hlt164148205 _Hlt490818427 _Hlt469929113 _Hlt79570691 _Hlt490818660 _Hlt79572097 _Hlt490818675 _Hlt469929088 _Hlt469929091 _Hlt164148197 _Hlt490818493 _Hlt164148181 _Hlt79570754 _Hlt79570756 _Hlt79572194 _Hlt79572126 _Hlt79405951 _Hlt79417395 _Hlt79417380 _Hlt491312873 _Hlt79417397 _Hlt163634300 _Hlt136959634 _Hlt493859188 _Hlt475774521 _Hlt475774522 _Hlt490882405 _Hlt79417331 _Hlt79417332 _Hlt475774634 _Hlt518928815 _Hlt58751350 _Hlt467830265 _Hlt490884281 _Hlt490893921 _Hlt492312837 _Hlt524866612 _Hlt467830465 _Hlt490880695 _Hlt490883843 _Hlt515781344 _Hlt79417407 _Hlt79510333 _Hlt79687163 _Hlt79687164 _Hlt79690249 _Hlt490878674 _Hlt493861202 _Hlt163621634 _Hlt490714610 _Hlt161999504 _Hlt161999505 _Hlt79417418 _Hlt490208018 _Hlt492312051 _Hlt79405954 _Hlt79417396cardiacphysiology _Hlt79667831 _Hlt79667833 _Hlt79417296 _Hlt79417333 _Hlt79417398cardiacphysical _Hlt79667835 _Hlt490883751 _Hlt136961501 _Hlt490883720 _Hlt493859201 _Hlt136961801 _Hlt79667838 _Hlt493859206 _Hlt136961775 _Hlt490883770 _Hlt79667840 _Hlt79667848 _Hlt163622428 _Hlt136962109 _Hlt136962110 _Hlt163622665jvp _Hlt163634348 _Hlt163634596 _Hlt79504111pulsusparadoxus _Hlt146510119ecgekg _Hlt79417410 _Hlt79667851 _Hlt492315426 _Hlt492312933 _Hlt492314842 _Hlt79665829 _Hlt79665830 _Hlt79665837 _Hlt79665843 _Hlt79665872 _Hlt79665864 _Hlt490879009 _Hlt163622189 _Hlt163622195 _Hlt79665860 _Hlt79665862 _Hlt492315306 _Hlt79665874 _Hlt490894046 _Hlt492314831 _Hlt79665841 _Hlt493861209 _Hlt490883904 _Hlt492553189 _Hlt492553072 _Hlt79665878 heartrate _Hlt79665873 heartrhythm _Hlt490879010 _Hlt79665861 _Hlt163622194 intervals _Hlt79665863 _Hlt79504729 _Hlt80846675qt _Hlt79689037 _Hlt79688523 _Hlt79693265 _Hlt79688735 _Hlt79688736 _Hlt492553261 _Hlt164137262 axisdeviation _Hlt492315317 _Hlt79510391 _Hlt79510400 _Hlt490879875 _Hlt79665882 _Hlt494727579 _Hlt58320332 hypertrophy _Hlt79665875 _Hlt492314836 _Hlt79665842 ekgischemia _Hlt156903127 _Hlt79665884 _Hlt79667856 _Hlt524866886 _Hlt524866893 _Hlt163622867 _Hlt21197870 _Hlt79668051 _Hlt163645332 _Hlt79691054 _Hlt79691123 _Hlt79691136 _Hlt21197744 _Hlt79691444 _Hlt79691384 _Hlt493862057 _Hlt79667872 _Hlt79668049 _Hlt21197693 _Hlt145566062 _Hlt145566063 _Hlt163713582 _Hlt21197670 _Hlt163645391 _Hlt163645486 _Hlt79691393 _Hlt79691340 _Hlt145566400 _Hlt145566401 _Hlt79690821 _Hlt163713546 _Hlt79692838 _Hlt163714199 _Hlt163714208 _Hlt163714217 _Hlt163714223ecgmi _Hlt156552541 _Hlt163644583 _Hlt163644584 _Hlt145567254 _Hlt23005786 _Hlt145567250localizationofinfarct _Hlt79665912 _Hlt62819651 _Hlt62819601 _Hlt79690493 _Hlt62819602 _Hlt79665913 _Hlt79690494ladswanganz _Hlt475774523 _Hlt467823940 circulatory _Hlt147580450 _Hlt498077534 _Hlt163644761 _Hlt163644762 _Hlt146882823 _Hlt147633414 _Hlt145738390 _Hlt145738292 _Hlt145738285 _Hlt57989152 _Hlt57989153 _Hlt147633382 _Hlt79665915 _Hlt467823937 _Hlt78685737 _Hlt78685802edema _Hlt78686035 _Hlt145738395 _Hlt78567413 hypovolemia _Hlt146882824freewaterdeficitshock _Hlt486746790 _Hlt79665920chf _Hlt469049671 _Hlt30431914 _Hlt520444955 _Hlt79665923 _Hlt145569431 _Hlt163634100 _Hlt163634101 _Hlt79665925 _Hlt145569130 _Hlt33073773 _Hlt33073774 _Hlt33073792 _Hlt33074127 _Hlt213813323 _Hlt213813394 _Hlt484489835 _Hlt147495420 _Hlt484489843 _Hlt484489858 _Hlt469049918 _Hlt147495928 _Hlt147495929 _Hlt485032083 _Hlt485032084 _Hlt164148232 _Hlt149889760 _Hlt149889761 _Hlt163649668 _Hlt79665924 diastolic corpulmonale _Hlt77924326 _Hlt79665916 _Hlt148955850 _Hlt145738358 _Hlt79245600 _Hlt77924116 _Hlt77924323 _Hlt79665929 hypertension _Hlt467824177htn _Hlt156544354 secondaryhtn _Hlt145742339 _Hlt145739138 _Hlt145739006 _Hlt145739102 _Hlt145739091 _Hlt145739042 _Hlt145739053 _Hlt145739040 _Hlt145743335 _Hlt145742668 _Hlt145739038 _Hlt148002748 _Hlt148002749 _Hlt153805393 _Hlt153805394 _Hlt145739036 _Hlt78441424 _Hlt153097208 preeclampsia _Hlt524864897 _Hlt146178930 _Hlt79570502 _Hlt491315511 _Hlt79570451 _Hlt79570504 _Hlt491315492 _Hlt491315533 _Hlt457205672atherosclerosis _Hlt491315535 _Hlt57990509 _Hlt79570342 _Hlt79417037 _Hlt57990432 _Hlt58584467pvd _Hlt145481775 _Hlt161481361 _Hlt161481336 _Hlt145737874 _Hlt145737947 _Hlt153170842 _Hlt145737741 _Hlt145737742 _Hlt162262582 _Hlt162262583 _Hlt145737499 _Hlt79417029acutearterialocclusion _Hlt145738226hyperlipidemia _Hlt79570319 _Hlt145987576 _Hlt155695296 _Hlt156901173 _Hlt146907199 _Hlt490893793 _Hlt79417041 _Hlt79417162 _Hlt58584469 _Hlt79570521 _Hlt79570537cad _Hlt79569205 _Hlt79569297 _Hlt79569308 _Hlt79569228 _Hlt79569233 _Hlt79569310 _Hlt79569313 _Hlt57964710 _Hlt79509618 _Hlt155856611 _Hlt155856612 _Hlt155856617 chestpain _Hlt79569219 _Hlt79569301 _Hlt79510101 _Hlt490893532 _Hlt146613413 _Hlt146613414 _Hlt146613518 _Hlt20061044 _Hlt145319696 _Hlt490893704 _Hlt154460911 _Hlt154460912 _Hlt154460913 _Hlt154460914 _Hlt156552530 stresstest _Hlt79149401 _Hlt79569309angina _Hlt79509974 _Hlt79509975 _Hlt58751975 _Hlt79509946 _Hlt524865179 _Hlt495206680 _Hlt79397990 _Hlt156552579 _Hlt79397720 stableanginaunstableangina prinzmetals syndromex _Hlt146990251 _Hlt146990252 _Hlt154564016 _Hlt154564023 _Hlt467824320 _Hlt79569232 _Hlt79569311mimyocardialinfarction _Hlt471812706 _Hlt145566907 _Hlt79569329 _Hlt79569497 _Hlt163712916 _Hlt145568000 _Hlt145569395 _Hlt469929768 _Hlt79569552 _Hlt62819024 _Hlt79569602 _Hlt145567787 _Hlt145569396 _Hlt79569626 _Hlt79569631 _Hlt62707218 _Hlt79569334 _Hlt79569715 _Hlt163621545 _Hlt79508310milabscardiacenzymes _Hlt145566987 _Hlt213813349 _Hlt79417437 _Hlt62884883 _Hlt62884462 mitreatment thrombolysis _Hlt145567205 _Hlt79406310 _Hlt163644606micomplications _Hlt79569550 _Hlt62819108 _Hlt145568007 _Hlt469929770 _Hlt149890273 _Hlt152559986 _Hlt152560298 _Hlt163717385 _Hlt163717386 _Hlt152560321 _Hlt484489825 _Hlt484489826 _Hlt495206184 _Hlt145568078 _Hlt145569393 _Hlt152560217 _Hlt152560218 _Hlt62706975 _Hlt79566102 miprognosis _Hlt79566127 mifollowup _Hlt79569628 _Hlt79569580othercausesofmi _Hlt79569666 _Hlt162514174 _Hlt158430894 _Hlt158431782 _Hlt158430354 _Hlt158430297 _Hlt158430298 _Hlt79247084 _Hlt157677665 _Hlt157677670 _Hlt79417075 _Hlt79416937valvular _Hlt79417077 _Hlt79571297 _Hlt79417012 _Hlt79569258 _Hlt79413886 _Hlt62707240asaorticstenosis _Hlt79415007 _Hlt157054819 _Hlt145820911 _Hlt79432130 _Hlt79432136bicuspidaorticvalvemitralstenosis _Hlt147331013 _Hlt147330216 _Hlt164160420 _Hlt158090347 _Hlt79672073 _Hlt79672074 _Hlt157054849 _Hlt158090327 _Hlt157054835 _Hlt157054843 _Hlt157054929 _Hlt157774998 _Hlt158090317 _Hlt158090318 _Hlt158090319 _Hlt163555046 _Hlt163555051 _Hlt157054935arai _Hlt146511742 _Hlt145822425 _Hlt34067187 _Hlt465950726 _Hlt465950727 _Hlt10868365 _Hlt79417110mr mitralregurge _Hlt23006600 _Hlt163554807 _Hlt23006542 _Hlt525736820 _Hlt23005439papillarymusclepapillaryrupture _Hlt152560004mvp _Hlt23005486 _Hlt163553057tr _Hlt79504635 _Hlt145903185 _Hlt518929451 _Hlt79665968 _Hlt491313651 _Hlt163634267 _Hlt163634277 _Hlt157772890 _Hlt163634239 _Hlt163634257rheumaticfever _Hlt466203344aorticdissection dissection _Hlt79417119 _Hlt157831701 _Hlt146622004 _Hlt56096139 _Hlt79665972 _Hlt79668072 _Hlt490709149 _Hlt491423649 _Hlt518929422 _Hlt78966039 _Hlt484489827ventricularaneurysm _Hlt152560227 _Hlt163708229aaa _Hlt79417113 _Hlt146346440 _Hlt79417083 endocarditis _Hlt462291729 _Hlt465950742 _Hlt79417499 _Hlt157058174 _Hlt157058590 _Hlt495206770 _Hlt160955687 _Hlt463751424 _Hlt495206775 _Hlt495206197 _Hlt466641092 _Hlt467057313 _Hlt160954382 _Hlt163121039 _Hlt146438046 _Hlt146437992 _Hlt462147217antibioticprophylaxis _Hlt79572181endocarditisprophylaxis _Hlt163553058 _Hlt79572245 _Hlt79572340 _Hlt163552982 _Hlt79572589 _Hlt79416930 _Hlt79417481 _Hlt161915904cardiomyopathy _Hlt145569387cm _Hlt79417057 _Hlt147580297 _Hlt147580298 _Hlt146342064 _Hlt162513183 _Hlt163042387restrictivecardiomyopathy _Hlt79429013 _Hlt79416990hocm _Hlt58752855 _Hlt79245448 _Hlt493764171postpartumcardiomyopathy _Hlt147580299 cardiactumors _Hlt164148203 arrhythmias _Hlt490893744 _Hlt79416940 _Hlt79417149 _Hlt79508238 _Hlt79508250 _Hlt79505502 _Hlt163622201 _Hlt157055824 _Hlt79505406 _Hlt163621367 _Hlt145821486 _Hlt157055898 _Hlt79508191 _Hlt79508174 _Hlt163644227 _Hlt163644228 _Hlt79690247 _Hlt79508177 _Hlt79688426 _Hlt79508194 _Hlt147580468 bradycardia heartblock _Hlt79505503 _Hlt156901249 _Hlt156901252 _Hlt156901565 _Hlt156901181 _Hlt156901171 _Hlt156901362 pacemakersavconductiondelaylbbbrbbbbundlebranchblocks hemiblocks _Hlt157055826sicksinussyndrome _Hlt79035827 _Hlt20756397 _Hlt20756382 _Hlt20756383atrial _Hlt157055886 _Hlt157056005 _Hlt157056055 _Hlt157056073 _Hlt157056192 _Hlt157056180 _Hlt157055414 _Hlt157055362 _Hlt157055353 _Hlt157059659 _Hlt157059607 _Hlt157059608pat _Hlt157055416 _Hlt80846645afib _Hlt79575724 atrialflutter _Hlt79504825 _Hlt79504829 _Hlt157055364wanderingpacemakermat _Hlt79304243 _Hlt79304228 _Hlt79304210 _Hlt79304207npjtavnrt _Hlt157056059wpw _Hlt157056012 deltawave _Hlt163622960 _Hlt79504671 _Hlt79504719 _Hlt79508214 ventricular _Hlt157055900pvcront _Hlt79508170 _Hlt79504995 _Hlt79508192vt _Hlt157059610 _Hlt79688921 _Hlt79688989 _Hlt147633411torsades _Hlt79689079aclscodes hypothermia _Hlt157055736 _Hlt157055710 _Hlt157055716 pericarditis _Hlt79504374 _Hlt79429319 _Hlt79504150 _Hlt79504165 _Hlt163634551 _Hlt163634581 _Hlt79428913 _Hlt79428822 _Hlt79428768 _Hlt79428866 _Hlt161915908pericardialeffusion _Hlt156544459 _Hlt157055752acutepericarditis _Hlt145902353 _Hlt154413046 frictionrub _Hlt62818995 _Hlt79665991 _Hlt484061850 _Hlt484062265 _Hlt79668081 _Hlt491964058 _Hlt145902170 _Hlt145902171 _Hlt492555244 _Hlt11279022 _Hlt79668083infectiouspericarditis _Hlt79428823 _Hlt79428880viralpericarditis _Hlt484062112tbpericarditis dresslers _Hlt79428871uremicpericarditis _Hlt79504152constrictivepericarditis _Hlt163634580restrictivepericarditis _Hlt156900967cardiactamponade _Hlt152560323 _Hlt146510023 _Hlt146510046 myocarditis _Hlt79415559 _Hlt79415560 _Hlt79415576 _Hlt79415467 _Hlt79415468 _Hlt161915922 _Hlt161999424 _Hlt79417158subclavianstealcardiactransplanthearttransplant _Hlt164148258 _Hlt457205778oncology _Hlt492347764 _Hlt500222084 _Hlt78627905 _Hlt78888813 _Hlt491425577 _Hlt489948214 _Hlt489948419 _Hlt492554274 _Hlt77576501 _Hlt146347947 _Hlt489947782 _Hlt77513383 _Hlt499696792 _Hlt499697275 _Hlt499697276 _Hlt33354408 _Hlt162614831 _Hlt481118784 _Hlt481119072 _Hlt481119142 _Hlt57439249 _Hlt212527872 _Hlt491426877 _Hlt472675820 _Hlt481118937 _Hlt489948572 _Hlt475450913 _Hlt475625081 _Hlt481118725 _Hlt481118726 _Hlt57438839 _Hlt19375429 _Hlt162614501 _Hlt162614142 _Hlt162615315 _Hlt57438857 _Hlt486748730 _Hlt499697044markers _Hlt79243486 _Hlt163043080 associations _Hlt156283520 _Hlt156283479 hamartomatumorsyndromes _Hlt495302072 _Hlt472673889 _Hlt472673845 _Hlt533076605 _Hlt468344868 _Hlt79667085plummer _Hlt468344858 _Hlt146340669 _Hlt156468106 muirtorre _Hlt162512195 _Hlt491425880 _Hlt79668089 _Hlt146340663 _Hlt79668093 _Hlt153173179 _Hlt78739041 _Hlt78887182 _Hlt162515583 _Hlt162515586 tumorbiology _Hlt489948359 _Hlt162783523 _Hlt162783524tumorsuppressors _Hlt489948361 carcinogenstobacco _Hlt163120847 _Hlt148348801 _Hlt148348802 _Hlt164148308 tumorspreadfibromusculardysplasia _Hlt145738029 _Hlt78970301 irradiation _Hlt158525745 _Hlt492347689 _Hlt493089605 _Hlt77047254renal _Hlt457206768 _Hlt457183776 _Hlt490371394 _Hlt79861712 _Hlt490019251 _Hlt489032193 _Hlt493146771 _Hlt489032180 _Hlt146178916 _Hlt146178919 _Hlt489032122 _Hlt19973399 _Hlt489032178 _Hlt489032120 _Hlt145903456 _Hlt145903457 _Hlt490477167 _Hlt489957797 _Hlt490368149 _Hlt490368290 _Hlt493765049 _Hlt147031609 _Hlt493089612 _Hlt78971406 _Hlt498084138 _Hlt492288300 _Hlt148201150 _Hlt489956320 _Hlt78970885 _Hlt493092367 _Hlt489505472 _Hlt489955217 _Hlt145843926 _Hlt145843927 _Hlt145845382 _Hlt145844011 _Hlt78971039 _Hlt489957088 _Hlt489031703 _Hlt489956927 _Hlt489956997 _Hlt148201090 _Hlt494095792 _Hlt153170977 _Hlt80705996 _Hlt489956317 _Hlt148201455 _Hlt79860529 _Hlt486747428 _Hlt60434390 _Hlt10867968 _Hlt60434796 _Hlt77326059 _Hlt463264741 _Hlt474494357 _Hlt467140629 _Hlt77326882 _Hlt77327739 _Hlt60434814 _Hlt60434827 _Hlt60434859 _Hlt60434857 _Hlt60434858 _Hlt60434866 _Hlt79033447 _Hlt145986491 _Hlt471812129 _Hlt145986488 _Hlt145986489 _Hlt493146720 _Hlt463264756 _Hlt77327750 _Hlt463264739 _Hlt463264740 _Hlt77172894 _Hlt463264763 _Hlt496247466 _Hlt78969710 _Hlt145986493 _Hlt79153468 _Hlt79154012 _Hlt80705956 _Hlt77172914 _Hlt498051495 _Hlt23176846 _Hlt490820830 _Hlt475622145 _Hlt475622146 _Hlt490475674 _Hlt463264327 _Hlt489504793 _Hlt463264494 _Hlt78970342 _Hlt147030732 _Hlt147030775 _Hlt79861971 _Hlt488590225 _Hlt79862700 _Hlt79861666 _Hlt467140562 _Hlt486746774 _Hlt486746791 _Hlt500415097 _Hlt486746787 _Hlt147031629 _Hlt147031720 _Hlt467140733 _Hlt467832752 _Hlt500415115 _Hlt79863438 _Hlt148350035 _Hlt463264557 _Hlt493092515 _Hlt463264622 _Hlt463264626 _Hlt476384551 _Hlt476384552 _Hlt478521928 _Hlt478521981 _Hlt463264629 _Hlt463264634 _Hlt153277508 _Hlt79900602 _Hlt78826391 _Hlt465086437 _Hlt467834911 _Hlt77326114 _Hlt465177470 _Hlt79900080 _Hlt156282769 _Hlt463264929 _Hlt489031867 _Hlt461805468 _Hlt475768364 _Hlt474494418 _Hlt463264875 _Hlt489031585 _Hlt461805535 _Hlt486747371 _Hlt486747421 _Hlt486747476 _Hlt486747490 _Hlt155715332 _Hlt79860511 _Hlt79860515 _Hlt145480296 _Hlt145480898 _Hlt467758479 _Hlt78995195 _Hlt78995218 _Hlt78995303 _Hlt214341878 _Hlt214342158 _Hlt463267890 _Hlt463267654 _Hlt155715346 _Hlt79900121 _Hlt78995401 _Hlt490477078 _Hlt79901466 _Hlt79901476 _Hlt463267988 _Hlt469068646 _Hlt77271552 _Hlt161481839 _Hlt487798374 _Hlt487798375 _Hlt146880684 _Hlt146880757 _Hlt489032194 renalstudiesrenalus _Hlt492286866 _Hlt78968020 _Hlt78967983ivp _Hlt145986484 _Hlt145986485 _Hlt156895612 _Hlt156895602 _Hlt156895603 _Hlt156895604 _Hlt156895608 _Hlt156895610 _Hlt79861962 proteinuria _Hlt489032181 _Hlt146178918nephroticsyndrome nephrotic _Hlt79033446 hematuria _Hlt489032179 _Hlt145903493 _Hlt145903471 _Hlt153099066 _Hlt153099026 _Hlt153099069 _Hlt148118266arf _Hlt79666038 _Hlt498084437 _Hlt156207269 _Hlt156207270 _Hlt489957707 _Hlt498084438 _Hlt79666039arfaidstumorlysissyndrome _Hlt79300244 _Hlt79300223 _Hlt79301283 _Hlt79301370 _Hlt79301380 _Hlt146179016 _Hlt79299904 _Hlt146255557 _Hlt146255558 _Hlt78970921 _Hlt490895102 _Hlt148201556 _Hlt489031577 _Hlt489956926 _tegretol _typethree _patentductus_atherosclerosis_mai_mtbrenaldrugtoxicity _Hlt491876958 _Hlt489957170 drugprerenal _Hlt145845379 _Hlt79857128 _Hlt79857174 drugpostrenal _Hlt489957116 _Hlt79861647crf _Hlt80706000 _Hlt488588855 _Hlt488588856 _Hlt521666489 _Hlt77172905 nephritic _Hlt467140631psgniganephropathybergers _Hlt77326788 _Hlt78473863 _Hlt78473883gbm _Hlt157410511 _Hlt60434845cryoglobulinemia _Hlt60434868 _Hlt79153909 _Hlt147037021 _Hlt148365488 _Hlt148365557 _Hlt79154335rpgnanca _Hlt524441843 _Hlt78969712 _Hlt496247469 _Hlt79033997 _Hlt79033506 _Hlt145986514 _Hlt80705942mcd _Hlt145905341 _Hlt475677309fsgsmgnmpgn _Hlt79154374 _Hlt80705957hcvrenal _Hlt148365517 _Hlt148365459 _Hlt524087079 _Hlt467140619 renalother _Hlt486747480 _Hlt78995273 _Hlt78995300 _Hlt147329504 _Hlt147329505 _Hlt147329507 _Hlt78995299 _Hlt469067830 _Hlt488327511hydronephrosis _Hlt147329506 _Hlt78995400renalmechanicalrenalarterystenosis _Hlt78995317 _Hlt79862325renalhypertensionnsf _Hlt493092345 _Hlt494727710 diabetesrenal _Hlt23176815 _Hlt57990461 _Hlt23176911 _Hlt156891528 _Hlt467325890 amyloidosis _Hlt490887979 _Hlt490820815 _Hlt79415250 _Hlt466129614 _Hlt490475932 _Hlt146605671 _Hlt146605866 _Hlt497127396 _Hlt490475868 _Hlt490475909 _Hlt79894603 _Hlt79894604 _Hlt490475981renalendocarditis _Hlt462291692 _Hlt462291725renalsle renallupus _Hlt466129567 _Hlt78887707renalpan renalwegeners _Hlt489504740 _Hlt489504741renalscleroderma _Hlt78970343 _Hlt147030733 _Hlt147030777 _Hlt77257660 _Hlt466129507 _Hlt463264519 _Hlt469642942 _Hlt476386164 _Hlt60432842 thrombosisrenalthrombotic _Hlt490883115 _Hlt475290756 _Hlt79576062 _Hlt492347591 _Hlt492347595 _Hlt471742737 _Hlt469642832 _Hlt473602243 _Hlt467628981 _Hlt78686102 _Hlt78685927 _Hlt78686026 _Hlt158804200 _Hlt58585624 _Hlt493334523 _Hlt78686103 _Hlt60432949 _Hlt499789046 _Hlt499789054 _Hlt79241857 _Hlt79241870 _Hlt79241873 _Hlt79900542 _Hlt79900580 _Hlt79900987focalthrombosis _Hlt79666058 _Hlt78686158 _Hlt145738182 _Hlt79666060 _Hlt79901883 _Hlt163040859dvt _Hlt146613801 _Hlt58585645 _Hlt58585646 _Hlt158804295 _Hlt158804324 _Hlt158804325 _Hlt467813460 _Hlt467813461 _Hlt158804425 _Hlt158804426pvt _Hlt467823935 fatembolism _Hlt146945106 _Hlt473602589cholesterolembolism _Hlt493092453livedo _Hlt157494501 _Hlt155853095 _Hlt78686025systemicthrombosisrenaldic _Hlt463264624dic _Hlt78685771 _Hlt79665922 _Hlt467134785 _Hlt60464109 _Hlt147049890 _Hlt147050218 _Hlt147049841 _Hlt147049852 _Hlt147049797 _Hlt147069277 _Hlt147049755 _Hlt147069268 _Hlt472669585 _Hlt472669559 _Hlt156467028 _Hlt156467067 _Hlt156467144 _Hlt55827465 _Hlt79241436 _Hlt147049398 _Hlt499789055 _Hlt499789081hellp _Hlt79241872 _Hlt79241877 _Hlt147049756 _Hlt147069275 _Hlt524864887 _Hlt490476577 _Hlt524864859 _Hlt524864860 _Hlt524864899 _Hlt79241421 _Hlt146347593 _Hlt146347594 _Hlt153099915 _Hlt145743386 _Hlt463264628 _Hlt466343808 _Hlt463264630 _Hlt60433020 _Hlt79900611 _Hlt79900690ttp _Hlt147069401 _Hlt472590369hus _Hlt461804852 _Hlt462235007 _Hlt462293911 _Hlt462236029 _Hlt462293998 _Hlt461804861 _Hlt461804849 _Hlt461804850 _Hlt461800591 _Hlt466640656 _Hlt60433000 _Hlt79900537 _Hlt524086526hsp _Hlt77326436 _Hlt77327743 _Hlt79576170 _Hlt79576181 _Hlt79576446 _Hlt79666261 _Hlt162597524 _Hlt77326191 _Hlt79900525pyelonephritis _Hlt79900113 _Hlt147031063 _Hlt147031336 _Hlt147031724interstitialnephritis _Hlt463264886ainchronicnephritis _Hlt79901149 _Hlt79901065 _Hlt79901093 _Hlt79901049 _Hlt79901061 _Hlt79901875 _Hlt79901111 _Hlt79901109 _Hlt79901311 _Hlt79901333analgesicabusenephropathy _Hlt147030685 _Hlt147030697balkan _Hlt79901479 _Hlt79901463 renaltubular _Hlt486746780 _Hlt500415108 _Hlt79862716atn _Hlt79031127 _Hlt79031227 _Hlt79031185 _Hlt79031211 _Hlt79031224acidbase _Hlt148346574 _Hlt155715412aniongap _Hlt147761892 _Hlt156467258 _Hlt156467263 _Hlt79901873 _Hlt149566397 _Hlt145478637 _Hlt145479211rta _Hlt79860481 _Hlt79863439 _Hlt79038440 _Hlt79860483 urineaniongapttkgrta1 _Hlt79901322 _Hlt79901358 _Hlt79857196rta2 proximalrta _Hlt148350074rta4 _Hlt148350335 _Hlt148350313 _Hlt79038289 _Hlt79038300 _Hlt79038301 drugacidbase _Hlt490477815 nephrogenicdi _Hlt147031698 _Hlt147031719 _Hlt147031684 _Hlt57440843 _Hlt78968021 _Hlt79860512fanconis _Hlt147031717 _Hlt148350026 _Hlt79861707 renalstones _Hlt145822525 _Hlt155715334 _Hlt78968015 _Hlt79860524 _Hlt146346501 _Hlt146346438 _Hlt146346439 _Hlt153099035 _Hlt153099064 _Hlt158171173 _Hlt146346455 _Hlt146346449 _Hlt158110663 _Hlt158110664 _Hlt162425053 _Hlt162425054 _Hlt148366539 _Hlt79860370 _Hlt491694771 _Hlt475768396 _Hlt145480368 _Hlt475768315 _Hlt475768363 _Hlt475768373 _Hlt490366452 _Hlt490366453 _Hlt492308038 _Hlt148366549 _Hlt492308508renalmalformations _Hlt146604728 _Hlt146604732apkd _Hlt145742392alports _Hlt147760228renaltransplant _Hlt164148168 _Hlt463267999 _Hlt77271550 _Hlt77271506 _Hlt77271526 _Hlt58583300 _Hlt58583247 _Hlt58583248transplantglomerulopathy _Hlt77327738rcc _Hlt79901480 _Hlt155715410 _Hlt157660086 _Hlt153097646 _Hlt153097727 _Hlt153097591 _Hlt153097485 _Hlt153097588 _Hlt162615874 _Hlt145480894dialysisdialysisindications _Hlt145846166 hemodialysis _Hlt146604730 _Hlt146604758 _Hlt77271486 _Hlt77271551 calciphylaxis _Hlt161482854 _Hlt78971404 electrolytes _Hlt492347759lytes _Hlt78971408 _Hlt147031624 _Hlt490368130 _Hlt80846459 _Hlt492553191 _Hlt492553263 _Hlt77170936 _Hlt80846454 _Hlt492309915 _Hlt492298837 _Hlt488161904 _Hlt489957786 _Hlt489957784 _Hlt500414348 _Hlt510972399 _Hlt489957779 _Hlt496247021 _Hlt489800906 _Hlt146604384 _Hlt146605868 _Hlt77170945 _Hlt77170947 _Hlt146604733 _Hlt162590448 _Hlt489801008 _Hlt489800974 _Hlt490368029 _Hlt493765052 _Hlt489957788 _Hlt490477825 _Hlt500415385 _Hlt493089615 _Hlt489957782 _Hlt490880253 _Hlt490883907 _Hlt58841639 _Hlt79667953 _Hlt79668042 _Hlt489027032 _Hlt489027033 _Hlt510972061 _Hlt162617279 _Hlt490880439 _Hlt489950125 _Hlt489957777 _Hlt76484462 _Hlt77139352 _Hlt77139563 _Hlt489800638 _Hlt489800639 _Hlt533077337 _Hlt490880555 _Hlt80846468 _Hlt77139556 _Hlt492287193 _Hlt492310013 _Hlt524448164 potassium hypokalemia _Hlt489957783 _Hlt79304211 _Hlt156901254 _Hlt146878246 _Hlt146878247hypokalemiaecg _Hlt79691413 _Hlt79691453 _Hlt79692839 _Hlt79692851 _Hlt145566404 _Hlt79667956 _Hlt79666268 _Hlt510972298 _Hlt79691346 _Hlt510972114 _Hlt510972290 _Hlt79667993 _Hlt79668039 _Hlt79668041 _Hlt145566444 _Hlt79666276 _Hlt492553326 hyperkalemia _Hlt489957785 _Hlt156901251 _Hlt500414452 _Hlt147742988calcium _Hlt80846457 hypercalcemia _Hlt77170946 _Hlt79147613 _Hlt156552343 _Hlt164502561 _Hlt146603958 _Hlt146603959 _Hlt146605956 _Hlt154415432 _Hlt154415433 _Hlt146605965 _Hlt146605979 _Hlt162590507 _Hlt146606093 _Hlt146605648 _Hlt146605867 _Hlt163048974 _Hlt146603682 _Hlt162590638 _Hlt146603655 _Hlt146605041 _Hlt146603653 _Hlt146603649 _Hlt146989764 _Hlt146604757 hypocalcemia _Hlt489957778 _Hlt77139544 _Hlt79666298 _Hlt148201451 phosphatehyperphosphatemiahypophosphatemia magnesiumHypermagnesemiahypomagnesemia _Hlt77139558 _Hlt79304209 _Hlt79666299 _Hlt80846637 _Hlt80846668 _Hlt147041420sodium _Hlt489957787 hypernatremia hyponatremiasiadhddx _Hlt147760874 _Hlt146604382 _Hlt79863409lungs _Hlt77487531 _Hlt495078705 _Hlt495078732 _Hlt147210882 _Hlt23692143 _Hlt158111515 _Hlt495303127 _Hlt467753079 _Hlt493172793 _Hlt60806969 _Hlt481673192 _Hlt493347637 _Hlt518749025 _Hlt486749000 _Hlt163625821 _Hlt481667082 _Hlt146643678 _Hlt466955398 _Hlt481660887 _Hlt481671448 _Hlt22034262 _Hlt481668374 _Hlt469930480 _Hlt481666050 _Hlt147385625 _Hlt156880941 _Hlt504726753 _Hlt164149378 _Hlt495075047 _Hlt495078699 _Hlt495077849 _Hlt504718184 _Hlt504718185 _Hlt158111521 _Hlt146905608 _Hlt495078002 _Hlt78974501 _Hlt495075611 _Hlt495075901 _Hlt153169760 _Hlt495075493 _Hlt495075647 _Hlt495075771 _Hlt492347785 _Hlt147203746 _Hlt164137084 _Hlt504674125 _Hlt78974417 _Hlt158350711 _Hlt495075897 _Hlt495075842 _Hlt78974084 _Hlt495075580 _Hlt495075860 _Hlt524502084 _Hlt77487434 _Hlt147203738 _Hlt148951630 _Hlt164137264 _Hlt164137255 _Hlt465413344 _Hlt78974410 _Hlt78974665 _Hlt78974454 _Hlt481672897 _Hlt77923645 _Hlt488424664 _Hlt497231895 _Hlt147385229 _Hlt147385230 _Hlt471894511 _Hlt77487592 _Hlt158351324 _Hlt156879985 _Hlt164147841 _Hlt526004287 _Hlt79859153 _Hlt148947634 _Hlt148947783 _Hlt156879957 _Hlt156879970 _Hlt526006222 _Hlt22034125 _Hlt77487608 _Hlt77487946 _Hlt155844644 _Hlt155844657 _Hlt146622662 _Hlt146622692 _Hlt155844573 _Hlt155844610 _Hlt155844613 _Hlt79859500 _Hlt148947157 _Hlt526004767 _Hlt77487510 _Hlt77598873 _Hlt77599199 _Hlt146643672 _Hlt495075963 _Hlt146645010 _Hlt146787988 _Hlt158349951 _Hlt146644622 _Hlt495076143 _Hlt495076235 _Hlt495076294 _Hlt495076373 _Hlt495076474 _Hlt495076293 _Hlt495076308 _Hlt520134251 _Hlt495076183 _Hlt163055541 _Hlt163055542 _Hlt495076743 _Hlt19968685 _Hlt19968686 _Hlt19967761 _Hlt19967712 _Hlt493172798 _Hlt495077188 _Hlt78974469 _Hlt23700972 _Hlt518749673 _Hlt183175267 _Hlt504672320 _Hlt77865915 _Hlt146645399 _Hlt518749712 _Hlt146469910 _Hlt146469913 _Hlt495077577 _Hlt495077618 _Hlt495077674 _Hlt495077560 _Hlt520565136 _Hlt495077572 _Hlt155952329 _Hlt158026983 _Hlt158026992 _Hlt495077453 _Hlt495077373 _Hlt495077426 _Hlt77749412 _Hlt77749413 _Hlt520565269 _Hlt504718364 _Hlt495076855 _Hlt495076728 _Hlt495076762 _Hlt77866106 _Hlt495076890 _Hlt147405542 _Hlt77866109 _Hlt495076976 _Hlt77866143 _Hlt495077028 _Hlt495077122 _Hlt504794816 _Hlt60433034 _Hlt60434551 _Hlt60434558 _Hlt495075405 _Hlt495078081 _Hlt156540708 _Hlt496841340 _Hlt77866153 _Hlt146469936 _Hlt146469990 _Hlt496841446 _Hlt495078117 _Hlt156467668 _Hlt55752398 _Hlt504718255 _Hlt504718689 _Hlt77866147 _Hlt495077816 _Hlt504718701 _Hlt504795434 _Hlt495216280 _Hlt504726799 _Hlt504718421lungphysiologyabgabgspfts _Hlt156394953 _Hlt158111517 _Hlt488425105 _Hlt491314785 _Hlt79666306 _Hlt156394961 _Hlt147211344 _Hlt147331125 _Hlt147211501 _Hlt164136979dlco _Hlt147211345 _Hlt147331369 _Hlt147331333 _Hlt147331367 _Hlt147210878peepcpapbipappulmonaryprocedures _Hlt495074322 _Hlt495074323 _Hlt495074357 _Hlt146519556 _Hlt146519557 _Hlt147211061 _Hlt495074659 _Hlt495074426 _Hlt504674382 thoracentesis _Hlt146519558 _Hlt158111602 _Hlt158111556 _Hlt164160243 _Hlt164160248 _Hlt214342854 _Hlt214342855pnbp thoracoscopytubethoracostomy _Hlt147211062 bronchoscopyptnamediastinoscopymediastinotomy thoracotomy _Hlt495078792trachealaspiration _Hlt493172796 _Hlt78685814pepulmoneyembolism _Hlt79330728 _Hlt146613799 _Hlt488162121 _Hlt146613630 _Hlt481660418 _Hlt481660419 _Hlt158461678 _Hlt158461679 _Hlt488424462 _Hlt488424498 _Hlt485278043 _Hlt79666310 _Hlt77747427 _Hlt77747428 _Hlt147331741 _Hlt482362013 _Hlt79666318 _Hlt481673205 _Hlt482361933 _Hlt482361960 _Hlt482362078 _Hlt485278130 _Hlt482362071 _Hlt493172120 _Hlt504726346 _Hlt485278091 _Hlt485278099 _Hlt482362088 _Hlt145567356 _Hlt212614191 _Hlt22039671 _Hlt163626007 _Hlt22034559 _Hlt60807167 _Hlt60807168 _Hlt498083208 _Hlt498083209Lemmierelemierrepulmonaryedema _Hlt79665926 _Hlt145569132 _Hlt33073777pulmonaryhypertension _Hlt79665932 _Hlt77924322 pneumonia _Hlt467170501 _Hlt467170502 _Hlt466723712 _Hlt473606358 _Hlt467170472 _Hlt466723811 _Hlt467170210 _Hlt467170211 _Hlt493173571 _Hlt493173572 _Hlt77398421 _Hlt77398402 _Hlt77398403 _Hlt77398438 _Hlt77398471 _Hlt77398431 _Hlt77398427 _Hlt77398446 _Hlt467170132 _Hlt467170133 _Hlt467169401 _Hlt466724109 _Hlt146640906 _Hlt467170228 _Hlt467170229 _Hlt466641017 _Hlt466641018 _Hlt466724396 _Hlt466724381 _Hlt77594875 _Hlt77600920 _Hlt493068742 _Hlt158350065 _Hlt164160236 _Hlt164160265 _Hlt164148676 _Hlt146641886 _Hlt464924653 _Hlt19967733 _Hlt475769989 pneumoniahiv _Hlt475769064 _Hlt475769648 _Hlt475769874 _Hlt475769875 _Hlt491967459 _Hlt475769330pneumoniaviral _Hlt155853198 _Hlt155853229 _Hlt155853230 _Hlt155853304 _Hlt155853305 _Hlt155853340 _Hlt155853341 _Hlt155853193 _Hlt155853214 _Hlt155853215 _Hlt155853265 _Hlt155853266 _Hlt493172818 _Hlt145655050 _Hlt145655052pneumoniafungal _Hlt475769342 _Hlt461421440 _Hlt475769519 _Hlt475769521 _Hlt475769564 _Hlt475769565 _Hlt475769577 _Hlt155850111 _Hlt155850112 _Hlt155850095 _Hlt146645073 _Hlt462239240 _Hlt462239246nosocomialpneumoniaaspirationpneumonia _Hlt146906120 _Hlt155844608 pneumococcus _Hlt77599019 _Hlt156208075 _Hlt146641544 _Hlt147124573 _Hlt146641098 _Hlt146641233 _Hlt146641070staphylococcusstrepa _Hlt147126322 _Hlt147126295gnr _Hlt77596058 _Hlt77596059 hinfluenza chlamydia _Hlt156208104 psittacosis _Hlt77861945 _Hlt77862783 _Hlt77862784viralpneumonia _Hlt156208443 _Hlt156208448 _Hlt156208446pcp _Hlt145571574 _Hlt145571575 _Hlt163055544 compromisedpostop _Hlt22034121 _Hlt22034127pulmonaryneoplasialungca lungcancer _Hlt156128803 _Hlt156879968 _Hlt156880936 _Hlt145486083 _Hlt158351788 _Hlt162615313 _Hlt155844656bronchogeniccabronchogeniccarcinoma _Hlt145485889 _Hlt526007777 _Hlt146622680 _Hlt146622691 _Hlt77487954 _Hlt77487973 _Hlt145485870 _Hlt163048310 _Hlt163047966 _Hlt163047972 _Hlt146622138 _Hlt146622695 _Hlt146622333horners _Hlt146622006pancoastpancoastsyndrome _Hlt146622097svc svcsyndroime svcsyndromeparaneoplastic _Hlt158809630 _Hlt504726756 _Hlt147331368 _Hlt148947781 _Hlt148947784spn _Hlt145486085 _Hlt146622656 _Hlt146622694 _Hlt57975743 _Hlt57975744 _Hlt79859519 _Hlt147401161 _Hlt147401162 _Hlt77487446 _Hlt78974083radasthma _Hlt147203743 _Hlt466640664 _Hlt147204553 _Hlt22398999 _Hlt147204980 _Hlt147204981 _Hlt22398181 _Hlt79858137 _Hlt156879543 _Hlt78974421 _Hlt79304245 _Hlt465413349 _Hlt78974409 _Hlt78974546lungobstructivecopd _Hlt148955848 _Hlt158350796 _Hlt148956696 _Hlt158351025 _Hlt164147803 _Hlt164147804 _Hlt79244759a1lungs _Hlt475771746 _Hlt148954659cysticfibrosiscf bronchitis _Hlt153170655 _Hlt153170656 _Hlt153170417lungrestrictive _Hlt465413346 _Hlt22034100 _Hlt78974411 _Hlt78974460 _Hlt78974677 _Hlt488424789 _Hlt491314738 _Hlt77427756 _Hlt77427759 _Hlt457206785 _Hlt481483876 _Hlt491314755 _Hlt488424737 _Hlt488425035 _Hlt488425036 _Hlt481668373osacsa _Hlt147205461 _Hlt77487436 _Hlt78974087bronchiectasis _Hlt164149287 atelectasis _Hlt78628386 aspirationaspirationpneumonitis _Hlt146644620 _Hlt146645008 _Hlt164148682 lungabscesspleurisy _Hlt504718187pleuraleffusion _Hlt147039832 _Hlt158111524 _Hlt164160246 _Hlt158111601 transudates _Hlt147328260exudatesempyema _Hlt158350148 _Hlt158350283 _Hlt158350284 chesttube _Hlt23695384 _Hlt156880935 _Hlt78974503pleuralfibrosis pneumothoraxptx _Hlt145483302ards goodpastures _Hlt60434374alveolarhemorrhagedah occupational _Hlt504718366 _Hlt77866108 inorganic Silicosiscwp blacklung asbestosis Berylliosisorganic organicdusts _Hlt155844643 _Hlt77866141 _Hlt77866145otherchemicals _Hlt78466443sickbuildingsyndrome _Hlt164138026 _Hlt164161170 _Hlt147406607ild _Hlt77752324 _Hlt60434092 _Hlt520560475 _Hlt520560686ipf _Hlt158351996uip desquamativedip _Hlt156879600aipnsiprbailboop _Hlt77749267 _Hlt77749243 _Hlt77749175 _Hlt77749192lip _Hlt146799831 _Hlt496247441 letterersiwehandschullerchristian _Hlt23701096eosinophilicgranuloma langerhans _Hlt145483203 _Hlt164160714 _Hlt164160715iph _Hlt77866149pap _Hlt504670326 _Hlt57976923 _Hlt57976924hypersensitivitypneumonitis _Hlt77749244 _Hlt146470016 _Hlt77866947 _Hlt77866992 farmerslung eosinophiliceosinophilicpneumonia _Hlt156879389 _Hlt156879390 _Hlt156879531 _Hlt156879598 aspergillus _Hlt504718259 _Hlt156879754invasiveaspergillosislungtransplant _Hlt164148166 _Hlt79859149 _Hlt78441513neuro _Hlt78627909 _Hlt534109498 _Hlt467756780 _Hlt77135185 _Hlt469852197 _Hlt74921851 _Hlt78441334 _Hlt78441425 _Hlt78441437 _Hlt78648910 _Hlt78649009 _Hlt493335342 _Hlt77135029 _Hlt78441290 _Hlt156049940 _Hlt156050157 _Hlt513807172 _Hlt513807173 _Hlt78441421 _Hlt78555825 _Hlt78441433 _Hlt146943975 _Hlt154565917 _Hlt154568120 _Hlt154568121 _Hlt157834949 _Hlt157835011 _Hlt146943754 _Hlt162588765 _Hlt78648992 _Hlt493335275 _Hlt519435901 _Hlt78441497 _Hlt78649066 _Hlt78441316 _Hlt78441592 _Hlt156284093 _Hlt78441617 _Hlt156049345 _Hlt467756775 _Hlt78441590 _Hlt78368497 _Hlt78441696 _Hlt467756783 _Hlt78552825 _Hlt78441588 _Hlt525054352 _Hlt78001125 _Hlt78441578 _Hlt78972733 _Hlt78972740 _Hlt146949169 _Hlt146949189 _Hlt162589371 _Hlt515024657 _Hlt146950461 _Hlt78648778 _Hlt78552893 _Hlt146949457 _Hlt146949309 _Hlt156279096 _Hlt156050123 _Hlt78382450 _Hlt156283680 _Hlt146990866 _Hlt156283564 _Hlt467756689 _Hlt78567303 _Hlt58462005 _Hlt503697696 _Hlt503697718 _Hlt58750394 _Hlt58750913 _Hlt78441878 _Hlt78442127 _Hlt78442708 _Hlt503699263 _Hlt78441841 _Hlt147031479 _Hlt147031544 _Hlt78567337 _Hlt146948576 _Hlt146989632 _Hlt146990109 _Hlt146990110 _Hlt146989629 _Hlt154568041 _Hlt146989800 _Hlt146989793 _Hlt475448157 _Hlt78552879 _Hlt78553030 _Hlt78553066 _Hlt78553035 _Hlt78553032 _Hlt78553054 _Hlt79245678 _Hlt79245700 _Hlt515027708 _Hlt515024619 _Hlt146948633 _Hlt78567329 _Hlt467756821 _Hlt465088800 _Hlt78567311 _Hlt467756797 _Hlt78470411 _Hlt58469521 _Hlt515188371 _Hlt146948455 _Hlt514932049 _Hlt467756919 _Hlt154566679 _Hlt481128543 _Hlt481128544 _Hlt515024579 _Hlt515024580 _Hlt469852225 _Hlt469850614 _Hlt515192481 _Hlt520439291 _Hlt78470543 _Hlt493067978 _Hlt467757018 _Hlt467757192 _Hlt519435683 _Hlt534109516 _Hlt20902674 _Hlt467757190 _Hlt515193466 _Hlt68271117 _Hlt68271118 _Hlt78468513 _Hlt78468593 _Hlt467757187 _Hlt164160866 _Hlt164160949 _Hlt467757748 _Hlt467757100 _Hlt491099017 _Hlt493067966 _Hlt78708282 _Hlt154563493 _Hlt467756791 _Hlt78470491 _Hlt467756788 _Hlt78470519 _Hlt154563393 _Hlt154563542 _Hlt469332034 _Hlt467757813 _Hlt469331992 _Hlt469332004 _Hlt467756272 _Hlt467756445 _Hlt467756542 _Hlt467756590 _Hlt154563535 _Hlt467757811 _Hlt467757863 _Hlt146945329 neuroexam _Hlt78473860 _Hlt78473842 _Hlt78473856 _Hlt154568326 _Hlt78473561 _Hlt78473562anatomicdiagnosisneuroradiologycnsmri _Hlt214342193cnsct cnsultrasoundtranscranialdopplercerebralangiographyeeg _Hlt512752096 _Hlt512752097 _Hlt79666428 _Hlt515422451 _Hlt515422452 _Hlt78000589 _Hlt78000590 cnsneoplasms _Hlt489948574 _Hlt78972738 cnsneoplasia _Hlt146949193 _Hlt78441587 _Hlt465414003 _Hlt78628820 _Hlt465414195 _Hlt77527196dementia _Hlt147031542 _Hlt146949304 _Hlt146990131 _Hlt503702957 _Hlt58469094 _Hlt146948853 _Hlt146949305 _Hlt503702906 _Hlt78567163 _Hlt78567167 _Hlt156544168 _Hlt156544169 _Hlt503703787 _Hlt78567122 _Hlt78567125 _Hlt78567115 _Hlt78567098 _Hlt78441868 _Hlt146949023 _Hlt146949075 _Hlt78568063 _Hlt78568117 _Hlt78567072 _Hlt148947986 _Hlt148947973 _Hlt146949191 _Hlt146949166 _Hlt78442224 _Hlt156284017 wernickes _Hlt472666112 _Hlt524443392 _Hlt78382263 _Hlt146341811hepaticencephalopathy _Hlt490820108 _Hlt78966345 _Hlt467757466 _Hlt500414569 _Hlt79330726 _Hlt79330727 _Hlt157678318 marchiafava _Hlt467757505 neurological _Hlt465088801 _Hlt467756799 _Hlt78567315 _Hlt78567334 _Hlt78470422 alzheimers _Hlt466108430 _Hlt146948676 _Hlt146949306 _Hlt146948526 _Hlt146948508 _Hlt146990164 _Hlt213552582 _Hlt78567164picks _Hlt78567123 _Hlt79245717 huntingtons _Hlt78567132 _Hlt78473858 parkinsons _Hlt154566761 _Hlt154568634 _Hlt78385433lewybodymsa shydragerscjd _Hlt78567116 _Hlt147285335motormotorneurondiseaseals _Hlt78473748 _Hlt519230553 _Hlt154422013 _Hlt154422196 _Hlt154422197smawerdnig kugelbergessentialtremorrls stiffperson demyelinatingademahem westonhurst guillainbarregbs _Hlt154564017 _Hlt78554571 _Hlt78554563 _Hlt164149850 _Hlt78554619 _Hlt163134970 _Hlt78468610ms _Hlt78000795 _Hlt78554564 _Hlt78444070 _Hlt19106036 _Hlt519787115 _Hlt519787116 _Hlt74765082 _Hlt78445189 _Hlt79666445 _Hlt146949097 _Hlt519787159 _Hlt57975615 _Hlt20902720 _Hlt20902736 _Hlt20902750 _Hlt20902775 _Hlt57975600 _Hlt78444625 _Hlt79666447 _Hlt146949110 _Hlt146949114 _Hlt146949138 _Hlt19105938 _Hlt19105439 _Hlt19105519 _Hlt19106106 _Hlt78709944 schildersbalodemyelinatingsystemic neuropathiesperipheralneuropathyperipheralneuropathies _Hlt154564762 _Hlt79245633 _Hlt79245637 _Hlt78468591emgcmt _Hlt146948453cidp _Hlt162349349carpaltunnelsyndrome carpaltunnelcts spinalcordspinalcordinjuryspine _Hlt156050119myopathy _Hlt469334944 _Hlt472952430 _Hlt78627942 _Hlt469334269 _Hlt78708283 _Hlt157494884 _Hlt157494997 _Hlt469334401 _Hlt156812195 _Hlt469334306 _Hlt469334322 _Hlt469334318 _Hlt78708292 _Hlt147039935 _Hlt147039938 _Hlt522271337 _Hlt493068168 _Hlt493253094 _Hlt522273108 _Hlt469334336 _Hlt469334340 _Hlt520650757 _Hlt469334106 _Hlt520654159 _Hlt525908004 _Hlt469334179 _Hlt79030548 _Hlt146179047 _Hlt146179083 _Hlt147039990 _Hlt493146167 _Hlt493146168 _Hlt474471484 _Hlt77325113 _Hlt78708287muscularduchenne _Hlt469334403beckers _Hlt467757865emerymyotonicdystrophy _Hlt465083063 _Hlt461265135 _Hlt461265451 _Hlt467756793 _Hlt469334278myopathycongenital _Hlt467756790 _Hlt78470520myopathymitochondrial _Hlt467756796 _Hlt78470330 _Hlt78470346myopathyinflammatory _Hlt154563407polymyositismuscle _Hlt469334338 _Hlt147039936 _Hlt147039939 _Hlt469334355 _Hlt520652624 _Hlt522271340 _Hlt520653807 _Hlt522273110 _Hlt77139547 _Hlt78554572mg lamberteaton _Hlt163047968 _Hlt77324488 _Hlt77324503ibmeosinophilicfasciitiseosinophilicmyositispmr _Hlt19106247 _Hlt79666460 _Hlt19287957 _Hlt19287927 _Hlt19288742 _Hlt19288057 _Hlt19287978 _Hlt19289069rs3pe myopathyother _Hlt503699328 _Hlt522270514 _Hlt522270542 _Hlt522270545 _Hlt520650078 _Hlt157919260 _Hlt474471422 _Hlt474471380 _Hlt520650062 _Hlt520650147 _Hlt520650186 _Hlt145486357 _Hlt145487293 _Hlt469334481 _Hlt62885166 _Hlt62885167 _Hlt469334502 _Hlt162588941 _Hlt163048309 _Hlt79329152 _Hlt79329126 _Hlt79328905rhabdomyolysis _Hlt148201149 _Hlt148201387 _Hlt148201452 _Hlt78170411 _Hlt78385435 _Hlt78553481 _Hlt79299826 _Hlt79301288 _Hlt146179019nms _Hlt79327205 _Hlt79327206malignanthyperthermia serotoninserotoninsyndrome cnsinjury _Hlt467756781 _Hlt78441303 _Hlt78441341 _Hlt78649039 _Hlt78650234 _Hlt78650259 _Hlt157410029 _Hlt78648931 _Hlt77135269 _Hlt156050168 _Hlt78648983cva _Hlt78441434 _Hlt156279089 _Hlt158027167 _Hlt158027168 _Hlt158027030 _Hlt146945067 _Hlt146945038 _Hlt146945085 _Hlt146945135 _Hlt154566165 _Hlt78212814carotidstenosistia cvasyndromes _Hlt157834402 _Hlt469334875 _Hlt157835009 _Hlt157834422 _Hlt157834423 _Hlt157834408 _Hlt157834409 _Hlt467756777 _Hlt78441591 cnsinfection _Hlt78368706 _Hlt78368544 _Hlt78368940 _Hlt78369206 _Hlt78368844 _Hlt78369047 _Hlt78369053 _Hlt78441702 _Hlt78441819 cnsamoebiasis _Hlt467756784 _Hlt78441589 _Hlt78552853cnsmalformations arnoldchiari _Hlt465090640 dandywalker _Hlt467756787 _Hlt78441319 _Hlt78441498 cnstrauma _Hlt78441615epiduralhematomasubduralhematomavenoussinusthrombosis _Hlt78649407ich _Hlt78441482sahsubarachnoidhemorrhage _Hlt156283990seizures _Hlt146992139 _Hlt465089059 _Hlt521666320 _Hlt146992362 _Hlt78212670 _Hlt78212671absence _Hlt146990758 _Hlt146990759 _Hlt78383529statusfebrileseizuresalcoholicwithdrawalalcoholicseizures headaches _Hlt146950491 _Hlt146949492 _Hlt474997315 _Hlt490721701 _Hlt490721702tensionheadaches _Hlt78169732 _Hlt78169733 _Hlt78169735 _Hlt78169850 _Hlt78170869clusterheadaches _Hlt78552908icp _Hlt156283967 _Hlt78649435 _Hlt78567473nph _Hlt146948510 _Hlt78553031 _Hlt78567495 _Hlt156283678 _Hlt78381451 _Hlt78381466 _Hlt78480880 _Hlt146949049 _Hlt78553263 _Hlt78553041 pseudotumorpseudotumorcerebri _Hlt78553062 _Hlt465090795 _Hlt78552747 _Hlt465090626 _Hlt503698131vertigo _Hlt78000794bppv _Hlt146949455 _Hlt78001091 cnstumors glioblastoma _Hlt157410483acousticneuroma spondylosis herniateddiscpysc pyschiatric panicattacksanorexia _Hlt77252814 _Hlt78627793 ophthalmology _Hlt155715367 _Hlt155715493 _Hlt157677196conjunctivitis _Hlt157835378Endopthalmitis _Hlt79666501 _Hlt79666485 _Hlt79666514 _Hlt79666516 _Hlt79666520 _Hlt157830068 EpiscleritisIritis Keratitis Retinitis _Hlt157835148 _Hlt163205595 _Hlt163205574Uveitismaculardegeneration _Hlt148378452 _Hlt148378448 _Hlt148378810diabeticretinopathybrvo _Hlt79575930 _Hlt79575931 _Hlt79666527 _Hlt157832594centralretinalarteryocclusion _Hlt146943744 opticneuritis _Hlt78444179glaucoma _Hlt146436984 _Hlt146949726narrowangleglaucoma _Hlt146436837congenitalglaucomaoag hordeolum _Hlt77047336female _Hlt481118727 _Hlt481215315 _Hlt481215316 _Hlt521666499 _Hlt521666511 _Hlt521666447 _Hlt492519207 _Hlt521666494 _Hlt492519139 _Hlt79241256 _Hlt481061587 _Hlt481061441 _Hlt481061337 _Hlt163209625 _Hlt481061464 _Hlt156553097 _Hlt156553134 _Hlt145479869 _Hlt145480902 _Hlt156283268 _Hlt162783527 _Hlt77519330 _Hlt79859495 _Hlt79859499 _Hlt77486043 _Hlt77486419 _Hlt156553120 _Hlt156553186 _Hlt481122467 _Hlt490374204 _Hlt490374485 _Hlt490374535 _Hlt481061036 _Hlt481120619 _Hlt481061305 _Hlt481061220 _Hlt145480904 _Hlt481061644 _Hlt481212572 _Hlt481061610 _Hlt481212879 _Hlt481061231 _Hlt481061244 _Hlt481061266 _Hlt481061262 _Hlt480204739 _Hlt481119205 _Hlt490374364 _Hlt480204771 _Hlt481212254 _Hlt57438843 _Hlt80028250 _Hlt80028257 _Hlt481119315 _Hlt481119299 _Hlt76995654 _Hlt76995655 _Hlt481120584 _Hlt481215346 _Hlt148003475 _Hlt148003566 _Hlt481119506 _Hlt481119414 _Hlt157919677 _Hlt490374766 _Hlt157680482 _Hlt79167477 _Hlt156552055 _Hlt156553806 _Hlt156552123 _Hlt77172267 _Hlt490374689 _Hlt490374687 _Hlt77486395 _Hlt78985186pcos _Hlt79397022 _Hlt76995618 _Hlt145754558 _Hlt79397248 _Hlt79397310 _Hlt79397484 _Hlt149926132 _Hlt149926133 _Hlt148003609 _Hlt148003610 _Hlt156281957 _Hlt481061593femaleinfection _Hlt78884587 _Hlt478788452 _Hlt78884999 _Hlt78885176 _Hlt78884589 _Hlt78884590 _Hlt78884755 _Hlt78884756 _Hlt78885022 _Hlt78884691 _Hlt78884666 _Hlt156058061 _Hlt155852933vulva accuminatum _Hlt477685409 _Hlt481061485 _Hlt155952172 _Hlt156452704vaginabv _Hlt476144178 _Hlt476144179 _Hlt476144061 _Hlt148081586 Trichomonascervixpid _Hlt481061419 _Hlt466015830cin cervicalca endometrium _Hlt481061222 _Hlt481061331endometriumfxn _Hlt481061232 endometriumcaendometrialneoplasiaendometrialcancer endometriosis _Hlt481061624 endometrialca _Hlt162614499 _Hlt162785384 _Hlt481061245endometriummesenchymal gestationalca _Hlt481061275 _Hlt480204742 fallopiantube _Hlt79168066ectopic _Hlt479639928 _Hlt479639929 _Hlt481121581 _Hlt479641260 _Hlt479641261 _Hlt479642418 _Hlt479642419 _Hlt156281984 _Hlt479639569 _Hlt479639570 _Hlt479639548 _Hlt479639549 _Hlt481121953 _Hlt481121954ovaryfollicularcystfollicularcystspcod _Hlt481215200 ovarianca ovariantumors _Hlt79243658 _Hlt79243659 _Hlt79243660 _Hlt79243677 _Hlt148081022 _Hlt148081023 _Hlt153096774 _Hlt153096785 _Hlt79243860 _Hlt79243776 _Hlt79243714 _Hlt160953658 _Hlt79243584 _Hlt79243926 _Hlt79243904 _Hlt79243944 _Hlt79243971 _Hlt79244019 _Hlt79244058 _Hlt79244070 _Hlt79243485 _Hlt79243964 _Hlt79243577 _Hlt157919800 _Hlt79243663 _Hlt79243675 _Hlt79243580meigsovarianepithelialca _Hlt79243820 _Hlt79243870 _Hlt481119416 _Hlt79243588 _Hlt79243911 _Hlt79243931ovariangermcell _Hlt482377633 yolksactumor _Hlt79243957teratoma _Hlt77001622 _Hlt77001623 _Hlt79244014 _Hlt79244047 _Hlt79244068ovarianstromal _Hlt79243579 _Hlt148003565arhenoblastomaovarianmetastatic _Hlt79243582 _Hlt157919801 krukenberg _Hlt79243678 _Hlt148081027breast _Hlt156553118 _Hlt77519468 _Hlt156128919 _Hlt155715480 _Hlt78686594 pagetsbreast _Hlt77519582breastca _Hlt77486044 _Hlt79859498 _Hlt156128811 _Hlt156553128 breastcancerbreastcancerscreening _Hlt156553372 _Hlt156553400 _Hlt156553448 _Hlt163624666 _Hlt163624696 _Hlt163624693 femaleother _Hlt157919678femalehealthmaintenance _Hlt156552199 _Hlt153179056papsmear incontinence _Hlt157681806 _Hlt157681766 _Hlt157681783 _Hlt157681823 _Hlt157681824 _Hlt157681758 _Hlt157681759 _Hlt157681788 _Hlt157680694 menopause _Hlt153179078 _Hlt156279196 _Hlt156552682pmof obstetrics _Hlt79167789 _Hlt79168074 _Hlt79168065liverpregnancy _Hlt79241841 _Hlt79241875 _Hlt158089086 _Hlt153195853 _Hlt153195854 _Hlt153195686 _Hlt153195687 _Hlt472681949 _Hlt475334317male _Hlt155845125 _Hlt156129466 _Hlt156129467 _Hlt163624920 _Hlt77424468 _Hlt163043313 _Hlt145480908 _Hlt153099392 _Hlt77424465 _Hlt77425798 _Hlt77426718 _Hlt77426662 _Hlt156129478 _Hlt163625068 _Hlt77426715 _Hlt77426739 _Hlt77426943 _Hlt77431510 _Hlt77427286 _Hlt77430510penis urethritisacuteurethritis _Hlt146510945lgv _Hlt78884757 _Hlt62891433 _Hlt62891400 _Hlt62891401 _Hlt78885038granulomainguinale donavanosis chancroid _Hlt78885013 _Hlt78885193 _Hlt477684639warts _Hlt477685332 _Hlt155952159 _Hlt477685430carcinomainsitumaleprostate prostatitisbph _Hlt77481821 _Hlt77481832 _Hlt74937282 _Hlt145478953 _Hlt145478957 _Hlt74937228 prostateca _Hlt153099068 _Hlt156128805 _Hlt77481667testestesticularinfection _Hlt163625074orchitistesticularcancer _Hlt160953673 _Hlt160953628 _Hlt160953596 _Hlt154412852 _Hlt158431824 _Hlt158431796 _Hlt160953654 _Hlt77519474 _Hlt77519503germcelltumors Seminomatousseminomaspermatocyticseminomansgct _Hlt77427726 _Hlt77430585 _Hlt77427739 _Hlt77427742 _Hlt77430789embryonalcarcinomachoriocarcinoma _Hlt145479209 _Hlt78823252leydigcelltumor _Hlt77519502sertolicelltumortesticularlymphomarenalneoplasms bladdercancer bladderca _Hlt158171312 _Hlt158171205 _Hlt461805576 development _Hlt465092907 _Hlt476384759 _Hlt490478052 _Hlt60432698 _Hlt79246514 _Hlt79246528 _Hlt80845800 _Hlt80845802 _Hlt521584951 _Hlt157835383 _Hlt461267132 _Hlt464813100 _Hlt79248839 _Hlt465181343 _Hlt464812191 _Hlt464812228 _Hlt79248725 _Hlt79247832 _Hlt79248695 _Hlt79248707 _Hlt79248181 _Hlt79249841 _Hlt79248572 _Hlt79249839 _Hlt79246484 _Hlt60432676 _Hlt79248224 _Hlt79248213 _Hlt465415205 _Hlt79248238 _Hlt461422345 _Hlt79247221 _Hlt465415421 _Hlt465415522 _Hlt79248203 _Hlt79248233 _Hlt79247216 _Hlt79247293 _Hlt79248254 _Hlt79248261 _Hlt79247364 _Hlt79248543 _Hlt79246508 _Hlt79248066 _Hlt164137038 _Hlt79248336 _Hlt475100021 _Hlt460810430 _Hlt79247774 _Hlt79248396 _Hlt466039633 _Hlt79247765 _Hlt79247248 _Hlt465580583 _Hlt465415268 _Hlt79247268 _Hlt79247280 _Hlt147049179 _Hlt465415722 _Hlt147048898 _Hlt147049816 _Hlt147050327 _Hlt465415676 _Hlt465415340 _Hlt79246317 _Hlt79249007 _Hlt79246366 _Hlt79246704 _Hlt465418890 _Hlt462317610 _Hlt462317667 _Hlt466428939 _Hlt465087288 _Hlt464809597 _Hlt465081660 _Hlt79248097 _Hlt464808533 _Hlt79247456 _Hlt464808357 _Hlt464808226 _Hlt464807335 _Hlt464808467 _Hlt156037857 _Hlt156393240 _Hlt156393241 _Hlt79247864 _Hlt79248904 _Hlt465176050 _Hlt79248130 _Hlt79248888 _Hlt465086229 _Hlt79248136 _Hlt465414041 _Hlt79248944 _Hlt79248959 _Hlt464438642 _Hlt79248106 _Hlt79248121 _Hlt461266068 _Hlt465082149 _Hlt465414275 _Hlt79246482 _Hlt79245977 _Hlt79246007 _Hlt79248990 _Hlt79246698 _Hlt79248372 _Hlt79248931 _Hlt79248922 _Hlt79248964 _Hlt79245998 _Hlt490817838 _Hlt162615596 _Hlt462317702 _Hlt465091340 _Hlt464438491 _Hlt77055070 _Hlt77416336 _Hlt79246135 _Hlt466039786 _Hlt465743910 _Hlt79246929 _Hlt466039685 _Hlt464920820 _Hlt79246912 _Hlt79246953 _Hlt79246726 _Hlt79248967 _Hlt464920965 _Hlt79246853 _Hlt464742810 _Hlt79247785 _Hlt79247058 _Hlt79247091 _Hlt79247914 _Hlt79247083 _Hlt79247087 _Hlt79247946 _Hlt79247985 _Hlt79247999 _Hlt79247949 _Hlt79248034 _Hlt79248780 _Hlt460808519 _Hlt461265203 _Hlt464716012 _Hlt461265235 teratogenesismaternal morphogenesis _Hlt79247246 _Hlt79248215 _Hlt79248226 _Hlt463269005 disrupted _Hlt79248260 _Hlt521666632 _Hlt79248343 _Hlt475099997pedrespiratory _Hlt475100046 _Hlt475100060 _Hlt79246436 _Hlt79246434 surfactant _Hlt521666634 _Hlt460809781lungmalformations pedpulmonarybpd _Hlt460809736 _Hlt78628385 _Hlt79247430 pediatricheme _Hlt79247775 bilirubin pedbilirubin _Hlt466039972 _Hlt79247250 _Hlt79247278 _Hlt79247283 _Hlt62883934abo _Hlt147049075 _Hlt147049081 _Hlt154412302 _Hlt154412303 _Hlt145489801rh _Hlt79247362 _Hlt466039832 _Hlt466039849crigler _Hlt466039784gilberts dubinjohnsonrotors _Hlt79246487 _Hlt79248408 pedintestinal _Hlt148118326 _Hlt79247388meckels _Hlt77257379 _Hlt145655257 _Hlt466015811 _Hlt79246357pediatricliver _Hlt473440819 _Hlt78966093 _Hlt473440812 _Hlt164502121 _Hlt164502122 _Hlt461265880 _Hlt475100008pedheart _Hlt164148199 _Hlt465418894 _Hlt490880694 _Hlt79246367 _Hlt79246705 _Hlt493752653 _Hlt490818277 _Hlt490818280 _Hlt490818282 _Hlt490818380 _Hlt490818353 _Hlt163552398 _Hlt490818443 _Hlt490818472 _Hlt490818565 _Hlt490818666 _Hlt497801930 _Hlt469929137asd _Hlt490818278 _Hlt152560305vsd _Hlt490818281tof transpositionavmalformationsavvalvemalformations patentductus _Hlt490818447 coarctation _Hlt79245999 _Hlt79246009 _Hlt79246483 _Hlt79246702 _Hlt79248379 _Hlt79248925 _Hlt79248939 _Hlt79572144 _Hlt79572196 _Hlt464922215 _Hlt469067769 _Hlt492347694 _Hlt79246914 _Hlt79246933pediatricneuro _Hlt79247865 _Hlt79248986 _Hlt79247857 _Hlt79248060 pedtumorschildhoodtumors _Hlt465086380 _Hlt465176176 _Hlt465414371 _Hlt465176297 _Hlt465414753 _Hlt467064069 _Hlt465092647 histiocytosis histiocytoses _Hlt158026991hsc _Hlt79248133 pedtumorrenal _Hlt79248143 pedcnstumors neuroblastoma _Hlt467064076ganglioneuroma _Hlt79245183 _Hlt79245192 _Hlt79245240craniopharyngioma _Hlt78628822 _Hlt78628889 _Hlt78628796 _Hlt79245239 _Hlt465414226 pedtumorother _Hlt78628959 _Hlt78888051 _Hlt79248955genetic _Hlt79248966 _Hlt79244782 _Hlt79244834 _Hlt79244791 _Hlt79244749 _Hlt79244744 _Hlt79244728 _Hlt79244874 _Hlt79245915 _Hlt79245897 _Hlt158457489 _Hlt158457498 _Hlt158456944 _Hlt79245627 _Hlt79245647 _Hlt79245635 _Hlt79245716 _Hlt79245728 _Hlt79245571 _Hlt79245447 _Hlt79245477 _Hlt79245465 _Hlt79245453 _Hlt79245493 _Hlt79245564 _Hlt79245579 _Hlt164137196 _Hlt79245597 _Hlt164136999 _Hlt462317704 _Hlt462318261downs _Hlt462318402 _Hlt490818604turners Klinefeltersedwards _Hlt79245572marfans praderwilliapertsbloomsdeafness _Hlt490818181jln _Hlt465006712 _Hlt147760226 syndromesbwswilliamsfragilexpotters _Hlt465078964 nephrogenic _Hlt79248962 metabolic _Hlt155715415 _Hlt79666568 _Hlt491413885 _Hlt492310958 _Hlt491413939 _Hlt79246776 _Hlt79666570 aminoacids _Hlt467144264 _Hlt475768398 _Hlt481660843 _Hlt492310685 _Hlt475768337homocystinuria _Hlt145480374 _Hlt471743367 _Hlt472666123 _Hlt148366578 _Hlt78466779 _Hlt79666580 _Hlt79666572 _Hlt78467006 porphyria _Hlt521669264 _Hlt78554683 _Hlt78554692 _Hlt79666582 _Hlt521667140pct _Hlt78824298porphyriacutaneatarda carbohydratesotherenzymedeficiencies _Hlt79247066 leschnyhan _Hlt466039826 _Hlt466039847 _Hlt475712220 _Hlt79246847lysosomalstoragediseaseslysosomalstorage _Hlt490201592 _Hlt490201593gauchers _Hlt146613516fabrys _Hlt153169759 _Hlt77225132 _Hlt77225621 _Hlt519793812 _Hlt77225377 _Hlt77225466 _Hlt77225467 _Hlt77225629 _Hlt519793773 _Hlt79246884mucopolysaccharidoses _Hlt79247922glycogenstorage _Hlt79247991hepatichypoglycemia _Hlt79248005 _Hlt162778088 _Hlt162778089 _Hlt79248646muscleenergydisorders pedmuscle _Hlt79247140 _Hlt457983834mcardles _Hlt469334310 _Hlt156812197 _Hlt469334333 _Hlt79249002 _Hlt79248689 _Hlt79248699 _Hlt79248709 _Hlt79248727 _Hlt79248911 metabolism _Hlt475100042 _Hlt79248086 _Hlt79248117 endocrine _Hlt79248900 _Hlt155715356 _Hlt78627759 _Hlt78627772 _Hlt486748025 _Hlt463269551 _Hlt467069487 _Hlt145755329 _Hlt77168686 _Hlt77168688 _Hlt77142817 _Hlt77142828 _Hlt145843959 _Hlt145844009 _Hlt467070629 _Hlt489886766 _Hlt489886767 _Hlt490363448 _Hlt490363449 _Hlt467071541 _Hlt467070715 _Hlt474471650 _Hlt465739128 _Hlt77170951 _Hlt467070784 _Hlt77168590 _Hlt77168684 _Hlt77168690 _Hlt486748062 _Hlt490797697 _Hlt463268819 _Hlt467070758 _Hlt467071630 _Hlt486747915 _Hlt463269379 _Hlt146798802 _Hlt78630768 _Hlt79147629 _Hlt78630757 _Hlt79149359 _Hlt468345103 _Hlt78631363 _Hlt467070876 _Hlt503451504 _Hlt503451505 _Hlt515818726 _Hlt467070866 _Hlt145759997 _Hlt145759914 _Hlt469066466 _Hlt467070834 _Hlt77234458 _Hlt467071339 _Hlt475782415 _Hlt463269250 _Hlt463268995 _Hlt467070949 _Hlt467071368 _Hlt467071419 _Hlt463269007 _Hlt463269152 _Hlt146798835 _Hlt77139859 _Hlt467071283 _Hlt467071009 _Hlt467071140 _Hlt463269299 _Hlt77174285 _Hlt463269001 _Hlt503454233 _Hlt499697293 _Hlt467063282 _Hlt499696809 _Hlt157920715 _Hlt146798627 _Hlt146798691 _Hlt465178144 _Hlt497723098 _Hlt463269305 _Hlt77142835 _Hlt79147263 _Hlt472678545 _Hlt472681182 _Hlt146798757 _Hlt467071226 _Hlt79147660 _Hlt467063780 _Hlt499696818 _Hlt467063755 _Hlt79147709 _Hlt499697409 _Hlt146798595 _Hlt148350362 _Hlt148350478 _Hlt474471366 _Hlt79147683 _Hlt79147700 _Hlt79297270 _Hlt146798720 _Hlt79147317 _Hlt77142284 _Hlt77142814 _Hlt467063880 _Hlt467071493 _Hlt78972745 _Hlt469930313 _Hlt77173988 _Hlt77174295 _Hlt467064007 _Hlt467064087 _Hlt467064056 _Hlt474483731 _Hlt519786238 _Hlt475710251 _Hlt475710651 _Hlt79241061 _Hlt79241149 _Hlt494727933 _Hlt467325918 _Hlt467834558 _Hlt472674901 _Hlt467325884 _Hlt145987234 _Hlt145988346 _Hlt57990281 _Hlt62706980 _Hlt62706995 _Hlt147999550 _Hlt23176789 _Hlt23176664 _Hlt57989866 _Hlt23176950 _Hlt23176837 _Hlt467324272 pituitary _Hlt463269552 pituitarylabs _Hlt148000077 _Hlt148000019diabetesdm _Hlt57990602 _Hlt147999495 _Hlt23176786 _Hlt79397012 _Hlt79397023 _Hlt79397486 _Hlt156891649 _Hlt156891641 _Hlt156891547 _Hlt145987382 _Hlt145987395 _Hlt145987531 _Hlt161481933 _Hlt79241148 _Hlt156209296digiami _Hlt79566104dmhyperlipidemia _Hlt57990590 _Hlt79396230 _Hlt79396251 _Hlt79397487 _Hlt145987572dka _Hlt145566982 _Hlt145567000 _Hlt145567252 _Hlt145566867 _Hlt146880187alcoholicketoacidosispituitaryadenomapituitaryadenomas acromegaly _Hlt145739037 _Hlt146603651 _Hlt145486858corticotrophicadenoma _Hlt77142876 _Hlt77142827 _Hlt145487265 hypopituitary _Hlt145844008 _Hlt78628781 _Hlt78628887 _Hlt78628894 _Hlt78628941 _Hlt78628960 _Hlt465414602posteriorpituitarydiabetesinsipidus _Hlt145752570 _Hlt147031700 _Hlt147031718 _Hlt57440867 _Hlt148005395 _Hlt148005423 _Hlt148005418 _Hlt465078976 _Hlt465078978siadh _Hlt147760978 _Hlt474471699thyroid _Hlt77171067 _Hlt77171020 _Hlt77171033 _Hlt157920519 _Hlt503448819 _Hlt79298040 _Hlt145758999 _Hlt145759000 _Hlt145759032 _Hlt145759088tfts _Hlt77168683thyroidmalformations _Hlt457982203hyperthyroidism _Hlt522270544 _Hlt77171029 _Hlt79147632 _Hlt145739009 _Hlt146798804 _Hlt157056181 _Hlt145759842 _Hlt77168842 _Hlt490796915 _Hlt490796916 _Hlt497480644 _Hlt77171058 _Hlt145759802 _Hlt145759908 _Hlt145488111graves _Hlt466022693 _Hlt466022857 _Hlt524440542 _Hlt524442573 _Hlt146621765 _Hlt146621784 _Hlt466022687 _Hlt145489494lidlag _Hlt146889996 _Hlt146884339 _Hlt146884340 _Hlt146890705 _Hlt146891444 _Hlt146890701hypothyroidism _Hlt157920521 _Hlt157920711 _Hlt79149050 _Hlt79149012 _Hlt79149358hypothryoidismpregnancyhypothyroidismofpregnancy _Hlt79149052 thyroiditis _Hlt79298041 hashimotossubacutethyroiditis _Hlt147286063thyroidneoplasms _Hlt146890677 _Hlt146890702 _Hlt146891446 _Hlt467071347 _Hlt486759190 _Hlt481212871 _Hlt77237978 _Hlt79245203 _Hlt79245206 _Hlt77237960 _Hlt467070868 _Hlt467070909 parathyroid _Hlt463269261 _Hlt79147314pthvitamind _Hlt158457763 _Hlt472666700 _Hlt522270524 calcitoninpthrphyperpth _Hlt522270562 _Hlt146798836 _Hlt79147622 _Hlt146605989 _Hlt467755302 _Hlt79147612 _Hlt521668330 _Hlt77170892 _Hlt77170909parathyroidhyperlasiaparathyroidneoplasmsparathyroidadenoma _Hlt457982117 _Hlt467071358 _Hlt145489268 _Hlt145489257parathyroidcarcinoma _Hlt467071325 _Hlt77142252 _Hlt145489215 _Hlt467071128hypoparathyroidhypopth _Hlt77142832 _Hlt465579400 _Hlt490365233 _Hlt465091920 _Hlt490365289 _Hlt9788375 _Hlt9788376 _Hlt490365275 _Hlt496252284pseudohypoparathyroid pseudohypopth albrights _Hlt499696812adrenal _Hlt79147265 _Hlt145739041cushings _Hlt146798628 _Hlt146798692 _Hlt77142809 _Hlt77142813 _Hlt77142870 _Hlt77142845 _Hlt153196030nelsons _Hlt467063759 _Hlt79147664adrenaladenomaadrenalcarcinomaadrenallymphoma _Hlt79147712 _Hlt145739076 _Hlt467071228primaryhyperaldosteronismpha _Hlt467063879 _Hlt79147342 _Hlt474471344 _Hlt520650081 _Hlt520650184 _Hlt79147692 _Hlt79147704 _Hlt146798722conns _Hlt157919261 _Hlt79147338 _Hlt163650028cah _Hlt156281958 _Hlt146798759adrenalhyperplasia _Hlt467063793 _Hlt79147389 _Hlt79147417 _Hlt474471325 _Hlt79147270 _Hlt79147797adrenalinsufficiencyaddisons _Hlt146603654 _Hlt146798597 _Hlt146799258 _Hlt146799285 _Hlt148350658 _Hlt148350543 _Hlt148350470 _Hlt148351058 _Hlt148351050 _Hlt148351051adrenalmedullapheochromocytoma _Hlt78972752 _Hlt145739039 _Hlt467063966 _Hlt77174317 _Hlt145487649 _Hlt145488113 _Hlt77174282 _Hlt77174304 _Hlt525054613 _Hlt490820379 _Hlt77174101 _Hlt145742862 _Hlt77174050 _Hlt77174032 _Hlt467063429 _Hlt77174013 paraganglioma _Hlt467064040 _Hlt467064113 _Hlt457206208 infectious _Hlt519619139 _Hlt466640661 _Hlt147031212 _Hlt147031726 _Hlt147031111 _Hlt147031727 _Hlt521582924 _Hlt466640665 _Hlt520135143 _Hlt466640592 _Hlt466640658 _Hlt28369881 _Hlt147031731 _Hlt473003114 _Hlt147029245 _Hlt147030687 _Hlt147030700 _Hlt147031064 _Hlt147031725 _Hlt147030905 _Hlt147031060 _Hlt473606352 _Hlt467170465 _Hlt19968757 _Hlt77600437 _Hlt466640652 _Hlt19967342 _Hlt466723154 _Hlt77593826 _Hlt492523475 _Hlt77137650 _Hlt77138013 _Hlt492523440 _Hlt521583314 _Hlt521584459 _Hlt521584461 _Hlt25325665 _Hlt491215312 _Hlt491917599 _Hlt492006202 _Hlt521584469 _Hlt521584544 _Hlt521584901 _Hlt77136830 _Hlt77137072 _Hlt77138497 _Hlt77138632 _Hlt77138649 _Hlt156396583 _Hlt77137028 _Hlt467836996 _Hlt492522923 _Hlt77138475 _Hlt490964832 _Hlt77136043 _Hlt77136088 _Hlt465738070 _Hlt156396357 _Hlt492524442 _Hlt490797827 _Hlt466640632 _Hlt145988439 _Hlt520445364 _Hlt28370124 _Hlt145654951 _Hlt475677380 _Hlt489505953 _Hlt489505975 _Hlt77674435 _Hlt78628971 _Hlt491963305 _Hlt491963306 _Hlt519786672 _Hlt464925873 _Hlt465487845 _Hlt145654919 _Hlt465487675 _Hlt491317649 _Hlt466731756 _Hlt490896572 _Hlt461266185 _Hlt467324600 _Hlt491317731 _Hlt461267256 _Hlt78627567 _Hlt78627524 _Hlt145320228 _Hlt79571259 _Hlt79571289 _Hlt491971462 _Hlt460926612 _Hlt463751139 _Hlt467325619 _Hlt490896541 _Hlt493051701 _Hlt493051702 _Hlt493048012 _Hlt491963052 _Hlt515706407 _Hlt520445433 _Hlt520445407 _Hlt520445411sepsis _Hlt145988389 _Hlt481129104 _Hlt158349882 _Hlt158349883lacticacidosis _Hlt79666632 _Hlt79666612 _Hlt79666631 _Hlt466640594 _Hlt521582928primary _Hlt28369901uti _Hlt147031871 _Hlt473003087 _Hlt147031748 _Hlt147031836 candidauti _Hlt466723114 peritonitis _Hlt490797624 _Hlt490964822 cellulitis _Hlt504713169 _Hlt491101365 _Hlt491101366 _Hlt492524969 _Hlt155853767 _Hlt155853768 fasciitis Mediastinitis _Hlt147122523pharyngitisadult _Hlt152575241 _Hlt504713226 _Hlt152575362 _Hlt152575363 _Hlt152575275_osteomyelitishematagenous_osteomyelitishematogenous_osteomyelitisvertebral osteomyelitis _Hlt491012063 _Hlt491012060 _Hlt163133493 _Hlt491315955 _Hlt491315910 _Hlt491315911 _Hlt491315992 _Hlt491315928 _Hlt491316032 _Hlt491316002 _Hlt491316206 _Hlt491316222 _Hlt492524499osteomyelitiswbcscan _Hlt520445436 _Hlt520445393osteomyelitishematogenous _Hlt491316033osteomyelitiscontiguous _Hlt491316223osteomyelitisvertebral _Hlt152560894osteomyelitischronicosteomyelitisvascular antibioticprophylaxisbonesurgery _Hlt79572342 _Hlt163552985osteomyelitisrx _Hlt491012061epiduralabscess _Hlt152560898 _Hlt156464981 _Hlt156891306 meningitis _Hlt77138373 _Hlt78368566 _Hlt78369048 _Hlt78441760 _Hlt146950492 _Hlt78369289 _Hlt146436146 _Hlt25331227 _Hlt77138544 _Hlt77138473 _Hlt77138509 _Hlt77138524 _Hlt156396359 _Hlt146435650 _Hlt77138463 _Hlt146435639 _Hlt146436033asepticmeningitis _Hlt78368661 _Hlt78368879 _Hlt156396699 _Hlt467757603 _Hlt467757610 _Hlt491099105 _Hlt78369222 _Hlt78369184 _Hlt521585560viralmeningitis _Hlt23007894 _Hlt23007895 _Hlt521585890 _Hlt147157370 _Hlt147157371 _Hlt77138647 _Hlt77138638 _Hlt214342865 _Hlt521587127 _Hlt521587128 _Hlt147157317 _Hlt147157324 _Hlt157494996hsvencephalitis _Hlt465737942 _Hlt465737943 _Hlt465738005 _Hlt78368423 _Hlt78368991 _Hlt146787960 _Hlt146787987 _Hlt33354379 _Hlt33354380 _Hlt466016094 _Hlt465152828 _Hlt465180041 _Hlt521585530pmljc _Hlt491098942 _Hlt31641177 _Hlt31641178 _Hlt23008083 _Hlt23008108 _Hlt78368819 _Hlt492298819 _Hlt493067968bacterialmeningitis _Hlt77138496 _Hlt146435647 _Hlt77138685 _Hlt77138570 _Hlt146434499 _Hlt146435693 _Hlt146436021 _Hlt77138583 _Hlt77138687 _Hlt163134586 _Hlt163116992 _Hlt146435539 _Hlt146435878 _Hlt146436145 _Hlt146435978 _Hlt146435944 _Hlt146436131 _Hlt146436148 _Hlt146436020 _Hlt77138542 _Hlt156396408 _Hlt146437339 _Hlt146437342lp _Hlt154462230 _Hlt147157320 _Hlt147157323 _Hlt163133782latexagglutinationpanel _Hlt147157322 _Hlt146436287 agemeningitis _Hlt77138686meningitisorganisms _Hlt77138689chronicmeningitis _Hlt145654925 hematologic _Hlt154462957 _Hlt154462958 _Hlt156057869 _Hlt156057960 _Hlt154462993 granulomatis catscratch _Hlt23007582 _Hlt480071958 _Hlt463763543 _Hlt463763532ebv _Hlt461421046 _Hlt463750804leischmaniasis _Hlt154462527malaria _Hlt156891347 filariasishtlv1 _Hlt475677321sexual _Hlt155843368 _Hlt467073542 _Hlt475450445 _Hlt465738943 _Hlt469207042 _Hlt154463079 _Hlt490896902 _Hlt477684172 _Hlt478786470 _Hlt478786471 _Hlt478786354 _Hlt478786368 _Hlt478786405 _Hlt478786400 _Hlt478786401 _Hlt461261260 _Hlt461261261 _Hlt461260916 _Hlt461261286 _Hlt477684686 _Hlt477684629 _Hlt477684618 _Hlt461261431 _Hlt477685356 _Hlt461261417 _Hlt467330405 _Hlt464925926exotic _Hlt155843183 _Hlt155843184 _Hlt461266175fuodevelopmentimmune pedimmune _Hlt460933615pediatricinfectious _Hlt461267259 _Hlt79248840 childhood _Hlt79248827 _Hlt462037125 _Hlt157835288 _Hlt157835393 _Hlt464926417 _Hlt464926418 _Hlt464924185 _Hlt461420809 _Hlt461797435 _Hlt461797436 _Hlt461420839 _Hlt465139131 _Hlt486580404 _Hlt486580375 _Hlt461421025 _Hlt461865801 _Hlt463750800 _Hlt461282833 _Hlt461277900 _Hlt461330811 _Hlt463751599 _Hlt461263590 _Hlt463751669 _Hlt461265733 _Hlt461330807 _Hlt145655081 _Hlt461278217 _Hlt503185435 _Hlt461378608 _Hlt465175679 _Hlt467325520 _Hlt461330893 _Hlt465413402 _Hlt461285487 _Hlt464925760 _Hlt464925761 _Hlt521584501 _Hlt465152803 _Hlt461468323 _Hlt463233676 _Hlt464925544 _Hlt465175592 _Hlt461797468 _Hlt464813105 _Hlt467135227 _Hlt521584957 _Hlt461285495 _Hlt461797611 _Hlt461797451 _Hlt461266530 _Hlt463750811 _Hlt461808397 _Hlt467336722 _Hlt467336723 _Hlt461808226 _Hlt462745925 _Hlt462681988 _Hlt465185245 _Hlt461263856 _Hlt148118759 _Hlt490897217 _Hlt461808339 _Hlt148118537 _Hlt461285618 _Hlt490797909 _Hlt34068296 _Hlt462206758 _Hlt465139388 _Hlt461266757 _Hlt465176674 _Hlt461265446 _Hlt461809524 _Hlt461265519 _Hlt461264787 _Hlt461265129 _Hlt461265578 _Hlt461265520 _Hlt461266759pediatricsepsis pedsepsis _Hlt481129105 _Hlt490897545 _Hlt490897546 _Hlt461266532heentpedsconjunctivitis _Hlt157835336 _Hlt157835356 _Hlt157835315 _Hlt157835357 _Hlt157835394otitis otitismedia _Hlt461257405 _Hlt461257399 _Hlt461331708oititisexterna sinusitis _Hlt146519874 herpangina _Hlt147133023 _Hlt163118297 _Hlt163118295 _Hlt163118311 _Hlt163118293 _Hlt163118323 _Hlt78794222 pharyngitis _Hlt78794235 _Hlt57431402 _Hlt57431376 _Hlt491311293 _Hlt461258535 _Hlt461258536 _Hlt475200461 _Hlt462147977 _Hlt462147978 _Hlt461260002 epiglottitis _Hlt461797441 _Hlt145938676 _Hlt145938677 _Hlt486580371 _Hlt461277640 _Hlt461277641pedlungs bronchiolitis _Hlt461330808 _Hlt461330813rsv _Hlt461933745 _Hlt461933746 _Hlt461933500 _Hlt463751910 _Hlt463751978croup tracheitis _Hlt485361341 _Hlt79666945 _Hlt79666951 pertussis _Hlt461420844 _Hlt461279798 _Hlt461279799 _Hlt465139287 _Hlt475890341 _Hlt465139276childhoodpneumonia _Hlt461453428 _Hlt465577503 _Hlt461281065 _Hlt461281066 _Hlt461280619 _Hlt461280620 _Hlt465175700 _Hlt461281975 _Hlt461263784 _Hlt466016038 _Hlt77138471childhoodmeningitis _Hlt77138462 _Hlt79666976 _Hlt79667038 _Hlt79666969 _Hlt20902896 _Hlt20902904 _Hlt466016388 _Hlt461795315 _Hlt464813126 _Hlt466016399 _Hlt466016226peduti childhooduti _Hlt461809551congenitalinfections congenital _Hlt519431950 _Hlt519431951hsv exanthemsexanthem _Hlt147140711 _Hlt147140313 _Hlt464925294 _Hlt155950712 _Hlt155950713 _Hlt155854199 _Hlt155854200 opportunistic _Hlt465655673 _Hlt465655674 _Hlt490965107 _Hlt465655764 _Hlt465655958 _Hlt465655743 _Hlt465655744 _Hlt465655725 _Hlt465655730 _Hlt465655772 _Hlt465655518 _Hlt465655569 _Hlt465655560 _Hlt465655561 _Hlt465655897 _Hlt465655898 _Hlt145314746 _Hlt491317982 splenectomy _Hlt28369351 _Hlt146179242 _Hlt156542028 _Hlt28369661 _Hlt79571287 _Hlt457206727 _Hlt77578319 _Hlt78627742gi _Hlt9508656 _Hlt60873899 _Hlt60874024 _Hlt60874025 _Hlt76892021 _Hlt76890294 _Hlt57990976 _Hlt79576773 _Hlt57991187 _Hlt57991188 _Hlt76957065 _Hlt76957090 _Hlt80028259 _Hlt465657118 _Hlt484062410 _Hlt145412399 _Hlt485359562 _Hlt20061296 _Hlt482245934 _Hlt482245919 _Hlt468435787 _Hlt468435841 _Hlt468435610 _Hlt468435672 _Hlt481754895 _Hlt58836009 _Hlt76898874 _Hlt468435675 _Hlt468435677 _Hlt468435537 _Hlt468435680 _Hlt468435693 _Hlt468435696 _Hlt469192068 _Hlt484062414 _Hlt20060987 _Hlt469067977 _Hlt20061053 _Hlt58835967 _Hlt76893571 _Hlt77417374 _Hlt469068042 _Hlt57991343 _Hlt20061042 _Hlt77417493 _Hlt77417495 _Hlt77417508 _Hlt77417528 _Hlt466467706 _Hlt58835851 _Hlt78888057 _Hlt78888706 _Hlt484063301 _Hlt76921833 _Hlt467750947 _Hlt465419343 _Hlt56600177 _Hlt56600106 _Hlt58835855 _Hlt56600116 _Hlt56600185 _Hlt56602918 _Hlt57965052 _Hlt57965053 _Hlt58835877 _Hlt56600112 _Hlt20061193 _Hlt58835866 _Hlt162778399 _Hlt462234116 _Hlt482612034 _Hlt145479212 _Hlt484063292 _Hlt484063188 _Hlt484063189 _Hlt475713243 _Hlt462233712 _Hlt475449437 _Hlt485360614 _Hlt485359707 _Hlt485359914 _Hlt485359879 _Hlt482611792 _Hlt475713066 _Hlt475713109 _Hlt77416393 _Hlt148118314 _Hlt148118178 _Hlt148118382 _Hlt148118267 _Hlt148118293 _Hlt148118262 _Hlt148118485 _Hlt145489504 _Hlt145489519 _Hlt80763536 _Hlt80763747 _Hlt78727324 _Hlt156997839 _Hlt145412192 _Hlt145414228 _Hlt156997778 _Hlt153172696 _Hlt153173090 _Hlt212527878 _Hlt153173113 _Hlt153173094 _Hlt145742263 _Hlt77416598 _Hlt475713125 _Hlt475713322 _Hlt483465653 _Hlt484331880abdominalworkup _Hlt475713107 _Hlt475713113 _Hlt20903016 _Hlt20903006 _Hlt79667044 _Hlt20903032 _Hlt163113703 _Hlt79576597 _Hlt79667046 _Hlt163113708diarrhea _Hlt78627540 _Hlt78627558 _Hlt163113760 _Hlt156997305 _Hlt148086269 _Hlt156997296 _Hlt156997297 _Hlt158457768 _Hlt158457764 _Hlt158457796 _Hlt158458136 _Hlt158457762stoolosmolality _Hlt148085944 _Hlt148085945 _Hlt148085948 _Hlt148086021 _Hlt148086022 _Hlt148085735 _Hlt79245589 _Hlt157829308 _Hlt157829309 _Hlt157828508 _Hlt157828509oral _Hlt465419338 _Hlt57976215 _Hlt79667050 _Hlt57976155 _Hlt57976166 _Hlt57976174 _Hlt57976183 _Hlt79667057 _Hlt57976169 _Hlt519791289 _Hlt462317964 _Hlt472583910 _Hlt57976277 _Hlt79667236salivary esophaguszenkers _Hlt482245936esophagealwebs _Hlt482245921 _Hlt79667083 _Hlt79667084 _Hlt468344861 _Hlt468344843esophagealringshernias _Hlt468435845esophagealinjury _Hlt468435674gerd _Hlt58773811 _Hlt58836935 _Hlt58836752 _Hlt146519942 achalasia _Hlt80026856 _Hlt80026857 _Hlt80027139 _Hlt482245974 _Hlt468435678transferdysphagiasdedsdes _Hlt468435694 _Hlt148118222sclerodermaesophagus _Hlt468435715 _Hlt518748432 _Hlt518748433esophagealcancerbarretts _Hlt58773814 _Hlt469192073 _Hlt468344258 _Hlt58836000stomach _Hlt77269569 _Hlt79667092 _Hlt145412406 _Hlt77269586 _Hlt156465173 _Hlt473642907 _Hlt504711064 _Hlt491565400 _Hlt524443873pud _Hlt20061038 _Hlt148085568 _Hlt148085569hpylori _Hlt77416106 _Hlt80027838gastricvarices _Hlt77417494gastriccarcinoma _Hlt77417501gastriclymphoma _Hlt77415974 _Hlt77415928 _Hlt77415940 _Hlt77415918 intestineintestinevascular _Hlt462234205 _Hlt20060862 _Hlt77416382 _Hlt20060705varices givarices _Hlt20060677 _Hlt57991242 _Hlt76957088 ischemicbowelmesentericischemia _Hlt148118286 _Hlt76891883 _Hlt73770638 _Hlt73770646 _Hlt79667107 avmintestinal _Hlt148118427infectiousdiarrhea _Hlt461797603 _Hlt461263459 _Hlt461263460 _Hlt461263278 _Hlt73769238 _Hlt79667110 _Hlt156465246 _Hlt466965257 _Hlt462194929 _Hlt462194930 _Hlt148091826 _Hlt148091827 _Hlt148091990 _Hlt462194521 _Hlt462234306 _Hlt148091883 _Hlt462194690 _Hlt462194691 _Hlt462195129 _Hlt526000573 _Hlt526000596 _Hlt462195060 _Hlt462195061 _Hlt148118380 _Hlt526000790 _Hlt526000791nec _Hlt491433313 _Hlt155850004 _Hlt155850046 _Hlt511380052 _Hlt511380065 malabsorption _Hlt158090525 _Hlt158090530 _Hlt73770944 _Hlt156465268 _Hlt148083788 _Hlt155959419 _Hlt155959420celiac celiacsprue _Hlt77256926 _Hlt77256949 _Hlt77256950 _Hlt77256959 _Hlt77256971 _Hlt77256972 _Hlt78727788 _Hlt73769102 _Hlt77257453 _Hlt78727720 _Hlt156465275 _Hlt79667114 _Hlt468344366 _Hlt80763631 _Hlt80763746 _Hlt145489518 _Hlt77257256 _Hlt77257257 _Hlt77257273 _Hlt77257381 _Hlt156468225 _Hlt156468194 _Hlt473439842whipples _Hlt154462976 _Hlt155695683 _Hlt155695684 _Hlt77270954 _Hlt79667116 _Hlt79667143 _Hlt77270927 _Hlt154463011bacterialovergrowthlactasedeficiency _Hlt77416453 _Hlt77416465ibd _Hlt472675030 _Hlt472675808 _Hlt473208355 _Hlt473208356 _Hlt472674832crohns _Hlt145822523 _Hlt20060013 _Hlt145822148 _Hlt485212366 _Hlt485212262 _Hlt76963116 _Hlt146799907ulcerativecolitisuc _Hlt155852984 _Hlt155852985 _Hlt145822576 _Hlt145822747 _Hlt145822686 _Hlt73769579 _Hlt79667257 _Hlt145822613 _Hlt156465285 _Hlt73769575 ibdtreatment _Hlt148083893 _Hlt518889973 _Hlt79667283 _Hlt79575981 _Hlt79667322 _Hlt79575971 _Hlt156465306 _Hlt79575968 _Hlt79667323diverticulitisdiverticulosis _Hlt79576445 _Hlt146346835avcolon obstructions obstruction _Hlt485360676 _Hlt79667335intussusception _Hlt79576287 _Hlt79576305 _Hlt162598683gitumorsintestinaltumorsintestinaltumorjuvenilepolyposis _Hlt57976279 peutzjeghers _Hlt153173111 _Hlt79667344 _Hlt79667350 _Hlt480205519fapgardnersturcotscarcinoidtumors carcinoid _Hlt148947710 _Hlt148947632 gilymphoma _Hlt77417369colonca coloncancer _Hlt156997780 _Hlt485730651 _Hlt485730652 _Hlt481752614 _Hlt158171104appendix appendicitis _Hlt482611789 peritoneum _Hlt484063297peritonealinfectionsbppancreas _Hlt58835853 pancreatitis _Hlt145820218 _Hlt145820322 _Hlt475710649 _Hlt465656366 _Hlt465656367 _Hlt145820194 _Hlt145820203 _Hlt145321121hyperamylasemiaransonschronicpancreatitispancreaticcarcinoma _Hlt77514458 _Hlt77515610 _Hlt77514450 gastrinomazes _Hlt148003986men _Hlt77142270 _Hlt77237994 _Hlt79245205 _Hlt145489218 gallbladder _Hlt56600114 _Hlt56600223 _Hlt58835868 _Hlt78966206 _Hlt80029158mrcpcholelithiasis gallstones _Hlt145820321 _Hlt145820672 cholecystitis _Hlt56600431 _Hlt56602916 cholangitis _Hlt146799971spleen _Hlt145477587 _Hlt145477540liver _Hlt466466825 _Hlt473440814 _Hlt481118749 _Hlt56600108 _Hlt56600179 _Hlt58835859 _Hlt58835880 _Hlt155845214 _Hlt77578322 _Hlt492347802 _Hlt466467029 _Hlt466044585 _Hlt492288034 _Hlt76955307 _Hlt76955308 _Hlt467412200 _Hlt491414100 _Hlt523052729 _Hlt499791501 _Hlt520443189 _Hlt76955441 _Hlt492056723 _Hlt156542491 _Hlt520443329 _Hlt520443288 _Hlt20060130 _Hlt145744434 _Hlt145744443 _Hlt520443376 _Hlt520443437 _Hlt145744489 _Hlt467411327 _Hlt76963246 _Hlt466889394 _Hlt145320805 _Hlt145321123 _Hlt76963274 _Hlt145321031 _Hlt145321122 _Hlt145321023 _Hlt78966204 _Hlt56600135 _Hlt76960342 _Hlt56600220 _Hlt56600234 _Hlt56602917 _Hlt57965578 _Hlt57965187 _Hlt57965258 _Hlt20060102 _Hlt490202667 _Hlt491922105 _Hlt491922108 _Hlt519744600 _Hlt519744448 _Hlt20060057 _Hlt20059891 _Hlt475771779 _Hlt466043918 _Hlt466044031 _Hlt490365252 _Hlt466043840 _Hlt466044097 _Hlt77270307 _Hlt466043685 _Hlt466642154 _Hlt145760676 _Hlt145760969 _Hlt78966239 _Hlt78966316 _Hlt78966319 _Hlt145760430 _Hlt466465162 _Hlt490883522 _Hlt466043587 _Hlt466044307 _Hlt466484006 _Hlt466484007 _Hlt481118848 _Hlt466043806 _Hlt162778096 _Hlt486746359 _Hlt491172913 _Hlt466044082 _Hlt466043792 _Hlt482377578 _Hlt57964279 liverlabs _Hlt466039970 _Hlt466642147 _Hlt467412111 hepatitislabs _Hlt145743962 _Hlt145744059 _Hlt145744469 _Hlt145744471 _Hlt491414044 _Hlt79667363 _Hlt491414046 _Hlt79667365 _Hlt482377689 _Hlt482377626 _Hlt482377630 _Hlt482377586 _Hlt482377567 _Hlt482377577ascites _Hlt520435942 _Hlt78966281 _Hlt466041001portalcirrhosis pncirrhosis _Hlt20059893 _Hlt20060108biliarybiliarycirrhosis portalvenous _Hlt79667374 _Hlt156542626 _Hlt490883554 _Hlt78966258 _Hlt518744673 _Hlt518744674 buddchiari _Hlt466889395 hepatitis _Hlt467412120 _Hlt467412109 _Hlt486927879 _Hlt492288259 _Hlt520443197 _Hlt520443216 _Hlt491414112 _Hlt473440855 _Hlt473440889alcoholichepatitisnafldtpnautoimmunehepatitis _Hlt147035834 _Hlt147035835 _Hlt148116849 _Hlt148116808 _Hlt148116809 _Hlt148116882 _Hlt519744607pbc _Hlt147035933sclerosingcholangitispsc _Hlt20060083 _Hlt145822724 _Hlt146799969 _Hlt519787223 _Hlt9513618 _Hlt76963121 alpha1liver _Hlt79244754 _Hlt79244760 _Hlt78567074hemachromatosishemochromatosis _Hlt79244745 _Hlt466642184 _Hlt77270485 _Hlt148003147 _Hlt148003570 _Hlt79244730 _Hlt146000043wilsons _Hlt157756083 _Hlt78568118 _Hlt78568080 _Hlt78568116 _Hlt156543422 _Hlt156543423 _Hlt78571488 _Hlt78572657 _Hlt79249834 liverabscess _Hlt147124176 _Hlt147124380 _Hlt147331011liverneoplasia livercancer _Hlt466044084fnhfocalnodularhyperplasiahcahepatocellularadenomahepaticadenomahcchepatocellularcarcinoma _Hlt482377629 _Hlt77270491 _Hlt153097014 _Hlt78685783livertransplant _Hlt164148164 hematology _Hlt60432861 _Hlt78888708 _Hlt155715353 _Hlt78888704 _Hlt519775689 _Hlt212527869 _Hlt147069675 _Hlt147049143 _Hlt147049243 _Hlt147049798 _Hlt147049813 _Hlt147050330 _Hlt147049854 _Hlt147049101 _Hlt23701137 _Hlt496252567 _Hlt466129021 _Hlt500417290 _Hlt500418309 _Hlt515706599 _Hlt504473295 _Hlt79298706 _Hlt496249364 _Hlt496252576 _Hlt499693962 _Hlt499789079 _Hlt462318485 _Hlt9692224 _Hlt466093703 _Hlt462318597 _Hlt9692507 _Hlt465003519 _Hlt79900731 _Hlt79900984 _Hlt76808651 _Hlt146342048 _Hlt79900979 _Hlt79900983 _Hlt147050224 _Hlt147050322 _Hlt147069119 _Hlt79900860 _Hlt79900621 _Hlt60433002 _Hlt60433022 _Hlt79900672 _Hlt79900605 _Hlt60432988 _Hlt79900593 _Hlt79900762 _Hlt79900789 _Hlt79900634 _Hlt79900985 _Hlt9692450 _Hlt520454973 _Hlt520454986 _Hlt482377167 _Hlt524076975 _Hlt77046374 _Hlt481660498 _Hlt467135777 _Hlt490884173 _Hlt481117490 _Hlt490883157 _Hlt465003678 _Hlt467075601 _Hlt76808358 _Hlt466380662 _Hlt147069432 _Hlt147069672 _Hlt76808641 _Hlt494727663 _Hlt473444325 _Hlt473444377 _Hlt469643715 _Hlt78683029 _Hlt77527109 _Hlt77602034 _Hlt467135709 _Hlt467133396 _Hlt469642949 _Hlt499692116 _Hlt467075941 _Hlt520455503 _Hlt9692456 _Hlt520455543 _Hlt499788868 _Hlt78685569 _Hlt78685741 _Hlt78685772 _Hlt499694070 _Hlt147049889 _Hlt147049826 _Hlt156466953 _Hlt490884276 _Hlt519957822 _Hlt462318491 _Hlt520455222 _Hlt493070294 _Hlt465003696 _Hlt513803984 _Hlt466107741 _Hlt466466716 _Hlt475100794 _Hlt489947864 _Hlt78741324 _Hlt499693588 _Hlt466107765 _Hlt57439530 _Hlt57439531 _Hlt466107811 _Hlt520455762 _Hlt163041961 _Hlt162514004 _Hlt162514005 _Hlt466107870 _Hlt158171285 _Hlt158171313 _Hlt162784528 _Hlt466093382 _Hlt466107551 _Hlt466093866 _Hlt57439081 _Hlt466107593 _Hlt513803702 _Hlt162777514 _Hlt465151856 _Hlt465151775 _Hlt466107657 _Hlt520455013 _Hlt79298759 _Hlt493070316 _Hlt520455091 _Hlt520455433 _Hlt79298722 _Hlt164503104 _Hlt162599495 _Hlt466108263 _Hlt520455351 _Hlt466172048 _Hlt466189923 _Hlt466108323 _Hlt469155945 _Hlt466108354 _Hlt511309249 _Hlt472675534 _Hlt472675805 _Hlt466108432clottingcascade _Hlt9692580 _Hlt492310687 _Hlt492310828 _Hlt492308502 _Hlt147124076 _Hlt147124077 _Hlt162600295anemia _Hlt467325211 _Hlt492347631 _Hlt519775696 _Hlt157395062 _Hlt157395063 anemiaworkup _Hlt504476685 _Hlt146340555 _Hlt504476490 anemiaddx _Hlt79298704 _Hlt79298710 _Hlt504472889 _Hlt504472719 _Hlt475101660 _Hlt500418447 _Hlt504473058 _Hlt504473430 _Hlt504712325 _Hlt515706647reticulocytecountperipheralsmear _Hlt504476359 _Hlt158171590 _Hlt158171739 schistocytes _Hlt158430892 bonemarrowIneffectiveHematopoeisis _Hlt147313579 _Hlt153276316 _Hlt153276317idairondeficiencyanemiairondeficiency _Hlt504711734anemiaofchronicdiseasechronicdiseaseanemia _Hlt147046340 _Hlt504472840sideroblasticanemia _Hlt154413535 _Hlt504472891aplasticanemia _Hlt158456735megaloblasticanemia _Hlt156468371 _Hlt156468465 _Hlt156468386 _Hlt156468455 pernicious _Hlt520454208hemolyticanemia _Hlt147050319 _Hlt147050394 _Hlt472590323warmagglutinins _Hlt162782898 _Hlt162783234 _Hlt162783235coldagglutinins _Hlt162600529 _Hlt162600582 _Hlt162600538 _Hlt156466479 _Hlt156043615 _Hlt156043616 _Hlt496254335pnh _Hlt28369400 _Hlt79249669 _Hlt28369616 _Hlt79249710 _Hlt79249783g6pd spherocytosis _Hlt504476361 _Hlt66760343 _Hlt28369332 _Hlt28369622 _Hlt28369310hemoglobinopathyhemaglobinopathy _Hlt9692226methemoglobinemia _Hlt157677669 sicklecellhbs _Hlt156895755 _Hlt145314791 _Hlt475101915 _Hlt145314873hbchbe thalassemiaa2 _Hlt78568106 _Hlt78568126 _Hlt78568059 _Hlt79900854transfusionmedicine _Hlt162598093 _Hlt147069685 _Hlt147049080bloodtransfusionstransfusionreaction _Hlt147049887 _Hlt147050393 _Hlt147050217 plateletsffpcryoprecipitate _Hlt162598162 _Hlt162598136ivig _Hlt157762727 _Hlt157762728thrombocytopenia _Hlt79900982 _Hlt79900772 _Hlt147069195 _Hlt147069280 _Hlt79900923 _Hlt79900926 _Hlt147069104 _Hlt147069101 _Hlt147050455 _Hlt147050452 _Hlt79900960 _Hlt147069216itp _Hlt147050454 _Hlt153099931 _Hlt147068662 _Hlt469640956 _Hlt147069103hit _Hlt9692416 _Hlt153100207 coagulation _Hlt482377169 _Hlt488162275 _Hlt490883448 _Hlt490883449 _Hlt473464440 _Hlt490883349 _Hlt524445048 _Hlt79667391 _Hlt79667404 _Hlt79667401 _Hlt77046776 _Hlt467135920 _Hlt490883375 _Hlt490883387 _Hlt490884123 _Hlt465763209 _Hlt465763511 _Hlt524076956 hemophilia _Hlt162598154vonwillebrands _Hlt76808642vwf _Hlt79245916vwd _Hlt147069618 _Hlt147069666 _Hlt147069671hypercoagulability _Hlt475768797 _Hlt490884136 _Hlt490884137 _Hlt79667410 _Hlt158457403 _Hlt77602452 _Hlt146613637 _Hlt146613752 _Hlt499692177 _Hlt499693359 _Hlt481660845 _Hlt481660842 _Hlt158457479 _Hlt78683036 _Hlt481660701 _Hlt158457465 _Hlt158457466 _Hlt158457506 _Hlt467133606 _Hlt520828325 _Hlt467133663 _Hlt467133664 _Hlt467133842 _Hlt467133843 _Hlt467134025 _Hlt467134026 _Hlt473464442 _Hlt494727877 _Hlt481660835 _Hlt77602279 _Hlt481660837 _Hlt481660839 _Hlt520455525 _Hlt78684631 _Hlt481660833 _Hlt77602455apc factorvleidenleidenfactor5 _Hlt520455545 prothrombinprothrombinmutationg20210 _Hlt473444404 _Hlt481660836 _Hlt78638739antiphospholipidantiphospholipidsyndromeapaaps _Hlt147039837 _Hlt147039845 _Hlt146613750 _Hlt473444376 _Hlt475292152 _Hlt469643044 _Hlt475890390 _Hlt467748869 _Hlt524077166 _Hlt498433422 _Hlt524077076 _Hlt79667414 _Hlt79667423 _Hlt77272619 _Hlt481118025 _Hlt518754794 _Hlt518754795 _Hlt9789302 _Hlt156466032 _Hlt156466044 _Hlt156466042 _Hlt156466048 _Hlt157494455 _Hlt481660838proteinc _Hlt493071574 _Hlt79667426 _Hlt158461855 _Hlt493071639 _Hlt158461859 _Hlt493071628proteins _Hlt481660840 antithrombindysfibrinogenemia _Hlt158457492 _Hlt469644928 _Hlt475768325 _Hlt467144261 _Hlt471742863 _Hlt471742864 _Hlt78684346 _Hlt475768341 _Hlt475768357 _Hlt475768362 _Hlt481660846leukemia _Hlt493070300 _Hlt520454985 _Hlt472666599all _Hlt79301286 blastcrisiscll _Hlt162784587 _Hlt162784590 hairycell _Hlt162784565 _Hlt162784594myeloproliferativeaml _Hlt490818607 _Hlt79667440 _Hlt162784556 _Hlt162784558 _Hlt153277590 _Hlt462318391 _Hlt462318250cml _Hlt162784548 _Hlt79249575 _Hlt79249579 _Hlt79249784 _Hlt153257785 _Hlt153257786 _Hlt79249257 _Hlt148374868 _Hlt78741868 _Hlt78742002 _Hlt57439831 _Hlt148376332 _Hlt148376333 _Hlt79249838thrombocythemiathrombocytosis _Hlt467134561 _Hlt467134053 _Hlt467134076 _Hlt467134087 _Hlt467134059prv _Hlt467134495 _Hlt79249776 leukemoidmds myelofibrosis agnogenicammagnogenicmyeloidmetaplasia plasmacell monoclonalmgus _Hlt155693498 _Hlt155693499 _Hlt79031225multiplemyelomamm _Hlt148384435 _Hlt158430299 _Hlt162590509 _Hlt466129616 _Hlt490475920 _Hlt79031223 _Hlt513798436 _Hlt490887978 _Hlt490888563 _Hlt490888564 _Hlt490887990 _Hlt490888338 _Hlt490888339 _Hlt497127603 _Hlt146606134 _Hlt148000222 _Hlt148000223 _Hlt148384463wm _Hlt162777971 _Hlt524087750 _Hlt162777766 _Hlt524089974 _Hlt156050813 _Hlt156050814 heavychain castlemans _Hlt164148367lymphomahodgkinshodgkinsdisease _Hlt77514090 _Hlt77515613 _Hlt465176282nhl _Hlt79298906 _Hlt520455440 lymphomabsmalllymphocytic cleavedcelllargecelllymphomalymphomatoidgranulomatosis _Hlt158027396burkitts _Hlt79300239 _Hlt520455387 _Hlt156467748 _Hlt156466842 maltlymphoma lymphomat adulttcell _Hlt519010941 _Hlt79667467 _Hlt156465937 lymphoblasticmycosis _Hlt472677731sezary _Hlt155852572 _Hlt155852779 _Hlt464716964 _Hlt465488780 _Hlt78825574 _Hlt464716922 _Hlt472677725 _Hlt464716942 _Hlt464716945 aidslymphoma _Hlt145736522primarycnslymphoma _Hlt145736513 _Hlt147314563bone _Hlt473443803 _Hlt492347850 _Hlt155715370 _Hlt77252496 _Hlt78823031 _Hlt78823050 _Hlt156551947 _Hlt156551982 _Hlt491420257 orthopedics _Hlt77252498 _Hlt77252817 _Hlt77395400 _Hlt155715379 _Hlt77252826knee _Hlt77252745 _Hlt56602984 _Hlt56603005 _Hlt56602961 _Hlt56602933 _Hlt77134359 _Hlt77134360 fractures _Hlt77252829 _Hlt77395435 _Hlt163133489bonemalformations _Hlt157918005 _Hlt518747438 Osteopetrosisachondroplasiaoipagets _Hlt146961135 _Hlt163712376 _Hlt77519222 _Hlt77519236 _Hlt148000510 _Hlt148000511 _Hlt148000694 _Hlt148002060 _Hlt153179155Caffeysavascularnecrosis _Hlt77519640fibrousdysplasia _Hlt467063462mccune _Hlt79147411 _Hlt79147431 _Hlt77174030 _Hlt77252703 osteoporosis _Hlt156551981 _Hlt156552408 _Hlt146961131 _Hlt47923416 _Hlt20800435 _Hlt20800436 _Hlt47923231 _Hlt47923232 _Hlt491420254 bonecancer _Hlt78823049 _Hlt472681178 _Hlt461808870 _Hlt492347812 _Hlt492520406 dermatology _Hlt78739836 _Hlt78627787 _Hlt491420609 _Hlt161481338 _Hlt147333889 _Hlt467835550 _Hlt472673992 _Hlt147332640 _Hlt78826746 _Hlt490373085 _Hlt472674022 _Hlt156463299 _Hlt156465921 _Hlt467835001 _Hlt467835611 _Hlt147333997 _Hlt155951106 _Hlt155951107 _Hlt466610606 _Hlt472668277 _Hlt472675731 _Hlt472668204 _Hlt466610064 _Hlt472675751 _Hlt472675802 _Hlt156455695 _Hlt491425124 _Hlt491425125 _Hlt472673298 _Hlt215032420 _Hlt466610692 _Hlt472677192 _Hlt472668238 _Hlt495301855 _Hlt147332849 _Hlt162615904 _Hlt147332845 _Hlt472668387 _Hlt147332959 _Hlt147332962 _Hlt490891792 _Hlt472668439 _Hlt472677885 _Hlt472681184 _Hlt503353730 _Hlt215032425 _Hlt145481908 _Hlt466610300 _Hlt467835052 _Hlt467835643 _Hlt74763306 _Hlt78738763 _Hlt78739105 _Hlt78712916 _Hlt466610255 _Hlt466610378 _Hlt467835161 _Hlt78712274 _Hlt467835714 _Hlt467835655 _Hlt472681180 _Hlt466610375 _Hlt472668544 _Hlt490963664 _Hlt491426744 _Hlt472673476 _Hlt467835848 _Hlt472673508 _Hlt472676762 _Hlt80763765 _Hlt80763762 _Hlt78712626 _Hlt78738930 _Hlt78739103 _Hlt78739106 _Hlt467835879 _Hlt467835752 _Hlt467835964 _Hlt472669153 _Hlt472669569 _Hlt145822763 _Hlt145822776 _Hlt467834761 _Hlt495301880 _Hlt78712856 _Hlt491419163 _Hlt491420457 _Hlt156394899 _Hlt161481337 _Hlt78713064 _Hlt467835951 _Hlt472673856 _Hlt472673874 _Hlt466610912 _Hlt467835292 _Hlt155852453 _Hlt155844096 _Hlt155844097 _Hlt155714088 _Hlt155846716 _Hlt147334171 _Hlt147333656erythemanodosumen _Hlt78823570 _Hlt472683533 _Hlt491419758 _Hlt23011332 _Hlt158026582vitiligo _Hlt493071883 _Hlt147333673 _Hlt519828129 _Hlt23690513 _Hlt158026732 _Hlt524446469 _Hlt519828085 xanthomas _Hlt520654927 _Hlt156468674 _Hlt520654959 _Hlt79246132 pediatricskin _Hlt79247667 _Hlt155852463 eczematous _Hlt155713802 _Hlt155713803 _Hlt147333979 acanthosis _Hlt146799286acanthosisnigricans _Hlt156891644 _Hlt157762242 _Hlt156891654 _Hlt77578582 _Hlt156463937 _Hlt490891908 _Hlt79667481 _Hlt79667483atopicdermatitis _Hlt147332641atopic _Hlt78826831 _Hlt490891959 _Hlt490891985 _Hlt490891970 _Hlt78827036 _Hlt78827060 _Hlt78827047 _Hlt466616155 _Hlt466616156 _Hlt473439613 seborrheic _Hlt156393252 _Hlt156393254stasisdermatitis _Hlt472674006contactdermatitis _Hlt79667500 _Hlt79667501 _Hlt79576114 _Hlt156393280 skinfungal _Hlt467835008 _Hlt78825338 _Hlt461806723 _Hlt78825347 _Hlt156038085 _Hlt78825311 _Hlt519513587 _Hlt519513588 _Hlt78825640 _Hlt464716688 _Hlt464716689 _Hlt78825307 _Hlt464716697 _Hlt78825001mycosis1 _Hlt155852784 _Hlt465489924 _Hlt78825397 _Hlt464716902 _Hlt472677730papulosquamous psoriasis _Hlt473443329 _Hlt78824600 _Hlt155712231 _Hlt156463980 _Hlt79576010 _Hlt79667502 _Hlt155712046 _Hlt78779419 _Hlt78822919 lichenplanus lichensimplex pityriasispityriasisrosea _Hlt472664408 _Hlt481057012 _Hlt481057013 _Hlt485361121 _Hlt472675736 _Hlt472675823epidermaltumors _Hlt491426880 _Hlt481057090 _Hlt472675795 _Hlt491425844 _Hlt153172916epidermalbenign _Hlt79667510 _Hlt155846848 _Hlt155846849epidermalpremalignantepidermalmalignant _Hlt79667513bcc _Hlt156039086 _Hlt156039087 _Hlt495301858 dermaltumorsdermaltumorsbenign _Hlt472673294 _Hlt147332754 neurofibroma _Hlt490820360neurofibromatosis _Hlt79245469 _Hlt472664830 _Hlt472664776 _Hlt156455857 hemangiomas _Hlt147332846 _Hlt147332850 _Hlt155856050 spiderangioma _Hlt156463737 _Hlt475769335 _Hlt491967461kaposiskaposissarcoma _Hlt472668339 _Hlt79667520 _Hlt57976386sweetssweetssyndrome _Hlt519827752 _Hlt78887958pathergy _Hlt519827914 _Hlt519827920 _Hlt519827926 _Hlt79667475 _Hlt155847574 melanocytic _Hlt472668258melanocyticbenign _Hlt147332960 _Hlt147332963 _Hlt79667526 _Hlt156058553 _Hlt156058554cafe _Hlt460815293 _Hlt460815154melanocyticpremalignant _Hlt156058559 _Hlt156058562 _Hlt156058566 _Hlt79667528 _Hlt79575688 _Hlt79575700 _Hlt156058570melanoma _Hlt472668420 _Hlt79667532 _Hlt79667538 _Hlt156058573 _Hlt79667530 _Hlt490891810 _Hlt491426897 _Hlt491427727 _Hlt145481975 _Hlt155714407 _Hlt155714430 _Hlt491427666 _Hlt79667546 _Hlt472666490acne _Hlt472668451 _Hlt156038907 _Hlt156038908 _Hlt156038870 _Hlt156038871 _Hlt155843567 _Hlt155843591 _Hlt466610261 _Hlt467835645 _Hlt78712944vesiculobullous _Hlt74763819 _Hlt79576080 _Hlt74763794 _Hlt79576109 _Hlt79576447 _Hlt78824271 _Hlt78824272 _Hlt78824297 _Hlt156058073 _Hlt74763694 _Hlt74763781intraepidermal _Hlt78712618 _Hlt464716236 _Hlt491421881 _Hlt491421922 _Hlt491421923 _Hlt467835725 subepidermal _Hlt490893256 typeonederm _Hlt490373203 _Hlt467835698 _Hlt490893298 typetwoderm pemphigus _Hlt467835866 _Hlt155850356 _Hlt157945846 _Hlt78739102 _Hlt78739107 _Hlt491426803 _Hlt78738950 _Hlt156463415 _Hlt472672889paraneoplasticpemphigus _Hlt79576032 _Hlt74763803bullouspemphigoid pemphigoid _Hlt155850374 _Hlt155850364 _Hlt79576083 _Hlt79667556 _Hlt78892834 _Hlt155850333herpesgestationis _Hlt80763815 _Hlt155850325epidermolysisbullosa _Hlt80763764 _Hlt155850319 _Hlt490893331 _Hlt520561947 _Hlt520561948 _Hlt520562548 _Hlt520562549dermatitisherpetiformis _Hlt78712896 _Hlt80763524 _Hlt80763512 _Hlt80763745 _Hlt78712852 typethreederm _Hlt490892735 _Hlt467835788 _Hlt467835905erythemamultiforme _Hlt146946413 _Hlt491432939 _Hlt491432915 _Hlt491432811 _Hlt491432814 _Hlt78727938 _Hlt491432993 _Hlt23008705 _Hlt490892262 _Hlt490892219 _Hlt491432968 _Hlt490892268 _Hlt23008717 _Hlt79667559 _Hlt490892265 _Hlt491432542 _Hlt491432578 _Hlt491432589 _Hlt79667562 _Hlt490892166 _Hlt490892175 _Hlt491432594 _Hlt79667560sjs _Hlt146946391 _Hlt490892642 _Hlt74763782 _Hlt146946388ten _Hlt490892636 _Hlt79667564 _Hlt495301902leukocytoclastic _Hlt156394900 skindrugs drugreactions drugeruptions _Hlt79667566 _Hlt78713082 _Hlt490891618 _Hlt490891609 _Hlt491433161 _Hlt156469165 _Hlt491433157 _Hlt79667568 _Hlt490892556 _Hlt490892553 _Hlt472669617 _Hlt148348483 _Hlt490891635 _Hlt491420745 _Hlt9349763 _Hlt79667570 _Hlt156469207 _Hlt490892435 _Hlt490892437 _Hlt472669542 _Hlt472669568 _Hlt472669570 _Hlt519828571 _Hlt79667572 _Hlt78727978 _Hlt519828577 _Hlt472673863skincongenital _Hlt466611008 _Hlt472671976 _Hlt472671977 _Hlt472664728 _Hlt466611005 _Hlt466611002 _Hlt466610998 _Hlt466610993 _Hlt466611009ehlers _Hlt466611007 _Hlt79245484 _Hlt145742866nf1 _Hlt472664788 _Hlt155854504 _Hlt155854505 _Hlt460815262 _Hlt466611004 _Hlt495302073ts _Hlt77174099 _Hlt466611000 _Hlt77174045sturge _Hlt77174067 _Hlt466610997ktwskinulceration legulcers _Hlt161481355 _Hlt464807204 environmental _Hlt157677575 _Hlt79901050metalsaluminum _Hlt79901083lead _Hlt148350015 _Hlt490713933 _Hlt78728005 _Hlt78728012 _Hlt78727998 _Hlt79667576arsenic _Hlt493071971 _Hlt519827955 _Hlt78823703 _Hlt78823704 _Hlt79667578 _Hlt156125735 _Hlt157661025nitrites _Hlt78777041 _Hlt79901110mercurycadmiumiron _Hlt465082317 _Hlt465657111organophosphatesetohethanolmethanolethyleneglycol inhalants _Hlt147406673 _Hlt156041727 _Hlt156041728 _Hlt157739810 _Hlt157739811 _Hlt156040311 _Hlt156040506 _Hlt156040507 _Hlt157740117 _Hlt157740118 _Hlt156039431 _Hlt157740317 _Hlt157740318 _Hlt156040182 _Hlt157740320 _Hlt156040613 _Hlt157740496 _Hlt157740449 _Hlt157740450 _Hlt157740504 _Hlt157740543 _Hlt157690618 _Hlt157690619cyanide _Hlt155714657 _Hlt155714658 _Hlt490478446 nutritionvitamins _Hlt155715417 _Hlt472665867 _Hlt472666228 _Hlt155714370 _Hlt488160991 _Hlt472666121 _Hlt472666129 _Hlt78467444 _Hlt472666210 _Hlt157755577 _Hlt472666088 _Hlt488160788 _Hlt158457775 _Hlt158457788 _Hlt147332425 _Hlt490819984thiamineb1 _Hlt158458134 _Hlt157745486 _Hlt163712374 _Hlt163712375 riboflavinb2 _Hlt490819957niacinb5 _Hlt157755477 _Hlt157755522 _Hlt158090751 pyridoxineb6 _Hlt158090526 _Hlt77675992b12 _Hlt146948530 _Hlt148947977 _Hlt156468209 _Hlt490819951 _Hlt156468442 _Hlt472666213 _Hlt490819954 _Hlt79509620folatevitaminc ascorbicacid _Hlt78552749 _Hlt146000031vitamina _Hlt472666488 _Hlt78779289 _Hlt472666543 _Hlt472666508vitamine _Hlt472666745vitamink _Hlt472666090 _Hlt472666943 _Hlt489710747vitaminadeficiencyvitaminedeficiencybiotinthiaminedeficiency b12deficiencyzincchromiumcopper _Hlt157756082selenium molybdenum _Hlt79901136surgery _Hlt146788047 _Hlt155715377 _Hlt164148072 _Hlt156997771 _Hlt164148256 _Hlt164148105 cardiacpreop _Hlt79570723 postopfever _Hlt147406870fluidstraumachest chesttrauma eyetrauma _Hlt145481450 _Hlt156463275burnstransplantmedicine _Hlt158525032 transplant _Hlt145481674 _Hlt164148162 _Hlt164148165 _Hlt164148167 _Hlt164148257 _Hlt164148158bmt _Hlt155850036 _Hlt155851629 _Hlt79666024 _Hlt79668097 _Hlt79668119 _Hlt79668129neutropenicfever _Hlt146348655 _Hlt146348721 _Hlt146348895 _Hlt146348862 _Hlt146348839 _Hlt146348781 _Hlt146348792 _Hlt146348828 _Hlt77576277 _Hlt77576462 _Hlt158525882 emergency _Hlt157677695 disclaimer>>>>>>>>>>>>>>>>>>>>>>>>>?????????????@@@@@@@@@@@@@@@@CCCCaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaee)********+++++++++++++++++++,,,,,,,,,,,,------------JJJJJJJJJJJJJKKKLLQQQlllllmmnnnnss     !!"######$$$%%%%%&&LLLLMMMMMMMNNNNNNoooooopppqqrssyyy !%'HHHHHHHIIIIJJJJJJJJKKOrtuuuvwww 003SSTTppp%uGIJKKKLQRb : J M O R W  9 : : : : ; < < = > > B v { H I P 2 3 4 K K r r s t u {{}CCDE,22lss._N",lM#((( !!!""\###$S$$%&&(J* , , , , , , , , , , , ,,>1A1A1A1A1145Y7Z7Z7[7\7\7`7`7e7g77777777f888[;[;r<=B>C>??$????`BaBCEEXEwEGGGGG5H5H5H5H5H5H5H5H5H5H5H5H5HeIIIJK K K KK(MOOOOOOOOO6O6O7OVVoYYYYYYYYYZ[[W\W\W\W\-].]/]/]]2____#`aa#f>fk#m#mmmmmmmm n n>nAn^n^nxnxnnnnnnnaobojoooooooo p pppp>p@pFpHpRpopop\qqqqqrrrrrr2s2s4s4s5sss,t,tot!u!u$uRuuuuv4w5w5wwwwyyyy%|}}~~~s -i&&&&&kllnn؍p@FFLLBb ]~!####'9E666q55٪԰TϴϴԴմڴԹٺٺpɼ;K'(())022@OOOOOPQQVVw<bb3333]"((((Ett\\./0Z:;=>>@@3333\\0 h h  A F K K K K T @        4 M =>HH}$&&+aUVooooILWR%R%%3&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&3'3's') *x*y*{***++--.01111 2 2 2b2b22223333b4}7}7888:::::;<<>J?n?AAA0B0B0B0BGGQHHHHII)J)JJJLLLMMMMMMMN6PPSSSSSSSPUPUUUUUUU'WTWWXXYY*Y*Y*Y*Y@YJYZ*]dneeeeeefgh!i!i"iouzzzx}z<Hrrtvxyz!!HHHHHaaaaaaaaabfρρЁЁҁӁԁ      ,OPPQQRUttuuw|||||;]]a  Ee$$$$$$$<@@bfff~߅ !!#MPW(((OX‰ljʉ"""vdۋۋۋ-..002xyyzzz 33#Bɓ/0ٖ*6JJՙؙٙ 56Қؚ֚ښ:ppʝʝʝʝנ ѣ#?A@@ACCCDEEEtиииżżȼR\6Ǿʾ˾˾ssssuIIIi!@CCnukDfjjQQJ'q||9999/CEGGGqqt$<}V V X  - |     *+T\\\\F(555MMMFFI    )))]]``BBDM;"`$Y' * ***-------...@.@.B.B.E.s.s.s.....f/u03333335$5Z:@@@@L*LPPPPQ5Q5Q5QvQQQQQQQQ4R;R@R3S4S4SSTUVlWlWnWtWtWY]]]^^^^^^^U^oopDqr?w?w yy{{{{q|q|q|q||||||||||~Ń    nnnي"7Q̕ט,,,OOOO6 hY,-/2::;;;cee|}}Gb.HHppp|}}:h(3KKKhjl\\ fok&}} +,..]^z$%]]@@%    l].Qzz|||X[llll#($($%u%v%v%%%%%%&&H&&''''''()*+S..///B/B/B////{2{2H5H555T89999:=???cAmACCCCDDDeDmJJsLsLsLXMXMXMXMXMZMMMM@NtNvNNNNNNNN*O*O*O*OBOPOwOOOOOOOP;Pr\rrrrrrrrrrrrrrrrrrrEs_sas{sssssss?t?tAtvtxt~ttttttttttttttttt7u>>_mmoooVvvvzj:=uuL                        M        J J K K K        x x  EEFG\,&&       n r r r r !!!A""########& ,......//1/_0k0k0k0k001H1H1H1H1H1z44444'5'566778888889?9:::4:4:;<<===M>U>K??AAA5B5B5BLB^G^G_GqGmIoIoIIJJgJhJJ~KLLLhLLLMNNNPPySyS-VdYYYYY[[;[M[[n\n\n\n\z\\]L]L]]]]]]eeeeff g"g#g$g$g$g$g$g$g$g%ghlln)o'q'qrrrrsssss\tuww xy1z2z3z`zbzG{{{{|o|o|o|މTW]يڊۊۊۊ܊܊܊܊݊ފ =jjkms‹‹‹Y   <<=@BDJpsttttwx??^ޣ)++ [ͦM EEײײǸϼ]\\).} ""JJJKKp%-^d$$FFFGLijjjjkkk667;WXXYYYYYYZ[[[[[\\\\\]]^c//A..~###$VVWWXZ[[!'LO 9vxLLb!l#__abbR@@*y=!!G#G#G#G#D%a())))))**/,R,T,T,X,#-#-------/000)3@5C9;;;v<v< > >k>k>TATATAtCtCtCC!G^G^G_GbGGGIIIIJJJJJJJJJJJJJJJJJbKdKPLMMNNOHPcUCWXXYKYKYKYKYYYYZZZZZZZZZZZZd[[[4\t\y\\H]N]N]]^^^%_i_i_i_aja,bbccccnnnntPvTvwxxC{||=uuu|YYY[d{^>00RkkkϓГГ~~3RRRP @@JJKDD+3374q5555y|@@d//OOOSk    6###$%%5(11::::k>WKLsN:TUUUVdlbnbnpp]rrxF|R}R}܁܁֎֎W!!ecޫ,YwĮ'=Xxc<U%<rr  '   a .nn&'(((()GGqr   22344667Y\]]^b ?Aoovwijj3qqqq"'OOtz<5"v"v"v"d#d#$(8) +++,,C,7.7.7.6666888888e9g9j9;AABBBBBBBBBBBC_CcClCCCCCDDDDD5E??h@h@h@(BHHIqIKNKNKmKmKKKKKLMjNNNNNOOPPUXR[]]t^^j_bbfi(k(k7ktlmmmmmmmm#oooooooooorr2s8sdtvvxxy{||D|D|}}{&gjNJ[E#%&'Pۓ**.//012eϔϔBEy|W  1677:13ef>Oyy[ĴŴceʵ!!ڷo½½ɽ^'ddd~Tf}}}A33 B<>@ACCCCG(5ccesw          % % : : :   " #    @ @ @     o  x x x x x x     :' :' $( V* V* * C+ 1, 2, 2- . . . . . . . . . / / V0 X0 1 P2 y2 2 2 3 G4 G4 7 +9 +9 g9 g9 |: |: |: |: : : : : +; .; /; R; R; R; S; S; X; ; ; ; ; ; ; ; @= > ]? ? ? *@ 2@ 2@ ?@ A A D D D E E uF F F G J J CP CP CP Q Q QR RR S S S F[ \ a a b Vd We ]e e e f f +f uf uf j j k fl l jm km m m n Mp Jq q q s s t t t t t v Dv :x x x x x x x x x x x x x x x x x y +y .y 0y 0y 5y 5y ey ey fy oy y y y y y y y z z z z z z z z z z 8z :z =z sz tz z z z z z z z z z { { { { { { { { { i{ { { { { { { { { { { { | | | | J| K| K| | | | | | | | | | | | | | | | | -} 2} 2} 2} 3} 4} 4} 5} 5} 6} X} X} Y} Y} }} }} } } } } } } } } } } } } } } } ?~ ~ ~ ~  & ( b c      { L L        ' ɗ t ޛ ޛ ޛ Q Q Q Q Q Q Ρ ʥ ʥ ե ե ڦ 2      v e ڴ е K K  ; h  7 7  s  c c S S S J Y Y Y ` ` ` i i i { { } q *     h  P P U  ? s D O Y * + j A    R R i           $ O X l |     & 0    ?           & & @! # # # $ $ $ c$ c$ '' ' }) + @+ @+ + + + + + + 0 0 1 z3 z3 3 3 4 4 8 8 8 8 8 8 8 8 S9 9 9 9 9 9 9 9 ]; !< !< !< !< !< *< *< S< T< U< < < < < < < < < < < < < = = = C= C= D= D= D= D= E= E= F= F= F= F= G= L= u= = = = = = = = = = = = = > > > > > > > > > > > > > > ? h? i? ? ? ? ? ? ? ? ? ? ? @ @ @ @ @ @ @ @ P@ @ @ @ @ @ @ @ @ @ A A A A A A "A "A ;A A A A A A A B B \B \B ]B ]B ]B ]B ^B _B _B _B `B cB cB dB dB dB dB eB fB fB gB lB nB pB pB {B B B hC hC hC hC pC F F F aK cK K K K K L IN N R R dV V V V V V W {Y Y Y Y WZ c d d ]g ]g ]g k gn gn pn op p p q Rq Zq Zq Zq w w 8x 8x {x {x x y y y y y y z } X} } } } } } )~      ҆ 0 ! P R R  Č (  ~ C # h h A A A ݪ  ] ] ] ٻ ׼ Q R R S o i i q u z   # $ %    Z Z  W W Y Y ) ) ) + + 5  3 3 A ~ ' ' L  b { { | |    1 _                     ' ( ) 5 V V V W W X Y _ _ _ ~ ~ ~ ~ ~                           Z                 F I s z       T U V |         K K u p           d i           c c " $ & & & & & & & ( ( ( ( ( ( ( :) ;) ;) <) >) I) }) ) ) ) , , , "1 3 3 5 5 8 8 7: ; ; ; K= K= C =D =D KE @H @H @H @H @H @H LH yH H H H H H H H H H H H I I J K HK IK xK }K K K M M M M M PO hO nO oO oO sO sO O P P P P P P S S S S T T T T VV VV \V W W X X RY Y Y Y Y Y QZ RZ RZ ZZ ZZ Z Z Z [ 4` ` -a b b b b 3c e h Ck Vk o o 9q 9q Dq t t v x x g} g} h B B f f h h i q ݉ ݉ ݉  ` Ȋ L X + + M t u v v w ? g g j j Y [ s u , 6  y y      / L R ~ ؚ  2 4 W X x z ~ ܛ ܛ ݛ ^ e ? ? ? @ A C C D F m q t ~ ڞ ߞ d f 6     O O ɧ ɧ ʧ ʧ ʧ Ψ Ψ ө  F  [ \ ' & ' (  : ; ; j j > b b b u   F    t 8   y y  B . 2 3 5 8   v v 7  1 1   ^ C C z 7 7 8 h i i i i       3 4 O  1 1 2 g  G S   $ & * R T T z  s   j l 9 Q Q Q Q Q a a         ; _ _ c   t     g r         ? w y ' c   3 3 | |          M" Y" # 6$ v$ v$ x$ w% ( ( ) ) ) * |, , , , - / / X0 [0 F3 F3 q3 q3 q3 r3 s3 6 6 6 6 F9 Z9 : : = B F M M U U [ \ \ \ \ x_ ` ` ` ` ` ` ` ` 1a [a f f f i i i i %j \j k l l l m Bn Bn Cn n n n n n ho p p :p ep ep )q q q q q s s s Vt v v jv v v v {w }w &z Yz Zz z z | | B} B} B} B} B} B} ~ o o o o   dž 7 7 ( x  ] ] ] ] ^ { m $ F Ǡ Ǡ   V | C C D D } @ 2 " " q q { L L 6 d d d q F F F U { P 0  * 0 H H H m m n S ] K K  ( P P Z 6 8  I I I K  y   n n p x x o! o! o! o! o! % % % % % % K% [& [& [& b( ~, - - 3 3 8 $: &: y< y< y< y< y< y< y< y< y< {< < < < < < < < < < < < < < < != J= J= K= K= = = = > "> (> \> \> d> > > > > > > > > > ? ;? B? ? ? ? ? ? ? ? ? ? @ "@ "@ #@ L@ M@ T@ V@ @ @ @ @ @ @ @ IA QA UA VA VA A A A A A A A B UB aB B FQ FQ FQ Q Q Q Q Q Q Q Q S T T >T ?T ?T V iW f] h] _ ` ` ` ` ` ;a ya }a a a a a $b b b b b *c ,c ,c ,c 0c d d d e hk n o o o p p p p p q ts s t u v wz { { {~ ~ ~ 6 6 6 6 i i K K K K > W Z q s  S { | | Ԏ Ԏ Ԏ я я я l l -  I I Ś , - - - - W _ : : < = = > > > ͜ ͜    % * * * C a a a a f f     R S S U U V V X Z Z Z \ | | ƞ  ! ! ß ğ ǟ  ) j k q ˠ 2 Q Q R Ȣ Ȣ ʢ     7 ˣ գ ٣ O W Ť    =       0    >  _ _  ζ Y Y Y < < < (  ' ' f g ] 4 | y y c ] ` ` Z Z R T W &U  6    /@pGcgA[{WX       2!;!@!C!q!#$$$$w'w''(e*,,,,,Z/[/l/333333t4w4w44444455555w555555G6G6666 7(77_88999999;;;;<<<<<<<<<<=====>?@@@@:DEEE#F#FFFeGGGHHHHHIIJJ*M*M(O)O*O+O+O+O,O,O,O3O>P>P>PGPQ!QSTPUqW[-].]^7^R^`4`8`?abbbd;e;e;e;e;e>>>>>B?p?AAYAYAmBCD5DgDlGUHgHiHiHiH^I^I^IJTKZKMNNOzOOOOWPfPQQR0R(TSTSTTTT[:[@[@[D[``^c^ceeeeee]fdfgfffiii5ipi{iiilmmm[m[mrmrmmmnnnnnnqqqqrGrCssvvvvvvwyyyyykzkzkzzz{{{{{||||}>ʂ67JJwVIIIIӅ   ''̊TR6ǐǐAAA  @g,66>WzϖӖӖEEEEDDD3EЩЩ֩o$AAAAmn5aJRPk\\t(hhFyyyzpp!!!!1vv&HI+ttt**WWLLLL888D555?Db'2.Qma%3)J@?#{{{;<9>>?? , p He@@@@@@@@@ @ @ @ @ @@@@@@@@R@S@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.1@2@3@/@4@5@06@7@8@9@:@;@<@=@>@?@@@A@B@C@D@E@F@G@H@I@J@K@L@M@N@O@P@Q@i@j@k@l@m@n@o@U@V@W@X@Y@Z@[@\@T@]@^@_@`@a@b@c@d@e@f@g@h@x@y@z@{@|@}@~@@@@p@q@r@s@t@u@v@w@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@E@F@G@H@I@J@K@L@M@N@O@P@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@8@9@:@;@<@=@>@?@@@A@B@C@D@Q@R@S@{@|@U@T@V@W@X@Y@\@]@^@_@`@a@b@c@Z@[@d@e@f@g@h@i@j@k@l@m@n@o@p@q@r@s@t@u@v@w@x@y@z@@@@@@@@@@@@@@@@@@@@@@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@$@%@&@'@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@"@#@@@ @!@(@ @ @ @ @ @@@@@@@s@)2@3@4@5@6@7@8@9@:@;@<@=*@+@,@-@.@/@0@1@n@>@?@@@A@B@C@D@E@F@G@H@I@J@K@L@M@N@O@P@Q@R@S@T@U@V@W@X@Y@Z@[@\@]@^@_@`@a@b@c@d@e@f@g@h@i@j@k@l@m@o@p@q@r@u@v@w@x@t@y@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@89@:@;@<@=@>@?@@@A@B@C@D@H@E@F@G@I@J@K@L@M@N@O@T@U@V@P@Q@R@S@X@W@YZ@[@\@]@^@_@`@a@b@c@d@e@f@g@h@i@jk@l@m@n@o@p@q@r@s@t@u@v@w@x@y@z{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@   @ @ @@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@('@)*@+@,@-@.@/10@23@4@5@6@7@8@9@:@;@<@=@>@?@ABCDEFGHIJKL@M@NOP@Q@R@S@TU\V@W@X@Y@Z@[@]^@_@`@a@d@e@b@c@f@g@h@i@j@k@l@m@n@o@p@q@r@s@t@@@@@z@{@x@y@u@v@w@@@@@@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@89@:@;@<@=@>@?@@@BA@C@D@EF@G@H@I@J@KLM@N@O@P@T@U@Q@R@S@V@W@\X@Y@Z@[@]@^@_@`@a@b@c@d@e@f@g@h@i@j@k@l@m@n@o@q@r@p@s@t@u@wxv@y@z@{@|}~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @@@ @ @ @ @@@@@@@@@@@@@@@ @!@@@"@#@$@%@&@'@(@)*@+@/,@-@.@0@1@2@3@4@5@6@7@8@:@9@;@<@=@>@?@@@A@B@C@D@E@F@IG@H@J@K@L@M@P@N@O@Q@R@S@TU@V@XYZ[W@\@]@^@_`a@b@cdefghijklmnopqrstuvwxyz{|}~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @@@ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@&@$@%@'@2@3@4@5@)@*@+@,@(-@.@/@0@1@9@6@7@8@:@;@<@=@>@?@@@A@B@D@E@C@FG@H@I@J@K@L@M@N@O@P@Q@R@TSUV@W@X@Y@Z@`@[@\@]@^@_@e@f@g@h@ia@b@c@d@j@k@l@m@n@o@p@q@r@s@t@u@v@w@x@y@@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@8@9@:@;<@=@>@?@@@AB@C@D@E@F@G@H@I@J@K@L@M@N@O@P@Q@RS@T@U@VW@YZX@[@\@]@^@_@`@a@b@c@d@e@f@g@h@i@j@k@l@m@n@o@q@p@r@s@ut@yv@w@x@{z@}@|@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @   @ @ @ @ @ @ @ @ @  @  @ @ @ @ @ @ @ @ @ @ @ @ @ @ @! @" @# @$ % @& @' @( @) @* @+ @, @- 1 . @/ @0 @2 @3 @4 @6 5 7 @8 @9 @: @; @< @= @> @? @@ @A @B C @F D @E @G @H @I @J @K @L @M @P @N @O Q @R @S @T @U @V @W @X @Y @Z @[ @\ @_ ] @^ @` @a @b @c @d @e @f g @h @i @j @k @l @m n @o @p q @r @s @t @u @v @w @x @y @z { | } ~ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @  @  @ @  @ @ @ @ @ @ @ @ @ @  @   @ @ @ @ @ @ @ @ @ @ @  @! @$ " @# @% @) & @' @( @* @+ @, @- @. @/ @0 @1 @2 @3 @4 @5 @6 @7 @= 8 @> 9 @: @; @< @? @@ @A @B @D C @E F @G @H @I @J @K @L M @N @Q O @P @R @T S @V U @Y W @X @Z @k @l @[ @\ @] @^ @` @_ @a @e @b @c @d @f @g @h @i @j @m o n @p @q @r @s @t @u @v w x y z | { @} ~ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @! " @# @$ % @& @' ( , @) @* @+ @- @. @0 / @1 @2 @3 4 @5 @6 @7 @8 @9 @; @: @< @= @> ? @@ @A @C B @D E F @G @H @I @J K L @M @N O @P @Q @R @S T U V @W @X @Y @Z @[ @\ @] @^ @_ @` @a @b @c @d @e @f @g @h @i @j @k @l @m @n @o @p @q @r @s @t @u @v @w @x @y @z @{ @| @} @~ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @  @ @ @ @ @ @ @ @ @ @ @   @  @ @ @ @ @ @ @  @ @ @ @ @! @" @# $ % @& @' @( @) @* @+ @, @- @. @/ @0 @1 @2 @3 4 5 6 7 8 9 : @; @< = @> @? @@ A @B @D C @E @F @G @H @J I @K L N M @O @P @R Q @W @X S @T @U @V @Y @Z @[ \ ] @^ @_ ` @a @b @e @d c @f @g h k i @j @l m @n @o @p @r q @s @t @u @v @w @x @y @z @| { @} @~  @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @  @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @  @ @  @ @ @ @ @ @ @! @" @# @$ @% @& @' ( @) @* @+ @, @- @. @/ @0 @3 1 @2 @4 @5 @7 6 @8 9 : @; @< @= @> @? @@ @A @B @C @D E @F @G H @I @L J @K @M @N O @P @Q @R @S @V T @U @W X @Y @Z @[ @\ @^ ] a _ @` @b @c @d e h f @g @i @j k l @m n @o @p @q @r @s t @u v @w @x @y @z @{ @| } @~ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @@@@@@@@  @ @ @ @@@@@@@@@@@@@@@@@@ !@$"@#@%@&@'@(@)@*@+@,@-@1@.@/@0@2@3@4@5@6@7@8@9@:@<;@=@>@?@@ABCDHE@F@G@I@J@K@LM@NOPQ@R@S@UT@V@W@X@Y@Z@[@\@]@^@_@`@a@b@c@d@e@f@g@h@i@j@k@l@m@n@o@p@r@q@s@t@u@v@w@x@y@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @  @@@@@@@@@@@@@@@ !"#$@%@&@'@(@)@*@+@,@/-@.@0@1@2@3@4@5687@9:;<=>@?@@A@BCD@E@F@G@H@I@J@K@L@M@R@N@O@P@Q@S@T@V@W@X@Y@Z@U@[@^@\@]@_@`@a@b@c@d@e@f@g@h@ijmk@l@n@po@q@rs@t@u@v@w@x@y@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@()*@,@+@-@.@/@0@12@3@4567@8@9@?:@;@<@=@>@@@A@B@C@DH@I@E@F@G@J@KLM@N@O@PQ@RS@TUV@W@X@Y[Z@_\@]@^@`@ab@cde@f@g@hi@j@k@lmnopqr@stvu@w@xyz{|}~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@8@:@;@<@9@=@>@?@@@A@B@J@C@D@E@F@G@H@I@K@L@M@N@O@R@P@Q@S@T@U@V@W@X@Y@Z@[@\@]@^@_@`@a@b@cd@e@f@g@h@i@jklm@nopqrs@t@u@v@w@x@y@}z@{@~|@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@     @@@@@@@@@ @!@"@#@$@%@(@&@'@)@*@2@3@+@,@-@.@/@0@1@4@5@6@7@8@9@:@;@=@>@<@?@@@ABC@DE@FGH@I@J@K@L@MN@O@PQ@R@S@UT@YV@W@X@Z@[@\@]@^@_@`@acb@e@d@fghji@k@l@m@n@o@p@q@rst@u@v@w@}@~@x@y@z@{@|@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @   @ @@@@@@@@ @!@%"@#@$@'&@(.@)@*@+@,@-@/0123@4@5@687@9@:@;<?@@@=@>@AB@CD@EF@G@HI@JKLM@NO@P@Q@R@S@T@U@V@W@X@Y@Z@[@\@]@^@_@a`b@c@d@e@f@g@h@i@j@k@l@m@n@o@p@q@r@st@x@u@v@w@y@z@{@|@@@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@ @!@"%#@$@(&@'@)*@+@,@-@.@/0@51@2@3@4@678@9@:@;@<@=@?>@@A@B@CDE@F@G@H@I@J@K@L@M@ON@P@Q@RSU@T@V@WX@Y@Z@[@\@]@^@_@`@ba@c@d@e@f@g@hi@j@k@l@m@n@r@o@p@q@s@t@u@vwxy@{z@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@&@'@%@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@8@9@:@;@<@=@>@?@@@A@B@C@D@E@F@G@H@I@J@K@L@M@N@O@P@Q@RSWT@U@V@X@ZY@[@\@`@a]@^@_@b@dc@e@fghi@j@k@ml@rsn@o@p@q@t@uv@w@x@y@z{|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@  @ @  @@@@@ @"!@#@$@%@'@&@(@)*@+@,@-@/@0.1@2@3@6@4@5@7@98@:@;@<@=@?>@@ACB@DE@G@F@H@IJK@L@MN@OP@W@X@Q@R@S@T@U@V@Y@Z[@]\@^_@`@a@b@cde@fig@h@j@k@l@m@n@o@p@qr@s@t@wu@v@x@y@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @@ @ @ @@@@@@@@@@@@@@@ !"%#@$@&)'@(@*+,@1@-@.@/@0@2@354@6@7@8@9@:@;@<@=@>?@@@AB@C@D@F@E@G@H@I@J@K@LM@NOVP@Q@R@S@T@U@W@X@Y@Z@[\@]@^@_`a@b@c@d@e@f@g@hij@k@l@m@n@o@rp@q@s@t@u@wxv@zy@{}|@@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@%@@@ @!@"@#@$@@@A@B@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6@7@8@9@:@;@<@=@>@?@C@D@E@F@G@H@I@M@N@O@P@Q@J@K@L@R@S@T@U@V@X@Z@W@Y@[@a@\@]@^_@`@b@c@d@e@f@g@h@i@j@k@l@m@n@po@q@r@s@tu@v@w@x@y@z{@}|@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@ @!"@#$@%@&@'@(@)*+@,@-@.@1/@0@23@45@678@9?@:@;@=@>@<@@@A@B@C@D@E@F@G@H@I@J@K@L@M@N@O@Q@P@R@S@T@UV@W@X@YZ[\@_]@^@`a@b@c@d@e@f@g@h@i@j@k@l@m@n@o@p@q@r@s@t@u@v@w@x@y@z@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @  @@@@@@@@@@@@ @!@"@#@$@%@&@'@,@-@(@)@*@+@./@01@2@3@4@5@67@8@9:@;@<@=@>@?@@@A@B@C@D@E@F@G@H@Id@J@K@L@M@N@O@P@Q@R@S@T@U@V@W@X@Y@Z@[@\@]@^@_@`@a@b@c@e@f@g@h@i@j@k@l@m@n@o@p@q@z@r@s@t@u@v@w@x@y@{@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @  @ @ @@@@@@@@@@@@@@ @!%"@#@$@&@()'@*@+@-.,@2@/@0@1@34@56@7@8@9@:@;@<@=@>@?@@@A@B@C@D@G@E@F@H@I@J@K@L@M@N@O@PQ@R@S@T@U@VW@X@[@Y@Z@\@]@^_`@a@b@c@d@e@f@h@i@j@k@g@l@m@n@op@q@r@s@t@u@v@xw@y@z@}@~@{@|@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @@@@@@ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@'&(@*)+/@,@-@.@3@4@0@1@2@5@7@6@8@9@:@;@<@=@A@>@?@@@B@C@D@E@F@G@H@I@J@K@L@M@N@O@P@Q@R@S@T@U@V@W@X@Y@Z@[\@]@^@_`@a@b@c@d@e@f@g@i@h@m@j@k@l@no@p@q@rst@u@vwxy@z@~@{@|@}@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@.@/@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@O@0@1@3@2@5@4@6@8@9@7@:@;@<@=@>@?@@@A@B@C@D@E@F@G@H@I@J@K@L@M@N@P@Q@R@S@T@U@Y@V@W@X@Z@[@_@\@]@^@`a@c@b@d@e@f@g@jh@i@k@l@m@no@p@q@tr@s@u@v@w@x@y@z@{@|@}~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@  @  @ @@@@@@@@@@@@@@@@@ @!@"@#@$@%@&@'@(@)@*@+@,@-@.@/@0@1@2@3@4@5@6789:@;<=>@?@@@CDEFA@B@G@H@L@I@J@K@M@N@O@P@Q@R@S@V@W@X@T@U@Y@Z@[@\@]^@_@`@a@c@b@de@fhg@i@j@k@l@m@n@o@p@q@r@us@t@v@xw@yz{@|@}~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @ @ @ @@@@@@@@@@@@@ @!@"@#@$%&@'(@)*@+@,@-@.0@/@1@6@2@3@4@5@7@98@:@;@<@=@@>@?@A@B@C@D@E@H@F@G@I@J@K@L@M@N@O@P@Q@R@S@T@U@V@W@X@Y@Z@[@\@]@^@_@`@c@a@b@d@e@f@g@h@i@j@k@l@mn@o@p@q@r@s@t@u@v@w@x@y@{@z@|@}@~@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@@ @ @     @ @ @ @ @ @ @ @ @ @ @  @ @ @   @  @ @ @  @ @" ! @& # @$ @% @' @* ( @) @+ @, - @. @/ @1 2 0 @4 @3 @5 6 7 @8 @9 : @; @< @= @> @? @ @C A @B @D @E @F @G H @I @J K @L @M @Q @N @O @P @S R @U @V @T @W @Z @X @Y @[ \ @] @_ @^ @` @b a @c @d @e @f @g @h @i @j @k @l m @n @o @p @q @r @s @t @u @v @w @y x @z @{ @| @} @~ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ @ !@!@!@!@!@!@!!@!@ !@ ! !@ !@ !!!!@!@!!@!@!!!@!!@!@!@!@!@!@!"!@#!@$!@%!@ !@!!@&!@'!(!@)!@*!+!,!-!@.!@/!0!1!2!3!4!5!@6!@7!@8!@9!@:!@;!@!@?!@@!@A!@B!@C!@D!@E!@F!@G!@H!@I!@J!@K!@L!M!@N!@O!@R!S!P!@Q!@T!@U!@V!@W!@X!@Y!@Z!@[!@\!@]!@^!@_!@`!@a!@b!c!e!@d!@f!@g!@h!i!j!@l!m!k!@n!@o!@r!s!p!@q!@x!t!@u!@v!@w!@y!@z!@{!@|!@}!~!!!@!@!!@!@!@!@!!@!!@!@!@!!!!!!!!!@!!!@!!@!@!@!@!@!@!!@!!@!!!!!!!@!!!@!!!@!@!@!@!@!!@!@!@!@!@!@!!@!@!@!@!@!@!@!@!@!@!@!!@!>????????????????????????@@@@@@@@@@@@@@AAAAAAAAAAAAAAABBBBBBBBCbbbbbbbbbbbbbbbbbbbbbbbbbbbbbbcccc)++++++++,,,,,,,,,,,,,,,,,,,------------............/KKKKKKKKKKKKKLLLMMmmmmmnnooooqqq !!!!""#$$$$$$%%%&&&&&''MMMMNNNNNNNOOOOOOppppppqqqrrstt!"$$$'IIIIIIIJJJJKKKKKKKKLLMOsuvvvwxxx1145TTUUqqq&'HJKLLLMRSc : K N P S q  9 ; ; ; ; < = = > ? ? C w | I J w 3 4 5 s s t u v x x ||~DDEF-33mtt.`R4,M.  $))) !!!""###$h$$%&&(u* , , , , , , , , , , , ,,>1B1B1B1B1145Z7[7[7\7]7]7`7a7f7h77777777f888[;p;<=C>D>??A????aBbBCEEYExEGGGGG5H5H5H5H5H5H5H5H5H5H5HLHLHeIIIJK K K KK1MOOOOOOOOO7O7O8OiOjOpOpOOOOOOOOOPPPPPPPAPFPFPKPKPLPLPhPhPhPhPiPiPiPjPjPjPjPjPPPPPPPPPPQ5Q9Qfk$m$mmmmmmn n n n?nBnynyn|n|nnnnnnnbocooooooooo p pppp?pApGpIpppppwp\qqqqqrrrrrr3s3s5s5s6sss-t-tot"u"u%u_uuuuv5w6w6wwwwyyyy&|}}~.~.~t .j&&&&:lmmooٍqAGGMMC^~!œ##'77QF6DKr66ڪհUддմִ۴|ʼ <K())**02@OOOOOTQRRWWx<""cc^````#(((3E]]/01[;<>??AA]]____0 i i  B G K K K ` ` A       & N P >?II~''')_VWJMWf%f%%3&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&='='s' * *y*z*|***++--.01111222222223333b4~7~7888:::::;<<>K?~?AAA1B1B1B1BGGaHHHHII)J^JJJLLLMMMMMMMN7PPSSSSSSSUUUUUUVV'WTWWXXYY*Y*Y*Y;Y@YKYZ*]dneeeeeefgh"i"i#iouzzzx}{=Hssuwyz{""$`abbbbbbbbcddddЁЁссӁԁՁ         -/PQQRRSuuvvxz<^^  Ff  =>>>>>>>cdd!""$NQX†f PWWXÉȉˉ""4weۋۋ.//113yzz{{{!44BBʓ/@ٖ+7KK֙ٙڙ  67Ӛךٚۚ;Bqqʝʝʝ֝--ؠLѣ$,ƫ@BAABDDDEFFFuѸѸѸӸ8ƼƼɼR\MȾ˾̾̾sssIIii"ADDovpDgjRRK(r}}4999F0DFHHHrru$ <W W Y  E |     +,UvvvvG)666MMhGGJ!!!!))8^^aaCCEZJ"~$z' * ***-------...A.A.C.C.F.t.t.t.....f/u0333333%5(5r:@@@@)L*LPPPPQ6Q6Q6QwQQQQQQQQ4R???dAnACDDDDDDfDmJJsLLLXMXMXMXMZM`MMMMANuNwNNNNNNNNCODODODODOxOyOOOOOPPPP>P^PPPPQQQRR'ShTTTTTTTTTUUZUUU^V^V^VVWWWWW;XX[[[[]a]^__M`|`reenn~ooooooooooooooooo p!p#p#p$pKpLpMpMpNpOpPpzp|ppppppppppppppppqHqKqNqSqTqqqqqqqqqqqqr?r]rrrrrrrrrrrrrrrrrrr`sbscssssssss@t@tBt}ttttttttttttttttttt8u=ucuuuuuuuuuuuuuuvvVvZvZv\v]v^v_v_v`vvvvvwwww wUwwwwwwwww+x-xhxxxxxxxxxqzqzP|]|o|)}0~6~~7ׅ̅؅ΈΈŠllpu:>'q@@tƯƯ56kCFCDHHf`bҸoo3++CG99S{""""22vH*X233>TU_moozVww;>d                        N       K K L L L            EGHH\-''       o s s s s !!!B""########&),......//1/_0k0k0k0001g1g1g1g1g1{44444(5(566$778888889@9::3:4:4:<<<===M>q>L??AAA5B5BIBUB_G_G`GqGnIoIpIJJJhJhJJKLL6LpLLLMNNNPPySS/VYYYYY[[M[M[[n\n\n\z\z\\]M]M]]]]]]eeeeff!g#g$g%g%g%g%g%g%g%g&ghlln3o'q8qrrrrsssssutuw xxy2z3z4zazczH{{{{*|o|o|{|߉UX]ڊۊ܊܊܊݊݊݊݊ފߊ >kklnËËË c  ==>ACEqtuuuuxy~GN_*,,2 \ΦM EQززŸظ߼)^\i5..} "+KKKLLq&._e%%GGGHjkkkkllln778;XYYZZZZZZ[\\\\\]]]]]^^_c00k//##$%WWXXY[\\ "(MP   :vy`` c!p7``bccSAAN%L!!G#G#Y#Y#D%b())))))**S,U,U,Y,Z,B-B-------/000H3A5D9;;;w<w< > >~>~>TATAcAtCtCCC*G_G_G`GcGGGIIIIJJJJJJJJJJJJJJJJJcKeKQLMMNNOIPdUCW9XXYLYLYLYLYYYYZZZZZZZZZZZZe[[[D\u\z\\I]O]O]]^^^&_i_i_}_aka,bbccccnnnntQvUvwxxN{||HvvvZ2ZZ\t^>XXlllnГѓѓ3(Q $AALMMEEββ,448rs66ISz}OOePPPQQS    7##<$$%%A(11:::;l>uKLNATUUUVdlbnrnpp]r sxG|m}m}܁ća..ey߫KuŮ(^iCd=j<<abr55 &)(   b Dn'())))*HHrs      33455778Z]^^`b@Bppwxjkk4#(PPu=6"w"w"w"##%0(C) +++,2,F,`.`.`.6666888888h9k9m9;AABBBBBBBBBBB;C`CdCCCCCCDDDDE6E=ETHI_LlMMMNOPP+S-SkSkSlSSS}T}T}T}TTTT|WYYUZwZZZ]]__ ` `abeewe??i@i@i@9BHIIrIKNKmKmKqKKKKLLMkNNNNNOOPPUX}[]]~^^k_bmf)i3k3kDk|lmmmmmmmm1oooooooooorr3shsktvvxxy{E|E|G|G|8}}@gjȊnW$&'(Qܓ++/00123fДДCFz}X  2788;ʗ24fg>Pzz\Ŵƴdfϵ!!+ڷuýýʽ_<'Fdd~ngBAAB=?ABDDDDH)ddfk     0     & & : : :   " P   > @ @ P     ~  x x x x       ;' ;' %( V* q* * D+ 1, <, >- . . . . . . . . . / / W0 Y0 1 Z2 2 2 2 3 H4 H4 7 ,9 ,9 h9 h9 |: |: |: : : : : : ,; /; 0; S; S; S; T; T; ; ; ; ; ; ; ; ; J= > ^? ? ? +@ 3@ 3@ ?@ B B D D !D E E F F F G J J CP CP `P Q Q RR SR S S S G[ \ a a b gd Xe ^e e e f f ,f vf vf j k k |l m km lm m m n `p Yq q q s s !t t t t t Ev Ov :x x x x x x x x x x x x x x x x y y ,y /y 1y 1y 6y 6y fy fy gy oy y y y y y y y z z z z z z z z z z 9z ;z >z tz uz z z z z z z z z z { { { { { { { >{ >{ { { { { { { { { { { { { | | | | K| L| L| | | | | | | | | | | | | | | | | .} 3} 4} 4} 4} 5} 5} 6} 6} 7} Y} Y} Z} Z} ~} ~} } } } } } } } } } } } } } } } @~ ~ ~ ~  ' ) c d      L a ,       '  ǖ ɗ u ޛ ޛ Q Q Q Q c c ϡ ˥ ˥ ֥ ֥ 2      e ۴ е μ L L   < i  8 8  5   c S c d r Y f f a a a i i { { { } *      Q Q V  @ t E P Z + , M    R g i        '  % Y Z m     & 0    @          . & @ K! # # # $ /$ /$ $ $ 0' ' ) + + + + + + + + + 0 0 1 z3 3 3 3 4 4 8 8 8 8 8 8 8 8 X9 9 9 9 9 9 9 9 ]; !< !< !< !< *< *< *< T< U< V< < < < < < < < < < < < < = != != D= D= E= E= E= E= F= F= G= G= G= G= H= v= = = = = = = = = = = = = = > > > > > > > > > > > > > > ? i? j? ? ? ? ? ? ? ? ? @ @ @ @ @ @ @ @ @ Q@ [@ @ @ @ @ @ @ @ @ @ A A A A A A A >A A A A A A A B B ]B ]B ^B ^B ^B ^B _B `B `B `B aB dB dB eB eB eB eB fB gB gB hB lB pB pB yB B B B hC hC pC pC pC F F F bK dK K K K K L IN N R (R sV V V V V V W |Y Y Y Y XZ c d d ]g ]g gg k gn pn }n op p p Sq [q [q [q gq w w 8x Rx |x |x x y y y y y y z } _} } } } } ~ *~      ҆ =  " Q S S  Č 7   J $ i i A A O ު  ] x x  R S S T r i q r u    $ % &  ' '  Z c  % % q q * * * , , F $ 3 W A  ( ( [   { | } }   , 1 `                     ' ) * W W W X X Y Z ]                                   v               G J J K t        U V W          K Q v            e j           d d " $ & & & & & & & ( ( ( ( ( ( ( ;) <) <) =) ?) ~) ) ) ) ) , , , <1 3 3 5 5 8 8 M: ; ; ; K= T= C >D >D LE @H @H @H @H @H JH vH H H H H H H H H H H H H I I J K IK JK yK }K K K M M M M M PO iO oO pO pO tO tO O P P P P P P S S S S T T T T ^V dV dV W W X X Y Y Y Y Y Z RZ SZ SZ [Z [Z Z Z Z [ 5` ` -a b Gb b b 3c e h Dk k o -o :q :q Eq t t v x x g} {} B W g g i i j Lj ݉ ݉ 3 a ϊ V _ + H u v x { { | @ h h k k Z \ t v - E     . . / M R  ٚ  3 5 X Y y {  ݛ ݛ ޛ _ f @ @ @ A B D D E G n r u  ۞ e g 7       P P ʧ ʧ ˧ ˧ ˧ ڨ ڨ ԩ  O   \ ] @ & ( )    ; < < ȸ k k ` b b t G K K   8   z z   C / 3 4 6 9   > > w w :  2 2   _ D D { 8 8 9 h i i i y   4 5  P 2 2 3 h  H T    % ' * S U U {  t k m  : Q Q Q Q a a g           < ` ` d u     r r   " " " " " @ x z 6 l   3 7 } }          N" Z" # ?$ w$ w$ y$ w% ( ( ) ) ) * , , , , - ,/ / Y0 \0 F3 M3 r3 r3 r3 s3 t3 6 6 6 6 ]9 ^9 : : = B F M M U U \ \ \ \ \ _ ` ` ` ` ` ` ` ` 2a [a f Af Af i i i i Ej \j k l l l m Cn Cn Dn n n n n n io p p fp fp jp *q q q q q s s s Yt v v jv v v v |w ~w Zz [z \z z z | | C} C} C} C} C} C} ~       dž ( $ ^ ^ ^ ^ _ n G O Ƞ Ƞ     D D E E ~ ״ ״ J M 3 3 r r y y 7 u u u F S T | } Q B / 0 > H T T n n o [ o K U & O P X l 7 9  J J J L "  7 o o q   o! o! o! o! r! % % % % % %% O% [& w& w& c( , - - 3 3 8 %: ': y< y< y< y< y< y< y< y< {< ~< < < < < < < < < < < < < < = K= K= L= L= M= = = = > #> )> \> ]> e> > > > > > > > ? =? C? I? I? ? ? ? ? ? ? ? ? ? #@ #@ $@ '@ M@ N@ U@ W@ @ @ @ @ @ @ @ JA RA VA WA WA A A A A A A A B VB B B FQ FQ TQ Q Q Q Q Q Q Q Q T T ?T @T @T NT V W g] i] _ 1` ` ` ` ` Ua za ~a a a a a /b b b b b +c -c -c -c 1c d d d e k o p p p p p p p p q s t t u v xz { { ~ ~ ~ 6 6 E E ) j j K K K [ X Z Z q  T { Ԏ .  I Y ƚ - . . . . 1 1 X ڛ ; ; = > > ? ? ? Μ Μ & D F F F b b b b    S T T V V W W Y [ [ [ ] } } Ǟ  ! " " Ÿ Ÿ ğ ş ǟ ǟ * , l o r ̠ Π Π 3 R R S  ɢ ɢ ˢ ͢     8 գ ֣ ڣ ޣ P X Τ    =      1     ? ò ( ` `  Ҷ u u u < U U )  ! g h i i n 4  } ^ ` q s s S U X 2h  7    @@q`gr !!!\]{XY       3!?@@@@;D$F$F%F%F%FFFeGGGHHHHIIIJJ*M;M)O*O+O,O,O,O-O-O-O3O>P>PFPGP!Q%Q+STQUrW[.]/]4^R^V^5`6`]`@abbbd>>>>>q?r?VAVA{A{AuBD3DeDDmGgHhHiHiHoHIIIJUK[KMNN OOOOOfPiP R R R1RTTTTVTTTT;[=[@[E[M[``_c_ceeeeef^fefhfffiii6iqi|iiilmmm[mpmrmmmmnnnnnnqqqqHrJrdssvvvvvwwyyyyykzkzzzz{{{{!|||||}?78xyy  W    }}}}!(**J'UIS7]]]33hi-77XZ{ЖӖEEEVDD^B\Щ֩'Ūp0nopppp6iQVP{jj.iiGzzz{qq$!!1AAww'IJ    +t++ffLLWW8DGG55?DIc(37-Zsq&;')JFH({<=69??@@ - q Ie}d{de{dܘf{dTg{dh{d,i{d42j{dak{dLnl{dm{dbn{dbo{dbp{dcq{dUr{d\Us{dTt{du{dv{d"w{d#x{d4(y{d\.z{dTe{{d|{d}{d̠~{d${d{dt{d4{d{d{dd{d{d\{d4{dd{d{d {d{dD {d {d {d|{d\{d{dܗ{dU{d{dt{d4{d{d4{d\b{d<{d{d{d<{d, {d {dtV{d{d{d<{d'{dA{dA{d$B{ddB{dB{dB{d$C{ddC{dC{dC{d$D{ddD{dD{dD{d$E{ddE{dE{dE{d$F{ddF{dF{dF{d$G{ddG{dG{dG{d$H{ddH{dH{dH{d$I{ddI{dI{dI{d$J{ddJ{dJ{dJ{d$K{ddK{dK{dK{d$L{ddL{dL{dL{d$M{ddM{dM{dM{d$N{ddN{dN{dN{d$O{ddO{dO{dO{d$P{ddP{dP{dP{d$Q{ddQ{dQ{dQ{d$R{ddR{dR{dR{d$S{ddS{dS{dS{d$T{ddT{dT{dT{d$U{ddU{dU{dU{d$V{ddV{dV{dV{d$W{ddW{dW{dW{d$X|ddX|dX|dX|d$Y|ddY|dY|dY|d$Z|ddZ |dZ |dZ |d$[ |dd[ |d[|d[|d$\|dd\|d\|d\|d$]|dd]|d]|d]|d$^|dd^|d^|d^|d$_|dd_|d_|d|dT |d!|d"|d#|dT$|d%|d&|d²'|dT²(|d²)|d²*|dò+|dTò,|dò-|dò.|dIJ/|dTIJ0|dIJ1|dIJ2|dŲ3|dTŲ4|dŲ5|dŲ6|dƲ7|dTƲ8|dƲ9|dƲ:|dDz;|dTDz<|dDz=|dDz>|dȲ?|dTȲ@|dȲA|dȲB|dɲC|dTɲD|dɲE|dɲF|dʲG|dTʲH|dʲI|dʲJ|d˲K|dT˲L|d˲M|d˲N|d̲O|dT̲P|d̲Q|d̲R|dͲS|dTͲT|dͲU|dͲV|dβW|dTβX|dβY|dβZ|dϲ[|dTϲ\|dϲ]|dϲ^|dв_|dTв`|dвa|dвb|dѲc|dTѲd|dѲe|dѲf|dҲg|dTҲh|dҲi|dҲj|dӲk|dTӲl|dӲm|dӲn|dԲo|dTԲp|dԲq|dԲr|dղs|dTղt|dղu|dղv|dֲw|dTֲx|dֲy|dֲz|dײ{|dTײ||dײ}|dײ~|dز|dTز|dز|dز|dٲ|dTٲ|dٲ|dٲ|dڲ|dTڲ|dڲ|dڲ|d۲|dT۲|d۲|d۲|dܲ|dTܲ|dܲ|dܲ|dݲ|dTݲ|dݲ|dݲ|d޲|dT޲|d޲|d޲|d߲|dT߲|d߲|d߲|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d|d|d|dT|d?#?#|#|#<??B)L)L\\^^Iee3'3'>@}E}EErr''#ƽƽ--116,==<&<&h:h:EEKKXX__```7a7aVaaacc5dpdpd+i+iiiUkUk o-o-o2oQqQq5u5u    ``ȋȋ}}_(66BBww**%%>4F4F/H/HJJbbwhwhhhyy]]QQ++Qnnooyyyǖ>>]T..;;AAii?-?-D-UUcchAAkQkQffԓԓ44SS_lۊZ I+ I+ , , / / : : )< K@ i@ y@ A sB sB S S T N N #M #M 3M { { N N  2  ~ m m  * *    4 G u = ? E? P P r r ʇ ܇ M G   v v $ $ Y Y PZ PZ e e 0 0 7 H H s q q    >   Z99__kkTTC==MMiiurr      !"#$%&'()*+,-./0123456789:;<=>?A@BCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUWVXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|B#B###<??B-L-L\\^^Nkk  ;';'>@EEEtt))!%%ѽѽ//488.??!!A&A&j:j:EEKK$X$X__```9a9aXaaacc7drdrd-i-iiiWkWko0o4o4oSqSq7u7u    bbʋʋa*;;DD}},,%%>:F:F1H1HJJbb{h{hhhyyeeWW,,QnnooyyyɖAA_[ . .==EEooB-F-F-UUgppAAnQnQffۓۓ66WWal݊\ N+ N+ , , / / : : /< O@ n@ @ A |B |B S S T  S S 2M 8M 8M { { T T  8  r r   . .     6 I w = ? G? P P r r ۇ  O I &  | | $ $ Y Y TZ TZ e e 7 7 D M M u } }   D `99(_(_kk]]-PCCMMllwww  !"#$%&'()*+,-./0123456789:;<=>?A@BCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUWVXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|:M*urn:schemas-microsoft-com:office:smarttagsStreet9f*urn:schemas-microsoft-com:office:smarttagsStateBh*urn:schemas-microsoft-com:office:smarttagscountry-region;N*urn:schemas-microsoft-com:office:smarttagsaddress9}*urn:schemas-microsoft-com:office:smarttagsplace8{*urn:schemas-microsoft-com:office:smarttagsCity=*urn:schemas-microsoft-com:office:smarttags PlaceType=*urn:schemas-microsoft-com:office:smarttags PlaceName \}}{{}{}}}{}}{{}{}}}}}h}f}}{}}{}f{}{}{}{}{}{}f{}NM{}MMM{}{}}{}{{}}{ff}{}{}{}f}{{}{}{}{}}{{}{}{{}{}{{}{}{{}}{{{}f{}{}}{{}{}{}{}{}{}{{}{}{}}}{}{}}f{}{}f{}}{}{}{}f}}{}f}h{}{}{}}h}f}f}{}f}}f}}}}}{}}{}{}}{}}{}f{}f}f}{}f}f}{}f}h}{}h}{}}f}}}h}}{{}}}}{}}}{}{}f}f{}}hh}}h}h}f}}{}}h{}}}}}}}}}h}}f}h}h}h}f}}{}f{}}}}}}}}h}{}}}}}hh}h}h}h}f}NM{}}{}{NM}{f}}f}}{{}}h}h{}}}}{}{}}}{f}f}}{}}}f}{,4H2N2ZZ[[HHK K 7H BH $ ( Ě ǚ $TTU UYYKSMNvv!` (` # * c #f%f\iciin!.JXNX33333333333333CC2N2e@fii^X^XXXXXH2N2qv"Q H]u?C"dvF4`zĈ %N NwCR6jbf$8SNd|~L;ڦ#$dl0)R0).0v*d:tF0B\:KRp5v-(ж( hTr%Ҁ9AB8P'd`xJRO#v04+)<q+ \P~A+o< bn 恾&f Wp (eY J l$n<t p~0{ NpX3 pj32( U{$  0:    f7b [ b*D\ 705f=5l\am"/=E\_25V&G}$ Av"#,bv$>,iTmuSJRoSDQt`o$XzB,ΐ#lf"Ь@Z;"cPE0|m.\" Ȏ$!8i% ~{u *r+ xT P!>dZD "x0"f1"ܤn/-#6p#zvI#C#MQ#HE#b}Sc#GZ|$J>8,%P{f%Fd. &N`.&$69&tx\&KQ&J' &6v('>x'2gD'M2(F7zNNt_(G4'( z5(^~b(Mt(xrh@))NLP)CpkF)`}f)q|*4or<*2DNf/+ q/+|w9+8|o+ZOO+4;+x6+MX f,Fp,NVj u'-D6Q- */y-P;{B--rA*- T.H%Wt.T_.HEs.:ff$.$*/ d6/Foh//<]y06*U 1*1$,2\e2\ppA2fk2"H@3%hnlJ3"Cw3 "30(24t%P4G#D4Hd{4{u256hLEi5 %5"*5֛ZR6h0[_7^qd47b yl7d`-57ZPtb]8[Hn8bC&)9*d`n9SOz9^(9Cfo:о");ֵv*;46*(;jϚ=*;jS55I9>& /O> !&g>?NDcy?G?z|c? h{?SzQ?휝=@J?@TRj@eP@eJ@ b@Mtq@pe)tB]IaBzNBl|%BJʄraBfPo ChZ(JCtcPC|Cπt96D o@2EfLwEY{jF4\G9Ff2 \FsldGY*GLY}GR "0fOG$ fIUfGl4*C H[@DgH JH#d'bH>jH5fHpMHPRj"Iު@Nx0Iz fI?tI؀^BI~ jI.NJ&J @cFJ;-EJDY qiJv? 6KXRG*K<,nL.:D!L|z8aLZM@M*¤R0pQMZLfhvMFEHxM8$sM8 ;MDjM nNjSx4cNzWOYF_0OFP(O }`OuV Pd?SP摪UPze lCPUP"PRI.QrFQLQvg&*QRowRz%SXܶ 3SPZyCSnQhSP+Z`ETSZT \^6Tr~<:TYuTdTJTR&T*^"TpQ&UvmAU!eUw =UBVr%frS{lfNl$+g, (gDb^Wg:L3#uh~h `hbĺkip+$NiiHN}iL,S4jRUjxv(`j{pjh$mAkNLhk7f'k~XulD!lV#$m8\mv|b?s~k$Xt&.Wtvʆ2 u09^ r:uj u"4IuB VvFVWrsv_?vNegwxx5|$wMwć,QnwZ:chqwF)w-Qw.1 w|m{wTcG4ax~cf#y@x`TBxI_y -yFe;z,V83Dz6 Kz1s{ EF V{JJN{:HaR2|e-te|Ь@v|t8l'}p?zp}| d}BiN~Ud&~k8J~Ԁ~Ȗ{ Ь@z5 ?WI ODh}\n hh^h`OJQJo(h ^`OJQJo(  ^ `OJPJQJ^Jo(-h   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJ QJ o(hHohpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh | | ^| `OJQJo(h LL^L`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh \\^\`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH888^8`OJQJo(hH8hh^h`OJ QJ ^J o(hHo888^8`OJQJo(hH8^`OJQJo(hH8  ^ `OJ QJ ^J o(hHo8  ^ `OJQJo(hH8xx^x`OJQJo(hH8HH^H`OJ QJ ^J o(hHo8^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hH8  ^ `OJQJo(hH8^`OJ QJ ^J o(hHo8  ^ `OJQJo(hH8  ^ `OJQJo(hH8xx^x`OJ QJ ^J o(hHo8HH^H`OJQJo(hH8^`OJQJo(hH8^`OJ QJ ^J o(hHo8^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH^`o()^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo( ^`OJQJo( ^`OJ QJ o(ohpp^p`.h@ @ ^@ `. ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH^`o()^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hH^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`o(()h pp^p`hH.h @ L@ ^@ `LhH.h ^`hH.h ^`hH.h L^`LhH.h ^`hH.h PP^P`hH.h  L ^ `LhH. ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(88^8`OJQJo(hH^`OJ QJ ^J o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH hh^h`OJQJo( hh^h`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH8 pp^p`OJ QJ o(o8 pp^p`OJ QJ o(o8 @ @ ^@ `OJQJo(8 ^`OJQJo(8 ^`OJ QJ o(o8 ^`OJQJo(8 ^`OJQJo(8 PP^P`OJ QJ o(o8   ^ `OJQJo(h^`OJQJo(hHh| | ^| `OJ QJ ^J o(hHohLL^L`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh\\^\`OJ QJ ^J o(hHoh,,^,`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh  ^ `OJ QJ ^J o(hHohxx^x`OJQJo(hHhHH^H`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohX X ^X `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh88^8`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh   ^ `OJ QJ o(oh   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`.h^`.hpLp^p`L.h@ @ ^@ `.h^`.hL^`L.h^`.h^`.hPLP^P`L.h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h@ @ ^@ `OJQJo(hHh ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHohpp^p`OJQJo(hHv@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH88^8`o(()^`. L ^ `L.  ^ `.xx^x`.HLH^H`L.^`.^`.L^`L.h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH pp^p`OJQJo( @ @ ^@ `OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( PP^P`OJQJo(   ^ `OJ QJ o(o ^`OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH hh^h`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH^`OJ QJ o(hHo  ^ `OJ QJ ^J o(hHo  ^ `OJQJo(hHxx^x`OJQJo(hHHH^H`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h88^8`OJQJo(hH^`OJ QJ ^J o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(88^8`OJQJo(hH^`OJ QJ ^J o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJ QJ o(hHohpp^p`OJ QJ ^J o(hHohpp^p`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH^`. ^`hH.h$ $ ^$ `. @ @ ^@ `hH. ^`hH. L^`LhH. ^`hH. ^`hH. PLP^P`LhH.^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(^`o(.  ^ `. L ^ `L.xx^x`.HH^H`.L^`L.^`.^`.L^`L.h 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h   ^ `OJ QJ o(oh   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo( ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo( ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oA  ^ `OJPJQJ^Jo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHhpp^p`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHh!!^!`OJ QJ ^J o(hHoh$$^$`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH^`OJPJQJ^J.pp^p`.@ L@ ^@ `L.^`.^`.L^`L.^`.PP^P`. L ^ `L.h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJ QJ ^J o(hHohxx^x`OJQJo(hHhHH^H`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohX X ^X `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hH hh^h`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hH^`OJQJo(hH8pp^p`OJ QJ o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h hh^h`OJQJo(h 88^8`OJ QJ o(oh ^`OJQJo(h   ^ `OJQJo(h   ^ `OJ QJ o(oh xx^x`OJQJo(h HH^H`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH hh^h`OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH ^`OJQJo(h^`OJQJo(hH pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJ QJ o(hHoh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH hh^h`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( ^`OJ QJ o(o8 pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(^`OJQJo(hH ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(^`o(.pp^p`o(.@ L@ ^@ `L.^`.^`.L^`L.^`.PP^P`. L ^ `L.h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhX X ^X `OJ QJ ^J o(hHoh(#(#^(#`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJ QJ o(hHohpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJ QJ ^J o(hHohxx^x`OJQJo(hHhHH^H`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohX X ^X `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH^`o(.pp^p`.@ L@ ^@ `L.^`.^`.L^`L.^`.PP^P`. L ^ `L.h ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH88^8`o()^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo( hh^h`OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hH^`OJQJo(hHh^`OJQJo(hHpp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(^`OJQJo(hH^`OJQJo(hH pp^p`hH. @ @ ^@ `hH. ^`hH. ^`hH. ^`hH. ^`hH. PP^P`hH.h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(^`o()^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h X X ^X `OJ QJ o(oh (#(#^(#`OJQJo( ^`OJQJo(   ^ `OJ QJ o(o   ^ `OJQJo( xx^x`OJQJo( HH^H`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH  ^ `o(.  ^ `.xLx^x`L.HH^H`.^`.L^`L.^`.^`.X LX ^X `L.hpp^p`OJ QJ o(hHoh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(^`OJPJQJ^Jo(h ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h  ^ `OJ QJ o(hHoh  ^ `OJ QJ ^J o(hHohxx^x`OJQJo(hHhHH^H`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohX X ^X `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJ QJ o(hHohpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH88^8`o()^`. L ^ `L.  ^ `.xx^x`.HLH^H`L.^`.^`.L^`L.h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h88^8`OJQJo(hHh^`OJ QJ o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`.hpp^p`.h@ L@ ^@ `L.h^`.h^`.hL^`L.h^`.hPP^P`.h L ^ `L.h@ @ ^@ `OJ QJ o(hHoh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hH^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hH  ^ `OJ QJ ^J o(hHo  ^ `OJQJo(hHxx^x`OJQJo(hHHH^H`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(^`OJPJQJ^Jo(h pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h88^8`OJ QJ o(hHoh^`OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h88^8`OJQJo(hHh^`OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH^`o()^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h 88^8`OJQJo(h ^`OJQJo(h   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h88^8`OJQJo(hHh^`OJQJo(hHh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH hh^h`OJQJo(^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hH ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h   ^ `OJ QJ o(oh   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH hh^h`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(^`CJOJQJo(^`CJOJ QJ o(opp^p`CJOJQJo(@ @ ^@ `CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(^`CJOJQJo(PP^P`CJOJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(h ^`OJQJo( pp^p`OJ QJ o(o @ @ ^@ `OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( PP^P`OJ QJ o(o   ^ `OJQJo( ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(h^`OJ QJ o(hHohpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh^`OJ QJ o(hHohpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh^`OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh  ^ `OJQJo(hHhxx^x`OJQJo(hHhHH^H`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh  ^ `OJQJo(hHh  ^ `OJ QJ ^J o(hHohxx^x`OJQJo(hHhHH^H`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohX X ^X `OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH^`OJQJo(hH88^8`OJ QJ ^J o(hHo^`OJQJo(hH  ^ `OJQJo(hH  ^ `OJ QJ ^J o(hHoxx^x`OJQJo(hHHH^H`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHpp^p`OJ QJ ^J o(hHo@ @ ^@ `OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hHPP^P`OJ QJ ^J o(hHo  ^ `OJQJo(hHh 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(^`o(.^`.pLp^p`L.@ @ ^@ `.^`.L^`L.^`.^`.PLP^P`L.h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h   ^ `OJ QJ o(oh   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHhpp^p`OJQJo(hH8@ @ ^@ `OJ QJ o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHPP^P`OJQJo(hH  ^ `OJ QJ ^J o(hHo^`OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh!!^!`OJQJo(hHh$$^$`OJ QJ ^J o(hHoh`'`'^`'`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH88^8`o(()^`. L ^ `L.  ^ `.xx^x`.HLH^H`L.^`.^`.L^`L.^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo( 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h TT^T`OJQJo(h $$^$`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh dd^d`OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h   ^ `OJ QJ o(oh   ^ `OJQJo(h xx^x`OJQJo(h HH^H`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h 88^8`OJQJo(h ^`OJ QJ o(oh   ^ `OJQJo(h   ^ `OJQJo(h xx^x`OJ QJ o(oh HH^H`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(pp^p`o(.^`o(() L^`LhH. ^`hH. ^`hH. L^`LhH. PP^P`hH.   ^ `hH. L^`LhH.88^8`OJQJo(hH^`OJ QJ ^J o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHopp^p`OJQJo(hH@ @ ^@ `OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHoPP^P`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h^`OJQJo(hHh ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hH hh^h`OJQJo( ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHhpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hH88^8`OJQJo(hH^`OJ QJ ^J o(hHo  ^ `OJQJo(hH  ^ `OJQJo(hHxx^x`OJ QJ ^J o(hHoHH^H`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h 88^8`OJQJo( ^`OJ QJ o(o   ^ `OJQJo(   ^ `OJQJo( xx^x`OJ QJ o(o HH^H`OJQJo( ^`OJQJo( ^`OJ QJ o(o ^`OJQJo(h^`OJQJo(hHh^`OJ QJ ^J o(hHohpp^p`OJQJo(hHh@ @ ^@ `OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hH^`OJ QJ o(hHo  ^ `OJ QJ ^J o(hHo  ^ `OJQJo(hHxx^x`OJQJo(hHHH^H`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo(h^`OJQJo(hHhpp^p`OJ QJ ^J o(hHoh@ @ ^@ `OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHhPP^P`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh@ @ ^@ `OJ QJ o(hHoh^`OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHohPP^P`OJQJo(hHh  ^ `OJQJo(hHh^`OJ QJ ^J o(hHoh!!^!`OJQJo(hHh ^`OJQJo(h ^`OJ QJ o(oh pp^p`OJQJo(h @ @ ^@ `OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh PP^P`OJQJo(h88^8`OJQJo(hHh^`OJ QJ ^J o(hHoh  ^ `OJQJo(hHh  ^ `OJQJo(hHhxx^x`OJ QJ ^J o(hHohHH^H`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hH88^8`o(.^`. L ^ `L.  ^ `.xx^x`.HLH^H`L.^`.^`.L^`L.h pp^p`OJQJo(h @ @ ^@ `OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h PP^P`OJQJo(h   ^ `OJ QJ o(oh ^`OJQJo(^`OJ QJ o(hHo  ^ `OJ QJ ^J o(hHo  ^ `OJQJo(hHxx^x`OJQJo(hHHH^H`OJ QJ ^J o(hHo^`OJQJo(hH^`OJQJo(hH^`OJ QJ ^J o(hHo^`OJQJo(hHh ^`OJQJo(h pp^p`OJ QJ o(oh @ @ ^@ `OJQJo(h ^`OJQJo(h ^`OJ QJ o(oh ^`OJQJo(h ^`OJQJo(h PP^P`OJ QJ o(oh   ^ `OJQJo( ^`OJQJo( ^`OJ QJ o(o pp^p`OJQJo( @ @ ^@ `OJQJo( ^`OJ QJ o(o ^`OJQJo( ^`OJQJo( ^`OJ QJ o(o PP^P`OJQJo(hpp^p`OJQJo(hHh@ @ ^@ `OJ QJ ^J o(hHoh^`OJQJo(hHh^`OJQJo(hHh^`OJ QJ ^J o(hHoh^`OJQJo(hHhPP^P`OJQJo(hHh  ^ `OJ QJ ^J o(hHoh^`OJQJo(hHuO#P@%(Z;"{B- 96DXul1' &Oz5 fIuTl4S-nnkiN Ld/= w8]g^(24*5-EJ JHhvMDgH yl7'xdRj@ 3S_P).Q(b]8!k8J~LEi5*-Cr@2E&T3 Ujv|cNMwQ yCSZes-y"r:u-QwN~{wG9F`O#y@x+,%QxWI9ABUA|o+r%Wg(9T\+gl'}5voh/n$,2kF)=@{jF\M[ \FQ&UGX#D4S4jD "?vsMCRf%kmGr )XNdQ?}i(2 u nN%f=5(H@3 vEP(`jOO+fo:G_G*Kw9+#,gG[Yy?G?fHfOG4axQ(TM0{ 8^zBjbzQhSM2(gwRCR|c {]Z~N{I?u= ]E#*U 1|CpA2);Z|$ ?SP#uh(JCf=$Xt%Wt."TUPk2Yfov*Av"rs?tI'kIu*/y-Wrsv[_7Q# B\4'(69& uP"PzsYZT0: $ u7Cw3I_y6Q-@T=  {lfu'-03cFJId6/c.]i%}JTzp}$dtq@ /O>MJr=*;8`&f Bu "3~0pQMhqwnwy%5r<*<(cY r+ x'TBxJ&J+$Ni*;+o< z %`h+qXLQE_~VvYZ jIT &)9HoDQ1s{^v2( 4s[y0" Sc#obMs?@. &`.&9f)dGD!LaR2|*/T.|c?,Z{4&g>hrP!p#wEMH@\7 X)wKRdSo5#$m (g>jHgD'qXo$4qhL`B=U~FddWaZR6[Ba-V\Nt_(pjlCP_0O,nL  ? 6Kt\^6TEHxM4;^q+t%P4wS5<jU`Nx0I_.gmAkF,4^Oz9hDzAA4e04+p,xU`IUfGu?}GiaB)R0 KzeUlJ3C HEbC#|V+*\S^oM@M Arp d} P dq/+b? _ ?k y  y{lGSHR*wD !/@ESndy*D/LoTfqen S-YZp$&IRksz "0pcEu$$IOkz$F>TBFL&(-oPuDSwK2fl~>  /0QRSTY_fP8g:H.J[l`q0tu>sxH0t:BJN]`i}   U# 4 `^ om s .u w z !!)!3!>!i@!^!"&""+"G"]")###{#NM#a#O#$ $b$u$#$ %$&%5/%9%#R%je%j%;~%&%&A+&-&''%'5('5'B='Y'ic'x'}'~' ((>(?(Vb(Mq(Z )5)E6)C)N)_V)e)'f)|)*e**(*/*z:*@*jT*b*++++ +C+`+,g+k+z+#,;,[@,Ki,Q-"[-o-+{-^-.B..$.].b.S}.a /F/f/Xo/u/00J0b-0]0+1C1W1_1f1g1Jv12R2{V2+Z2]2333!3x#3Y364,4<455%0585":5Q5ok5*{5"6 &6&6M6N6o6`x6|6}6V 77L7[7/g7sw7z+8\18D8~899s9(9959J9_9*:n+:%;in;ho;y;%};<<I<`i<x<=Q!=K4=B=R=4T=d=i==g>u>{>??=1?2?H?fV?@0@ <@L@g@BACAwAmBBaWBjB^lB|B.C@CbOC4PCrCDG+DtD8E@ECEDEwEF@'F/F2FZF]F9iFsFxF6G>GIGXGSYG H-HTHyH IJI}WI J(JKJ}J&KL K,KVKIhKvKzKLLb"Ls>L/MLNLSL]LwL:zL/LMM)M1M?M+TMbMpMqNwN)&N5NhN7}NOXO4[OxqO[wOnP PPP"PLBPgdP Q5QQ'QBQJQaQyQ RvURaRCjR1S $S-S%3S(KSoSmVT[T_TGpTuT -U4dUVVVQFV_MVUV)aVbVd~V~V<WJ/WIWbdW6XbXNkX5oXpuX4Yr0Y"4Y;Y^qYZ-Za5ZA;Z;Z>Za[)[H0[n8[kA[B\yI\J\vX\^]]] ]1]B]K]m]^;^)J^t^w^8z^{_)_0_!]_w_}_`;-`ea$a$aNl'l)l^lilml|BmXmnn#n1%n4nj@n6Gn"`nJjnnoo!o)o,o3oFoQoYokop2pMpq; qq!q2qQqTqdqreqN rrp&r(r?rGrgJrKrKr"Vr4wrV(s5sZstt%tCtWtjtpt;stVytLu4u0RuQ[ueulu%quIqusuvgvww "w/wk1wHwIwLw5Zw{xxx\x0x>x|CxQDxJxdxy6y0|:]|Fi|m|}3};}=}F}ZH}'T}/Z}_}d}t}Q~~~K&~5~j~A4Pe||29xItZX;abv# ))*1G{aU/]>'>,9mBo_p'DFu?b;fP(DIx $[$gV%.&v7yaTsJpKKP1 p #)sW355B)}` U'Rmfsyz #-Hv_a~iM{S %)/<=\G:YY6 $$W)/,9-.A)C-DPUVu:u+E3H/UaVdemz- SUZ78CZu,-V?`zz j((fH?I9j?ntt lZ..P?_\cJ%3TEPXWn ;'009I_14y<p}v[ q4E\dVfZI9|HRr$"()/1B% 0"zIKqOw-}9 EhX_ x$&DojD\Lbr t$#$l0\BR DNI=RSx;X'',NPk "%.p-/j}z ?<Ndq!Y#?P2htiru++aah6~$LXk7]w>INEfm?l)FMUi97(9[se A/1e57PSkF} s!(,/?MW{|/8B]KSY\jDlt|~ ":>J7S _pq qjsz~Kv~="*.KRU/>MCFX4irG{GKT'XYu'Z9J M oC?o%o79<=]jh}@D[Fac^tz  01;}k6B]; c+<LgbqA-I-:KfMKcol/ C!{"->FQGd8 ,6C!H8XYq-ux-zt_%VlV[ k,-2Q7+Z;=GGx+ 5Z7Bttfzf#7>H\`vJx %W1:;EFZoosr&s;.RG<c[f7qJ _ ){>i$68D Q`Uhx*W@X\t&x,.CSZ $h3e_/;;=]{P|V=^`ioKp? FMd R,/iNVZM #v(8ikyw $(R0M IGVpa0*At^8;v C'(77: :9:R:S:Y:::: ; ;";F;G;[;;;;;;;<<$<p<q<r<<<<<<<====>>>!?"?jjjj*j3jCjRjSjXjjjjjjjkkk/k0k6kkkkkk:=V++++++++++,,-,?,@,T,,,,,,,---A-B-R-S-T-HHHHHHHHHHHHIIIUIXIYI]IIIIIIIIIIIIJJJJJ%J&J'J4|5|F|I|Y|l|s|}|~||||||||||||||||||||||||||||||||||||||||||||}}}}}}#}.}/}0}1}2}3}>}B}C}D}E}F}G}S}\}]}^}_}`}a}i}r}s}t}u}v}w}x}y}z}{}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}}~~ ~ ~ ~~~~~~'~(~)~*~+~E~F~G~H~I~R~S~T~U~V~Y~Z~[~\~]~f~g~h~i~j~t~u~v~w~x~|~}~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~"#$%&-./01<=>?@ NOSijoȍɍ͍̍΍эҍӍ׍%&*+,j  xy01J+ !CEFP)*5464i444+5l6m6z666677798:8E8889Y9Z9h999^^^^^_ _ _Y___b`c`m`Ga[b@cddddde'e(e1eeefffffffffffcgwggggUh+iiiii8jjklkmkkkSll&m'm?mmm(nnn Rn'()F (3456CLMNO  !%)*.7BHMSTBCXЗїefw˜٘56-M6M>MDMHMIMOMZMdMnMoMzMMMMMMMMMMMMMMMMMMMMMMMMN #8DEbdix| !*/9:UW\ahmn 5PUZ`ef|Α->?Kcdt    / C D G 0    # \ a ڃ ۃ    1 2 N Y Z r Ą ń      , W X    $ % 7 > B I J ) 9* :* D* r* s* * * * * * * * * * * * * * + + + 3+ 4+ A+ z+ {+ + + + + + + q q q q q q q r r r @/B/CوىيiiWWWWWWWBWC>S>T>|>}>>>>>>>>h4h5VWcdjkBCmn55!"%%%I%JKLMRRљњѢѣѧѨAo Ap At Au   L= L> L? L@ LA LO LP Ld Le ~       4 4 4 4> 4? R S km kn k~ k   J J V V V V ) * L M q r    g h    9Q9R999  2`@`D`F`@`L`@``@@``@``@``@@``L@``p@``|@``@``@``@```@``@``@``@` `@``0@`"`H@``0@``H@``d@``@`*`X@`Z`@`l`@`r`@```|@``@``@``@`&`P@`z`@`` @``p @`` @`` @`` @`` @`2`4`l @`v` @``8 @``T @``d @``` @`` @`` @`&`P @`.`` @`:`x @``( @`` @`` @``<@`"`$`L@`N`@`z`@`6`p@`>`@`r`@`x`@``T@````@``@``@` `@` ` @`f `@` `@` `@`r `@` ` ` ` `d@` `@` `@` `@`& `P@`* `, `\@`J `@`P `R `@`f `h `@` `|@` `@` `@` `@`< `|@`V `@`Z `@`t `@` `@` `4@` `p@` `@``@`X`@`l`@`t`@`x`@``8@``D@``L@``@``@@`:`x@``@`HD@`x"`D@`"`E@`"`dE@`F@UnknownGz Times New Roman5Symbol3& z Arial;Wingdings;FLydian BT7& [ @VerdanaM ChickenScratch AOE7V  Stencil7Beatles?5 z Courier NewO  Rockwell Extra Bold;39 SmoothG"Copperplate33bcKpTimes New Roman5"Tekton?& Arial Black5& AvalonCFComic Sans MS9GaramondA Alleycat ICG5&  ImpactM& A.C.M.E. ExplosiveE& Britannic Bold5& zaTahoma"h&i f 84f 84$4dLL 7QXZ ?k2 Pathology Will ManuelWilliam Manuel                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                                   ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                                                      Oh+'0 $ D P \ ht| Pathology Will Manuel Normal.dotWilliam Manuel281Microsoft Office Word@2fV@4Bye@. C@0& f ՜.+,D՜.+,L px   MDCapsuleJ48L'  Pathology Title 8@ _PID_HLINKSA`> . environmental . methemoglobinemia}+ pharm.docepo ^} pharm.docgcsff<z pharm.docamphobWw pharm.doc cefepimeMt pharm.doczosynMq micro.docstaphepidermidis^n micro.docstaph+dkpics/bmt-complications.gif. h. gvhdpse. hearttransplant}`b. renaltransplantfk_. lungtransplanteh\. livertransplantp:Yprocedurevids/. p:Vprocedurevids/. txSpics/prevertebralemphysema.jpg. spP. endocarditisprophylaxisrmMpics/cardiacpreop-acp2.jpg. rnJpics/cardiacpreop-acp1.jpg. dyG.  transplantxfD. traumatt;. Wilsons4853http://dermis.net/dermisroot/en/34987/diagnose.htm. }w/. hemolyticanemia,.  vitamindhs).  pseudotumor&.  leukemiaI# pharm.doc accutane . acne .  psoriasisqp. megaloblasticanemia%y$http://en.wikipedia.org/wiki/Legume. E@pics/hartnups.jpg. ~? pharm.docniacin,cpics/pellagra-hands.jpg. YK pics/pellagra.jpg. cw. Pagets .  Wernickes .  vitamink.  vitamine.  vitamind.  vitamina.  vitaminc~k. folateb1. b12Ip.  _pyridoxinefd. niacin~r.  riboflavin.  thiamine P pharm.doc drugsofabuse . organophosphates$0;http://pier.acponline.org/physicians/public/d890/d890.html. (0http://www.acponline.org/bioterro/nerve_gas.htm. 0  more/acuteradiationsyndrome.pdf. T micro.docebolaH micro.doclassaH micro.dochemorrhagicfeversS micro.doc smallpoxb= micro.docanthrax-e#http://www.acponline.org/bioterro/. id. ida . methemoglobinemiaRZpics/aldrichmeeslines.jpg. pics/chronicerythroderma.jpg. )ppics/lir-porphyria.jpg. .  fanconis. calciphylaxispv. pvd953http://dermis.net/dermisroot/en/42531/diagnose.htm. <13http://dermis.net/dermisroot/en/42574/diagnose.htm. .  neurofibromayapics/neurofibromatosis.jpg. . cafe?53http://dermis.net/dermisroot/en/23420/diagnose.htm. 4;3http://dermis.net/dermisroot/en/39866/diagnose.htm. kt. ktwac. sturgets. tsnf. nf1{~. ehlersl9pics/drugwarfarin2.jpg. l:pics/drugwarfarin1.jpg. @~ pharm.doc warfarindi{. dicrhxpics/drug-lamictal2.jpg. qhupics/drug-lamictal1.jpg. Kr pharm.doc lamictalTo pharm.doc tegretol}jlpics/drug-dilantin1.jpg. ~jipics/drug-dilantin2.jpg. @f pharm.doc phenytoin\Bcpics/drugpustular.jpg. dv`pics/lichenoid.jpg.  ]pics/drug-urticaria2.jpg.  Zpics/drug-urticaria1.jpg. }:Wpics/drugmorbilliform2.jpg. I[Tpics/drugmorbilliform.jpg. y!Qpics/drug-morbilliform.jpg. *%Npics/drugamiodarone.jpg. Kpics/argyria.jpg. daHpics/drugbleomycin.jpg. ;3E3http://dermis.net/dermisroot/en/13645/diagnose.htm. hsB. hsp^?pics/ten1.jpg. <1<3http://dermis.net/dermisroot/en/30254/diagnose.htm. %*9pics/stevensjohnson.jpg. B6"pics/erythemamultiformemajor1.jpg. T3pics/emmajor1.jpg. b40#pics/erythemamultiformetarget3.jpg. b5-#pics/erythemamultiformetarget2.jpg. b6*#pics/erythemamultiformetarget1.jpg. W'pics/erythemamultiforme3.jpg. U$pics/erythemamultiforme1.jpg. V!pics/erythemamultiforme2.jpg. 053http://dermis.net/dermisroot/en/30218/diagnose.htm. 843http://dermis.net/dermisroot/en/43431/diagnose.htm. .  typethree;03http://dermis.net/dermisroot/en/30140/diagnose.htm. >;3http://dermis.net/dermisroot/en/29366/diagnose.htm. S pharm.docerythropoetin61 3http://dermis.net/dermisroot/en/40853/diagnose.htm. ?3 3http://dermis.net/dermisroot/en/26713/diagnose.htm. @ pharm.doc tetracycline7>3http://dermis.net/dermisroot/en/29935/diagnose.htm. urpics/bullouspemphigoid.jpg. !?pics/pemphigoid.jpg. 9;3http://dermis.net/dermisroot/en/29664/diagnose.htm. "pics/pps4em.jpg. 86pics/conjunctivitis.jpg. Ppics/pps2scaldedskin.jpg. !pics/paraneoplasticpemphigus.jpg.  Ipics/pps1oral.jpg. `> pharm.doccorticosteroidskvpics/pemphigus.jpg. ?<3http://dermis.net/dermisroot/en/29511/diagnose.htm. pk. typetwokr. typeonezb.  cellulitis|* micro.doc scaldedskinb; micro.doccapitis9:3http://dermis.net/dermisroot/en/29476/diagnose.htm. 5<3http://dermis.net/dermisroot/en/11499/diagnose.htm. :53http://dermis.net/dermisroot/en/36070/diagnose.htm. :53http://dermis.net/dermisroot/en/36070/diagnose.htm. s  micro.docvzvte. ten~> micro.docscabiespc. pct .  pemphigus.  lichenplanus .  impetigosr. erythemamultiforme. epidermolysisbullosarg. eczemacg. dermatitisherpetiformis. contactdermatitiszb.  cellulitis{w.  pemphigoidsl. slew= micro.doc Pseudomonas=;3http://dermis.net/dermisroot/en/36097/diagnose.htm. =;3http://dermis.net/dermisroot/en/36097/diagnose.htm. O pharm.doc erythromycin=73http://dermis.net/dermisroot/en/30730/diagnose.htm. 963http://dermis.net/dermisroot/en/30526/diagnose.htm. 163http://dermis.net/dermisroot/en/36249/diagnose.htm. h&pics/melanoma3.jpg. <=3http://dermis.net/dermisroot/en/18014/diagnose.htm. =4|3http://dermis.net/dermisroot/en/17570/diagnose.htm. =:y3http://dermis.net/dermisroot/en/18065/diagnose.htm. q=v pharm.docifn$%spics/amelanoticmelanoma.jpg. h'ppics/melanoma2.jpg. h$mpics/melanoma1.jpg. <5j3http://dermis.net/dermisroot/en/18195/diagnose.htm. hngpics/malignantmelanoma.jpg.  d!pics/dysplasticnevussyndrome.jpg.  Napics/dysplasticnevus3.jpg.  N^pics/dysplasticnevus2.jpg. N[pics/dysplasticnevus1.jpg. 61X3http://dermis.net/dermisroot/en/37428/diagnose.htm. 4<U3http://dermis.net/dermisroot/en/20986/diagnose.htm. 32R3http://dermis.net/dermisroot/en/21179/diagnose.htm. O. neurofibromatosis:4L3http://dermis.net/dermisroot/en/37575/diagnose.htm. FOIpics/melanocyticnevus.jpg. Z@Fpics/acquirednevi.jpg. ;5C3http://dermis.net/dermisroot/en/19487/diagnose.htm. 83@3http://dermis.net/dermisroot/en/25427/diagnose.htm.  =pics/pyodermagangrenosum.jpg. X:pics/pyodermagangrenosum3.jpg. X7pics/pyodermagangrenosum2.jpg. X4pics/pyodermagangrenosum1.jpg. 9013http://dermis.net/dermisroot/en/31053/diagnose.htm. 7&.pics/sweets.jpg. N+pics/kaposissarcoma-mouth.jpg. <6(3http://dermis.net/dermisroot/en/27156/diagnose.htm. ly%pics/pyogenicgranuloma.jpg. <5"3http://dermis.net/dermisroot/en/21601/diagnose.htm. n`pics/spiderangioma.jpg. 853http://dermis.net/dermisroot/en/40613/diagnose.htm. 943http://dermis.net/dermisroot/en/22725/diagnose.htm. ;+pics/hemangioma.jpg. <03http://dermis.net/dermisroot/en/37036/diagnose.htm. pics/acrochordon.jpg. 8* pics/keloid.jpg. 83 3http://dermis.net/dermisroot/en/22350/diagnose.htm.  *pics/dermatofibroma.jpg. nf. nf1;73http://dermis.net/dermisroot/en/23404/diagnose.htm. u;pics/scc-tongue.jpg. Epics/scc-lip.jpg. vpics/majolinsulcer.jpg. =43http://dermis.net/dermisroot/en/19297/diagnose.htm. :<3http://dermis.net/dermisroot/en/18406/diagnose.htm.  pics/bcc.jpg. :<3http://dermis.net/dermisroot/en/18406/diagnose.htm. 4+pics/sebaceouscarcinoma.jpg. ?33http://dermis.net/dermisroot/en/23246/diagnose.htm. ;43http://dermis.net/dermisroot/en/35352/diagnose.htm. -v pics/actinickeratosis-hands.jpg. V>http://dermis.multimedica.de/dermisroot/en/36857/diagnose.htm. 69pics/epidermoidcyst.jpg. V>http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htm. V>http://dermis.multimedica.de/dermisroot/en/22214/diagnose.htm. HMpics/sebaceousadenoma.jpg. W>http://dermis.multimedica.de/dermisroot/en/21934/diagnose.htm. |k. tumorsyndromesx{.  melanocytic .  dermaltumorsOmore/endoscopy/mi_sy_01.htm. T micro.doc syphilisT >http://dermis.multimedica.de/dermisroot/en/32735/diagnose.htm. ^>http://dermis.multimedica.de/dermisroot/en/33781/diagnose.htm. >33http://dermis.net/dermisroot/en/32551/diagnose.htm. HJpics/lichenplanus.jpg. _>http://dermis.multimedica.de/dermisroot/en/32882/diagnose.htm. u/ pharm.docmtxCpathology.doc vitamina*7pics/psoriasishands.jpg. kapics/psoriasis.jpg. Mpics/psoriasis-knees.jpg. x3pics/psoriasis-back.jpg. P >http://dermis.multimedica.de/dermisroot/en/31346/diagnose.htm.  .  psoriatic??3http://dermis.net/dermisroot/en/19720/diagnose.htm. }. mycosis{2 micro.doc malasseziaa; micro.doccandidaV micro.doctinea903http://dermis.net/dermisroot/en/14607/diagnose.htm. mtpics/contactdermatitis.jpg. 953http://dermis.net/dermisroot/en/14554/diagnose.htm. j2} pics/seborrhoeicdermatitis5.jpg. k2z pics/seborrhoeicdermatitis4.jpg. l2w pics/seborrhoeicdermatitis3.jpg. m2t pics/seborrhoeicdermatitis2.jpg. n2q pics/seborrhoeicdermatitis1.jpg. kanpics/seborrhoeicdermatitis.jpg. |:k pharm.doc tacrolimus^h pharm.doc cyclosporineKe2http://www.dermnet.com/moduleIndex.cfm?moduleID=2. JTbpics/atopicdermatitis.jpg. =;_3http://dermis.net/dermisroot/en/27284/diagnose.htm. 16\pics/eczema.jpg. /gYpics/eczema-fingers.jpg. tqVpics/acanthosis-malignant1.jpg. kySpics/acanthosis-benign3.jpg. jyPpics/acanthosis-benign2.jpg. iyMpics/acanthosis-benign1.jpg. DJpics/acanthosisnigricans1.jpg. KG2http://www.dermnet.com/moduleIndex.cfm?moduleID=8. :0D3http://dermis.net/dermisroot/en/41156/diagnose.htm. @\Apics/foreignbodygranuloma.jpg. ?7>3http://dermis.net/dermisroot/en/42210/diagnose.htm. A;"pics/pseudoxanthomaelasticum2.gif. A8"pics/pseudoxanthomaelasticum1.gif. M5 micro.doclepraym2.  sarcoidosis:;/3http://dermis.net/dermisroot/en/37282/diagnose.htm. d/,pics/vitiligo1.jpg. K)ddx.docen97&3http://dermis.net/dermisroot/en/30437/diagnose.htm. t8# pharm.docdoxepiny%  pharm.docatarax|)http://www.dermnet.com/. 0`/http://dermis.net/dermisroot/en/home/index.htm.  . pediatricskinz{. skincongenital . leukocytoclastic. dermatitisherpertiformissr . erythemamultiforme. epidermolysisbullosa . herpesgestationis{w.  pemphigoid .  pemphigus.  subepidermal{t. intraepidermalkz. vesiculobullous. acne .  melanomanf. melanocyticpremalignant. melanocyticbenignx{.  melanocytichg. kaposisom.  hemangiomaswo. dermaltumorsbenign .  dermaltumors`t. epidermalmalignant. epidermalpremalignantdl. epidermalbenignrl. epidermaltumors~y.  pityriasis. lichensimplex.  lichenplanus .  psoriasisrw. papulosquamouss{.  skinfungal. contactdermatitisb~.  seborrheicgg. atopics{.  eczematous .  skindrugs. osteomyelitisv1 pharm.doc alendronatecw. pagets 1http://www.annals.org/cgi/content/full/137/6/529. `6 pharm.docbisphosphonates. OsteomyelitisD pics/kneeexam-aim.jpg. oa. oa . inflammatoryjointdisease1http://www.annals.org/cgi/content/full/139/7/575. . bonemalformations.  fracturespw.  lowbackpain . knee.  osteoporosisdz~.  bonecancer{. bonemalformationsxmx.  orthopedics5?u3http://dermis.net/dermisroot/en/19924/diagnose.htm. Nr.  mycosis1`"opics/htlv1.jpg. rblpics/htlvlungs.jpg. "ti$pics/burkittslymphoma-starrysky.jpg. $%fpics/all-l3.jpg. 3&c$pics/lymphomatoidgranulomatosis.jpg. dz`3http://content.nejm.org/cgi/content/full/356/5/504. ya]. tumorlysissyndromezsZpics/reedsternbergcell.jpg. d%W#pics/hodgkins-nodularsclerosis.jpg. DT pharm.docmopp`8Q micro.docebv N micro.dochhv8m3K micro.dochiv OH pharm.doc rituximabYE labs.docspep`nB.  amyloidosisC?ddx.dochyperviscocityk5< pharm.doc Bortezomib(`9 labs.docalkalinephosphatase_6 labs.docupepY3 labs.docspepT0%pics/multiplemyeloma-plasmacells.jpg. `n-.  amyloidosisX*pics/mgus-comparisons.jpg. V'pics/mgus-workup.jpg. IR$5http://content.nejm.org/cgi/content/full/355/26/2765. 8(!http://content.nejm.org/cgi/content/full/342/17/1255?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&titleabstract=myelofibrosis&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jou. p8 pharm.doc hydroxyureaN pharm.doc imatinib#t labs.doclapKpics/cml-granulocytes.jpg. . downsdi. dicr8 pics/chloroma3.gif. r9 pics/chloroma2.gif. r:pics/chloroma1.gif.  [pics/aml-auerrods.jpg. C2pics/hairycellleukemia-cytoplasmicprojections.jpg.  pics/cll.jpg. k pics/cll-bcells.jpg. `p. homocystinurian1pics/proteinc2.jpg. n2pics/proteinc1.jpg. ?5pics/livedoracemosa.jpg. papics/livedoreticularis.jpg. r6 pharm.docheparin?}pics/h-clottingcascade.jpg. tm. tmasl. sleL_5http://content.nejm.org/cgi/content/full/348/15/1425. @ pharm.doc warfarin .  antithrombin.  proteins .  proteinc . antiphospholipidij. diabeteshypercoagulabledi. dictt. ttpx~. thrombocythemiapr. prv.  buergersor. behcetssl. slepn. pnh. Dysfibrinogenemia`p. homocystinuriazp.  prothrombinap. apc~;$pics/hypercoagulable-prevalance.jpg. ?}pics/h-clottingcascade.jpg. ?43http://dermis.net/dermisroot/en/25652/diagnose.htm. I pharm.docddavpn|. cryoprecipitateff. ffpdi. dicr6 pharm.docheparinl> pharm.doclovenoxP_pics/thrombin.gif. ?}pics/h-clottingcascade.jpg. ts. Hypercoagulabilityd6 pharm.doc argatrobanK| pharm.doc lepirudinJy pharm.docivigf(vddx.docthrombocytopeniaE\s5http://content.nejm.org/cgi/content/full/355/16/1699. dip. dicapm. apaitj. itpttg. ttphid. hitf(addx.docthrombocytopeniavw^. vwd][ micro.doctsstitX. itp}wU. hemolyticanemiaR.  plateletsO. ivign|L. cryoprecipitateffI. ffpNF pharm.doc pneumovaxCpics/sicklecellsmear.jpg. MU@pics/sickledcells.jpg. E =pics/eye-icterus.jpg. }i:.  splenectomyo"7ddx.doc splenomegaly#t4 labs.doclapf(1ddx.docthrombocytopenia.. hypophosphatemiac8+ micro.docbrownreclusespideru-( micro.doc mpneumoniael4% pharm.doc methyldopa\"*pics/microspherocytes-hemolyticanemia.jpg. tt. ttpdi. dic&|4http://www.nejm.org/content/1997/0337/0020/1441.asp. s&0pics/hypersegmentedneutrophil-b12deficiency.jpg. gk micro.docb19[Xpics/microcyticanemia.jpg. q5  pharm.docinhG )pics/microcytic-irondeficiencyanemia.jpg. *4http://www.nejm.org/content/1999/0341/0026/1986.asp. md. mdsL_pics/schistocytes.jpg. . myelofibrosis . spherocytosis.  porphyriaj{.  thalassemiaid. ida}w. hemolyticanemiazd. aplasticanemia|n.  bonemarrow`v. peripheralsmear . reticulocytecount]pics/pallor-nails.jpg.  .  anemiaddx|t. coldagglutininsMpics2/hematology.html. ?spics/f-clottingcascade.jpg. ?}pics/h-clottingcascade.jpg. {}. sezary. lymphoblasticou.  adulttcell.  lymphomat .  burkitts . largecelllymphomaqg.  cleavedcell. smalllymphocytic.  lymphomabnh. nhl .  hodgkins.  lymphoma. histiocytosesnn.  monoclonalq.  heavychainwm. wmcl. multiplemyelomasw.  plasmacell .  leukemoidpr. prvx~. thrombocythemia. myelofibrosiscm. cmlok. myeloproliferative.  hairycellcl. cllam. amlal}. allalz. allw.  leukemiahst. hsphuq. husttn. ttp k. hellph.  renaldicaie. renalthromboticzpb.  prothrombinap_. apcap\. apatsY. hypercoagulabilityz~V. vonwillebrandsuoS.  hemophiliaP.  coagulationapM. apaitJ. itpttG. ttphiD. hitf(Addx.docthrombocytopenia >. thrombocytopeniaj{;.  thalassemiasn8.  sicklecell5. hemoglobinopathyzd2. aplasticanemia /. hellp}w,. hemolyticanemia ).  anemiaddx&.  anemiaworkupmb#. anemiaqb . transfusionmedicine.  oncologyKP5http://content.nejm.org/cgi/content/full/356/15/1545. .s labs.docafpm9 micro.dochcv P pharm.docmetronidazoleQ pharm.docpenicillamine#t  labs.doclapa2. a2[ labs.doc ferritinhc. hccBU5http://content.nejm.org/cgi/content/full/350/23/2383. c#. a1lungsC pharm.doc ursodiol7 pics/n-psc2.gif. 4 pics/n-psc1.gif. ~j.  cholangitispf4http://content.nejm.org/cgi/content/full/332/14/924. -f labs.docalkphos.x labs.docama.x labs.docama~j. hemochromatosistt. wilsonsj9.  alpha1liver^ micro.doc hepatitis!'pics/portal.jpg. . hepaticencephalopathyZddx.docascites.  yolksactumorhc. hccZpics/hbv2.jpg. Zpics/hbv1.jpg. g+ micro.docviralhepatitislabs.  pedbilirubinhc. hcchc. hcafn. fnheh. livertransplantus. liverneoplasia.  portalvenouszs.  pncirrhosisij. portalcirrhosissb. sbpv. ascites~j. hemochromatosistt. wilsonsj9.  alpha1liveror. biliary~j.  cholangitis. cholecystitis`u. cholelithiasisl`.  gallbladder . nashgc. autoimmunehepatitisan~. alcoholichepatitisg+{ micro.docviralhepatitislabsn=x micro.doc hepatitiscn<u micro.doc hepatitisbn?r micro.doc hepatitisa^o micro.doc hepatitisl.  hepatitis i.  liverlabsDIf micro.doc#ebvWc. #itpd7` pharm.docvaccine]. mrcp~jZ.  cholangitis)iW labs.docgastrinIT pharm.doc streptozocinr<Q#pics/autoimmunepancreatitis-ct.jpg. KVN5http://content.nejm.org/cgi/content/full/355/25/2670. k0K pharm.doc didanosinerdH.  gallstones{cE. chronicpancreatitis\B.http://content.nejm.org/cgi/video/355/19/e21/. s>? pharm.doc Irinotecan-=< pharm.doc5fuR9pathology.docshortboweldeficiencyes6pics/carcinoidsyndrome.jpg. OZ35http://content.nejm.org/cgi/content/full/355/22/2349. 0. ovary\D-pics/peutzjeghers.jpg. nh*. nhl'pics/intussusception.jpg. E$more/endoscopy/mi_gs_01.htm. R!pics/paracolicabscess-ct.jpg. SCpics/radiationproctopathy.jpg. ql$pics/radiation-stenosis-jejunum.jpg. K_5http://content.nejm.org/cgi/content/full/344/24/1846. C pharm.docsulfasalazineiypics/ulcerativecolitis.jpg. ps. pscsr . erythemamultiformeR ddx.docerythemanodosum. ankylosingspondylitisps. psc.  ibdtreatment. ankylosingspondylitisj}.  renalstonesuc. ucbi. crohnsNpics/sf-whipples.jpg. Upics/whipples-mri.jpg. ]M9http://www.google.com/search?hl=en&q=whipple%27s+disease. TJ2http://content.nejm.org/cgi/content/full/356/1/55. b1. b12 . esophagealcancerkb. meckelscg. dermatitisherpetiformisrjpics/celiacdisease.jpg. cg. dermatitisherpetiformisd~3http://content.nejm.org/cgi/content/full/344/7/510. G labs.doc fecalfatql$pics/radiation-stenosis-jejunum.jpg. b6. b6. gvhdw$ micro.doccryptosporidiumg( micro.docgiardiaC micro.doc yersiniaC micro.doccampylobacter|5 micro.doc salmonellaX micro.doc shigellaQ micro.docehecf= micro.doc cdifficileZ micro.doc difficilef< micro.docsaureusnopics/infectiouscolitis.jpg. m' micro.doc calicivirusc, micro.doc astrovirusr' micro.doc adenovirusx. micro.docnorwalkH micro.doc rotaviruspics/ischemiccolitis.jpg. c{3http://content.nejm.org/cgi/content/full/345/9/669. ~n. hpylorif~3http://content.nejm.org/cgi/content/full/356/8/820. . portalgastropathy. portalgastropathynn. nntcx. gastriclymphoma~n|. hpyloriwty.  perniciousvpics/stomach.gif. ojs.  celiacsprue{ap.  sclerodermal<m pharm.docreglanh+j pharm.docppig.  barrettshdd. plummer{8apics/glossitis2.jpg. x8^pics/glossitis1.jpg.  [.  peutzjeghersslX. sle~cU. reitersorR. behcetsKDOpics/oralhairyleukoplakia.jpg. Lpics/oralcandidiasis.jpg. HI pharm.docopioidwithdrawal!eF labs.docalbumin(`C labs.docalkalinephosphatase&{@ labs.docinr=.  vitamind :.  vitaminKb17. b12dm4. stoolosmolalityj71ddx.doc diarrheaY.pics/normal-colon.jpg. R+pics/paracolicabscess-ct.jpg. cn(.  gilymphomain%. carcinoidtumorsfa". fapac. coloncaxz. intestinetumor .  obstructions .  whipplesoj.  celiacsprue. malabsorptionuc . ucbi . crohnsib. ibdib. ibd.  diarrhea|p. diverticulitis. avmintestinalzr. mesentericischemiagm. varices . intestinevascular. pedintestinal.  intestinemk.  peritoneum .  appendixl`.  gallbladder . liver .  pancreascx. gastriclymphoma . gastriccarcinomahh. gastricvaricespu. pud}z. stomach . esophagealcancer . sclerodermaesophagus. sdes . transferdysphagia .  achalasia. gerd . esophagealinjurysj. herniasxe. esophagealringsq}. esophagealwebsq|. zenkers.  givarices.  esophagus.  salivary. oralEddx.docgibleed.  diarrheas9ddx.docabdominalpaina< micro.docdf2pn. pnha; micro.doccandidap9 pharm.dochbvm8 micro.dochbvh; micro.docmaif7 micro.doccmvH micro.doc cryptococcusC} micro.doctoxoplasmosisu9z micro.docpcp Lw pharm.dochrzeh.t micro.docmtb^q micro.doc hepatitisn micro.dochhv6e)k micro.docmeaslesIh micro.doc exanthemsu$e micro.doc toxoplasmat7b micro.doc nmeningitisp/_ micro.doc hinfluenzaQ\ micro.doc pneumococcusTY micro.doc listeriaUV micro.docecolit)S micro.docstrepb]SPpics/purpurafulminans.gif. t7L micro.doc nmeningitist7J micro.doc nmeningitismlG.  meningitisOD pharm.doc erythromycinu3A pharm.doc macrolidesz(> pharm.doc cefuroximea,; micro.doc trachomatisC8 micro.doc chlamydiau-5 micro.doc mpneumoniaeQ2 micro.doc pneumococcusJ/ micro.doc agepneumonia,. dtapO) pharm.doc erythromycinQ& micro.doc pertussisD#more/endoscopy/mi_tr_01.htm.  S  pharm.doc ribavirin}s.  tracheitisG micro.docparainfluenzaG micro.docparainfluenzam+ micro.doc rhinovirusG micro.docparainfluenzaG micro.doc influenzaz(  pharm.doc cefuroxime . croupt* micro.docstrepaQ micro.doc pneumococcusQ micro.doc pneumococcusp/ micro.doc hinfluenzaeb. ebv. psgnmw. rheumaticfevereb. ebvw2 micro.doc mycoplasma8<3http://dermis.net/dermisroot/en/10181/diagnose.htm. b" micro.doc enterovirusSpics/herpangina-foot.jpg. Mpics/herpangina-hand.jpg.  Rpics/herpangina-lips.jpg. . gerd@ pharm.doc macrolideO pharm.doccephalosporinD pharm.doc augmentinw= micro.doc pseudomonasf< micro.docsaureus] micro.doc moraxellap/ micro.doc hinfluenzaQ micro.doc pneumococcusm) micro.dochsvrn. ConjunctivitisQ micro.doc pneumococcus. skinhs. hsvf* micro.docsyphiliscongenital . congenitalinfections .  pedimmuneQ micro.docrmsf.  endocarditisg( micro.docgiardiaC micro.doc yersiniax. micro.docvibrioU micro.docecoliX micro.doc shigella|5 micro.doc salmonellax. micro.docnorwalkH micro.doc rotavirus.  pedsepsis.  diarrhea.  childhooduti~k. bacterialmeningitiswe~. viralmeningitisC{ micro.doc chlamydiaTx micro.doc listeriat)u micro.docstrepbt*r micro.docstrepaf<o micro.docsaureusxtl. childhoodpneumoniab"i micro.doc enterovirusr'f micro.doc adenovirusc. bronchiolitis`. bronchiolitiseb]. ebv Z. croup W.  pertussis T.  epiglottitis{tQ.  pharyngitisosN. otitisfxK. pedsconjunctivitis H. heentFE micro.doclyme^B micro.doc hepatitisT? micro.doc syphilism*< micro.dochpv9.  chancroids*6 micro.doc trichomonas|(3 micro.doc ngonorrhealg0. lgvC- micro.doc chlamydiam)* micro.dochsvm3' micro.dochivt:$ micro.doc parvovirusv3! micro.docmalaria`. micro.doc Leishmania`8 micro.docebv. toxoplasmosiss, micro.doc bartonella .  whipplesB. hsv1H  micro.doc cryptococcusT  micro.doc listeriaz< micro.docherpesT micro.doc listeriaT micro.doc listeriap/ micro.doc hinfluenzaT micro.doc listeria@ micro.doc neisseriab" micro.doc enterovirusQ micro.doc pneumococcusQ micro.doc pneumococcusU micro.docecoliQ micro.doc pneumococcus@ micro.doc neisseriat) micro.docstrepbt|. latexagglutinationpanelp:procedurevids/. [ pharm.docbacteriocidal @ pharm.docciproM pharm.doc rifampinr' pharm.docdiamoxlp. lpq5 pharm.docinhs2 pharm.docnsaidsk' pharm.docbactrimsa. sahwe. viralmeningitisT micro.doc listeriap/ micro.doc hinfluenzat7 micro.doc nmeningitisQ micro.doc pneumococcusU micro.docecolit) micro.docstrepbx{. meningitisorganisms . agemeningitisi9 micro.doclcvT micro.doc syphilis_ micro.docmumpsf7 micro.doccmv micro.dochsv1lp. lpb" micro.doc enterovirus . cnsamoebiasisC micro.doctoxoplasmosisH micro.doc cryptococcus. chronicmeningitis~k. bacterialmeningitiswe. viralmeningitisE|pics/epiduralabscess-mri.jpg.  ypics/epiduralabscess.jpg. AQv5http://content.nejm.org/cgi/content/full/355/19/2012. oxs. epiduralabscessp. osteomyelitischronicm. osteomyelitisvasculartaj. osteomyelitisvertebraluzg. osteomyelitiscontiguousLtd. _osteomyelitishematogenousvua. osteomyelitismechanismsfl^. osteomyelitisrxt([ micro.docstrepct*X micro.docstrepaexU3http://content.nejm.org/cgi/content/full/344/3/205. {tR.  pharyngitisO.  lemmieres83L3http://dermis.net/dermisroot/en/10777/diagnose.htm. I. osteomyelitisF.  fasciitis|zC. peritonealinfectionxt@. childhoodpneumonia=.  pneumoniaje:. sepsisw~7. pyelonephritisj-4 pharm.docanticholinergic1.  childhoodutiLJ."pics/lir-anaerobicglycolysis2.jpg. OJ+"pics/lir-anaerobicglycolysis1.jpg. f=( micro.doc cdifficileHV%5http://content.nejm.org/cgi/content/full/355/16/1643. ".  pedsepsis. osteomyelitiswbcscanj{Bhttp://www.hopkins-id.edu/education/id_caserounds/index_case.html. bugs/. Z micro.doc. .  childhoodj7ddx.doc diarrheax;  micro.docfungus J  micro.doc parasitologyco. exotic. opportunisticzm.  hematologicm) micro.dochsvC micro.doc chlamydia^ micro.doc hepatitism3 micro.dochivj|. sexual.  endocarditispi. pid|z. peritonealinfection. osteomyelitiscy. infectiousarthritiszb.  cellulitisml.  meningitis.  pneumoniaw~. pyelonephritisut. utixm. primaryje. sepsisd3http://content.nejm.org/cgi/content/full/356/6/601.  . neuroblastoma`s. mccuneac. sturgenf. nf1me. menS labs.docreninX labs.doc Cortisol3~ labs.doc AldosteroneS labs.docreninre.  acanthosis`s. mccune.  secondaryhtnd3http://content.nejm.org/cgi/content/full/356/6/601. . adrenalcarcinomavj. adrenaladenoma. corticotrophicadenomatt. wilsonsme. mennk. sarcoid. hypercalcemiame. menh2 pharm.doc amiodarone. Hypothyroidismofpregnancy. thyroidneoplasmsB[ pharm.doci131B[} pharm.doci131f-z pharm.doc methimazoleh/w pharm.docptuMtpics/eye-exophthalmos.jpg. noq. celiachon. hoarck.  hashimotoscwh. gravesmae. hypothyroidismb. thyroidinfectious_.  thyroidstormcw\. graves ]Y pharm.doclevothyroxineV. thyroidneoplasmsrsS.  thyroiditismaP. hypothyroidismpiM. hyperthyroidismJ. thyroidmalformationsG.  siadhddx[D pharm.doc desmopressin A. nephrogenicdi >. craniopharyngiomav); pharm.doc octreotideH]85http://content.nejm.org/cgi/content/full/355/24/2558. 5.  aniongapie2. cardiacenzymesfh/. hyperlipidemia.$,@http://content.nejm.org/cgi/content/short/347/17/1342?query=TOC. W) pharm.doc diabetes10&3http://dermis.net/dermisroot/en/37833/diagnose.htm. #pics/necrobiosis.gif. A pics/diabetes-yellow.jpg. ss. acanthosisnigricans. pcos)f labs.docfshE labs.doc prolactinX labs.doc cortisol .  diabetes  . neuroblastoma. paraganglioma. pheochromocytomamd. adrenalmedulla`s. mccuneca. cah . conns.  addisonswd. adrenallymphomavj. adrenaladenomaut. adrenalhyperplasia.  cushings}`. adrenalme. men. parathyroidneoplasms`g. parathyroidhyperplasia . pseudohypopthhb. hypopth.  hyperpth`s.  parathyroid. thyroidmalformations. thyroidneoplasmsrs.  thyroiditisma. hypothyroidismpi. hyperthyroidismbs. thyroid . siadh . diabetesinsipidus . hypopituitary. pituitaryadenoma .  pituitaryhg. hepaticadenomaUI2http://content.nejm.org/cgi/content/full/345/1/55. 1http://www.annals.org/cgi/content/full/146/6/425. .  gauchersfp. crigler.  dialysis373http://dermis.net/dermisroot/en/24078/diagnose.htm. )ppics/lir-porphyria.jpg. b1. b12}>pics/lir-metabolism.jpg. gp. clottingcascadeq;pics/lir-glycolysis.jpg. }>pics/lir-metabolism.jpg. cw. alports073http://dermis.net/dermisroot/en/10038/diagnose.htm. am. aml{u~. cysticfibrosis{. hereditaryangioedemanfx. nf1 u. hocm~ir. marfans o. myotonicdystrophygul.  huntingtonscmi. cmtf. Dysfibrinogenemiavwc. vwfme`. men ]. apkdttZ. wilsons~jW. Hemochromatosisc#T. a1lungs Q. juvenilepolyposis N.  peutzjeghers K.  gardnersfaH. fap E.  gilbertsmeB. men;6?3http://dermis.net/dermisroot/en/12300/diagnose.htm.  <. neuroblastoma 9. pedtumorother 6. pedtumorrenal3. histiocytoses 0.  hodgkins-.  pedcnstumors*.  leukemia(v' psycdrug.doclithium^$. tof1vs!. vsd.  williamsjl. jlnoa.  praderwilli~i. marfans`a. edwardsci. turners . downsir .  coarctation.. _patentductus . avvalvemalformations . transpositionto. tofvs. vsdas. asdeh. livertransplant . liverf= micro.doc cdifficile- 2http://en.wikipedia.org/wiki/Kleihauer-Betke_test. qb. transfusionmedicineE pharm.docphenobarbitalbp. bpd.  pneumoniaze.  surfactantbp. bpdze.  surfactantze.  surfactantc& pharm.doc teratogens. developmentimmune. muscleenergydisorders{g. hepatichypoglycemiaig. glycogenstorage . Mucopolysaccharidoses . lysosomalstorageea. otherenzymedeficiencies`x.  aminoacids.  metabolicci. turners. downs}i. genetic.  pedtumorsse. pediatricneurob~.  seborrheicgg. atopic . pediatricskinvk. stills.  pedhearthy. pediatricliver. pedintestinalab. abo.  bilirubin. pediatricheme. lungmalformationsuz. pedrespiratory.  disrupted |. morphogenesis y.  maternalv. teratogenesisdos.  metabolismp.  vaccinesm.  childhoodz8j pharm.docBCG g.  teratomau/d pharm.docmtx`|a3http://content.nejm.org/cgi/content/full/356/8/842. !~^mailto:pharm.doc#bleomycin. H[ pharm.doc etoposideJX pharm.doc cisplatin.sU labs.docafp'vR labs.dochcg~kO. testicularlymphomaL. sertolicelltumorjuI. leydigcelltumor F.  teratomartC. choriocarcinoma @. yolksactumormale}g=. embryonalcarcinoma :. nsgct7. spermatocyticseminoma4.  seminoma1.  SeminomatousF.ddx.doc smalltestesJ+ pharm.doc flutamideo1( pharm.doc finasteride|w% pharm.docalpha1blockers>8"3http://dermis.net/dermisroot/en/14781/diagnose.htm. /?pics/bowens.jpg. uk.  accuminatum;03http://dermis.net/dermisroot/en/14003/diagnose.htm. pics/verrucavulgaris.jpg. M micro.doc ctrachomatism) micro.dochsvT  micro.doc syphilis . testicularcancer|. testicularinfectionbb. testes|d.  prostatecabp. bph.  prostate . penism, pharm.doc metyrapone.  cushingsKU5http://content.nejm.org/cgi/content/full/355/21/2237. c& pharm.doc teratogens . hellpae. ectopicc& pharm.doc teratogensH[5http://content.nejm.org/cgi/content/full/355/22/2338. c8 pharm.doc tolterodinek5 pharm.doc oxybutynin.  osteoporosisg9 pharm.doc exemestaneY pharm.doc Tamoxifen533http://dermis.net/dermisroot/en/17409/diagnose.htm. 1http://www.annals.org/cgi/content/full/122/7/539. cw. pagets.  klinefelters. testicularcancer . ovarianmetastaticse. ovarianstromald. ovariangermcell . ovarianepithelial'v labs.dochcg.s labs.docafpF labs.docca125ku.  krukenberg]ddx.doc amenorrheau/ pharm.docmtx. ovariantumorsMddx.docpostmenopausalbleedings* micro.doc trichomonas|( micro.doc ngonorrheab}pics/cluecells.jpg. bc. bcc?93http://dermis.net/dermisroot/en/14295/diagnose.htm.  pics/condylomata.jpg. ~> micro.docscabies_ micro.doc molluscumlg. lgv.  chancroidca}. cahinz. arrhenoblastomaCw pharm.doc metforminy2t pharm.docspironolactone Vqddx.docoligomenorrhea]nddx.doc amenorrhea k.  prolactinoma h. pmofe.  menopausejhb. femalehealthmaintenance _.  incontinence`p\.  femaleotherdY. ovariangermcell V. ovarianepithelial S.  ovariancaP. pcosgsM. follicularcystsJ. ovary G. fallopiantubeWD. _gestationalcagzA. endometriummesenchymal>. endometrialneoplasia;. endometriosisdk8. endometriumfxnqc5.  endometriumz}2.  cervicalcaci/. cinxk,. cervixi). vagina&. vulva#. breastcancerscreening .  breastcatg. breastpi. pidbv. bvbq. femaleinfectionhx.  obstetrics]ddx.doc amenorrheaM ddx.docpostmenopausalbleeding',pics/eye-pterygium1.jpg. "pics/eye-pterygium.jpg. &qpics/eye-hyperemia.jpg. ":pics/eye-hordeolum1.jpg. 'ipics/eye-hordeolum.jpg. r' pharm.docdiamox|" pharm.doc pilocarpinej?pics/eye-gerontoxon.jpg. W pics/eye-dermoid.jpg. ! pics/eye-chalazion2.jpg. " pics/eye-chalazion1.jpg. 'spics/eye-chalazion.jpg. p%pics/eye-arcusjunenilis.jpg.  ^pics/eye-actinickeratosis.jpg. 5~pics/eye-rothspots.jpg. ms. ms+'pics/eye-crao2.jpg. +$pics/eye-crao1.jpg. Fpics/eye-crao.jpg. /4pics/eye-cvro2.jpg. +3pics/eye-crvo1.jpg. Qpics/eye-crvo.jpg. n:pics/retinalveinocclusion1.jpg. x" pharm.doc Bevacizumabpics/eye-hypopyon-uveitis.jpg. *| path.docbehcets Mpics/eye-candidaretinitis.jpg. a; micro.doccandida]pics/eye-cmvretinitis.jpg. wh#pics/eye-keratitis-aspergillus.jpg. VY"pics/eye-keratitis-adenovirus.jpg. lcpics/eye-keratitis-hsv.jpg. ZZpics/hypopyon.gif. [pics/eye-endophthalmitis.jpg. GK&pics/eye-bacterialconjunctivitis1.jpg. B%pics/eye-bacterialconjunctivitis.jpg. L!pics/eye-viralconjunctivitis.jpg. XTpics/eye-conjunctivitis1.jpg. l6pics/eye-conjunctivitis.jpg. ] pharm.doc temozolomide`{. acousticneuromams. ms"! pics/postconcussionsyndrome.jpg. . pics/concussion.jpg. }*pics/concussion-management.jpg. b{3http://content.nejm.org/cgi/content/full/356/2/166. ~.  vitaminah"{ pharm.docsynemetvxx.  parkinsonsa{u.  alzheimersAr pharm.docssris2o pharm.docnsaids/rl psycdrug.docvpai.  glaucomaicf. ichcvc. cvaml`.  meningitisn+] pharm.docvpaPZ pharm.doc ethosuximideTW pharm.doc tegretolIT pharm.doc dilantinw6Q pharm.docseizureN. alcoholicseizureseqK. febrileseizuresgsH. status|dE. absenceicB. icpml?.  meningitis <pics/eye-cn6palsy.jpg.  9pics/eye-cn3palsy.jpg.  R6 pharm.doc thrombolysis3.  cvasyndromesyy0.  fatembolismbe-. lymphomatoidgranulomatosishw*. carotidstenosis '. cnsvasculitis$. venoussinusthrombosisic!. ichcv. cva| pathology.docectS pharm.doc clonidine_ pharm.doc levodopab! pharm.doc dantroleneT pharm.docbromocriptinedv . dvtep . rhabdomyolysis.  hypocalcemia]_ pharm.docp450c5 pharm.docstatins D micro.doc botulismuq.  acromegaly . conns.  hyperpthpi. hyperthyroidismma. hypothyroidismgc. gca'`pics/pmr-hands.jpg. .  polymyositis .  mcardles7 .  _werdnig . conns . myopathyotherep. rhabdomyolysisem. emfib. ibmmg. mglh. polymyositismuscle. myopathyinflammatory. myopathymitochondrial .  mcardles. emeryd|. beckers .  duchenne .  muscularkz. myopathycongenital.  Sjogrensdm. dmo9 micro.docjcw{.  marchiafava] pharm.doc pemolinef5 pharm.doc amantadinej.  stiffpersonljpics/msddx.gif. orpics/multiplesclerosis.gif. . opticneuritisem. emg D micro.doc botulism.  porphyria\ micro.docpolioal. als. cidpms. msmg|. mgj y pharm.doc pramipexole"+v http://www.utmed.com/psychiatry. Ms pharm.doc RiluzoleAnphttp://content.nejm.org/cgi/content/full/344/22/1688?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1688&journalcode=nejm. nmm. nmsh"j pharm.docsynemetm{g.  shydragers`8dhttp://www.alz.org/. z:a pharm.doc risperidoneu:^ pharm.docariceptnp[. nphb1X. b12maU. hypothyroidismR.  dementia O.  serotoninepL. rhabdomyolysisf<I pharm.docflagyl QF pharm.doc lactulosefdC. niacin~k@. folateb1=. b12:.  thiamineic7. icp 4. cnsvasculitis 1.  cnsneoplasiab1.. b12tt+. wilsonsze(.  hypothyroidml%.  meningitisms". msnp. nphcj. cjdgu.  huntingtonsal. alsvx.  parkinsons .  lewybody . picksa{ .  alzheimersMR5http://content.nejm.org/cgi/content/full/356/15/1527.  . craniopharyngiomamv. vertigoy8 pics/fn-oculomotor.jpg. ns . nsfee . eegyw . cerebralangiographyca . transcranialdoppler . cnsultrasound  . cnsctbj . cnsmrial . alsvx .  parkinsonsnp . nph . anatomicdiagnosiswx . neuroradiology  .  neuroexam . emeryd| . beckers  .  duchenne  .  muscularpm . pmr .  lamberteatonmg . mg . myopathyinflammatory . myopathymitochondrialkz . myopathycongenital  .  myopathypm . pml  . demyelinatingsystemicgb . gbs . ahem  . ademms . ms  . demyelinating .  kugelbergkh . werdnigal . als . motorms . msavx .  parkinsonsgu .  huntingtons . picksa{ .  alzheimers .  neurological  .  neuropathieshs} .  pseudotumornpz . nphicw . icpw-t ddx.doc deliriumq .  dementia n .  seizuresk .  headaches h .  cnsneoplasmse . cnsmalformationsb .  cnsinfection _ . cnsvasculitisic\ . ichY .  cnstraumacvV . cva S .  cnsinjuryP . invasiveaspergillosisdiM . dipJ . eosinophilicgranulomamG . hodgkinsdiseaseymD .  sarcoidosistbA . tb> .  churgstraussym; .  sarcoidosis8 .  typethree5 .  typefourI 2 !pics/alveolarproteinosis-cxr.jpg. (s/ 4http://www.nejm.org/content/2001/0344/0003/0212.asp. pt, . ptxpb) . pbche& . hypersensitivitypneumonitisH#  micro.doc cryptococcusy0  pharm.doc pirfenidone . nsipai . aipdi . dipui . uipip . ipfw| .  farmerslungu9  micro.docpcp-f #pics/pulmonaryhemorrhage-byage.jpg.  pics/pulmonaryhemorrhage.jpg.  . rpgn  .  pancreatitish2  pharm.doc amiodaronesl . slel+  pharm.doctpaq8  micro.doctbpe . pe . meigs .  exudatesvm .  transudates . Thoracentesisna . aspirationpneumoniacf . cfu5 pics/lungs1.jpg. H  pharm.doc bleomycinp&  micro.doc influenzaaC  micro.doc chlamydial-  micro.doc bpertussisw2  micro.doc mycoplasmaw)  micro.docrsvp&  micro.doc influenzaaKT 5http://content.nejm.org/cgi/content/full/355/20/2125. E . a1atfk . lungtransplantt-  pharm.doc tiotropium ] -pics/emphysema-consolidation-airfluid-ct.jpg.   .  corpulmonale .  churgstraussF  micro.docstrongyloidesrs . rsvT  pharm.doc Theophylline`>  pharm.doccorticosteroidsF  pharm.doc cromolynQ  pharm.doc atroventH  pharm.doc albuterolJT 5http://content.nejm.org/cgi/content/full/355/21/2226. vb .  asbestosis %pics/cavitation-consolidation-ct.jpg.  . bronchogeniccarcinoma~ .  hamartomaI{ )pics/progressivecerebellarataxia-ddx.jpg. e|x 3http://content.nejm.org/cgi/content/full/356/6/612. u .  LambertEatonSr pics/breastcancermets-mri.jpg. GGo "pics/paraneoplasticantibodies.jpg. h.l  micro.docmtbCHi pics/eye-horners2.jpg. @Hf pics/eye-horners1.jpg. Ec pics/eye-horners.jpg. ` .  pancoast] .  carcinoidZ .  LambertEatonSW pics/hoa-bonescan.jpg. hoT . hoaNTQ 5http://content.nejm.org/cgi/content/full/352/26/2714. spN . spnu9K  micro.docpcpf7H  micro.doccmvs E  micro.docvzvm)B  micro.dochsvw)?  micro.docrsvC<  micro.doc chlamydiaC9  micro.doc Chlamydiaq06  micro.doc klebsiella.f3  labs.docasopy0 . empyemaN-  pharm.doc pneumovaxQ*  micro.doc pneumococcuspy' . empyemas6$  micro.docvlma;!  micro.doccandida|6  micro.doc blastomycesH  micro.doc cryptococcus J  micro.doc coccidioidesn;  micro.doc histoplasmaH  micro.doc cryptococcusrs . rsvG  micro.doc influenzae)  micro.docmeasleshg . kaposisP  micro.doc pneumocystis~&  micro.doc francisellah.  micro.docmtbh;  micro.docmaik5 ddx.doc cavitary . aspirationpneumonitisqg . pleuraleffusion . Thoracentesispy . empyemaud @http://www.merck.com/pubs/mmanual/section13/chapter157/157d.htmA013-157-0878w=  micro.doc pseudomonasq8  micro.doctbrs . rsvQ  micro.doc coxiellaC  micro.doc chlamydiah5  micro.doc legionellaq0  micro.doc klebsiellau-  micro.doc mpneumoniaeQ  micro.doc pneumococcusJ  micro.doc agepneumoniak5 ddx.doc cavitaryxt . childhoodpneumoniap5  pharm.docflolans . horners^  pics/PE9.jpg. MQ 5http://content.nejm.org/cgi/content/full/347/15/1131. M  pharm.doc alteplaseJS 5http://content.nejm.org/cgi/content/full/347/15/1143. $8 0http://www.annals.org/cgi/content/full/139/1/19. S  pharm.doc coumadin^  pharm.doclmwh 1http://www.annals.org/cgi/content/full/146/3/211.  1http://www.annals.org/cgi/content/full/146/3/211. M\ 5http://content.nejm.org/cgi/content/full/356/14/1438.  E  pharm.docthrombolyticsQ  pics/PE6.jpg. P  pics/PE7.jpg. S  pics/PE4.jpg. R  pics/PE5.jpg. U  pics/PE2.jpg. V  pics/PE1.jpg. T  pics/PE3.jpg. /< pics/brown-PE8.jpg. j+ more/dvt-pe.doc.  . factorvleidents| . hypercoagulabilitydvy . dvtp:v procedurevids/. qgs . pleuraleffusionp . ptnam . pnbpj .  bronchoscopy g . tubethoracostomyd .  thoracoscopya . thoracentesisda^ . dahpr[ . prvcfX . cfU . dlcoR  pics/pft.jpg. paO . papfhL .  aspergillusI .  eosinophilicheF . HypersensitivitypneumonitisC .  goodpasturesl@ . otherchemicalsfz= . organic: .  inorganic7 .  occupationalip4 . iph 1 . boop . . rbail + . histiocytosisli( . lip % .  desquamativeip" . ipfil . ild .  pneumoniahivet . pneumoniafungalu . pneumoniaviralh.  micro.docmtbx| .  aspirationlk . postopb| .  compromisedpc . pcpgn . gnrmo .  legionella}` .  psittacosis .  chlamydiarh .  mycoplasmauu .  hinfluenzaqp . strepaQ  micro.doc pneumococcus .  pneumoniaas . lungcacs . csaos . osa{h . lungrestrictive  .  emphysemara . radxz . asthma  . copdfs . lungobstructivefs .  atelectasisle . bronchiectasisns .  bronchitiscz . pleuralfibrosisqg . pleuraleffusion  .  pleurisy . ardsak . alveolarhemorrhagewr . abscess .  pneumothorax .  pneumothoraxpe . pe . peepab . abgln . pulmonaryprocedures . pfts  . siadhqt . qt . afib{f . hypomagnesemia .  hemodialysisuq .  acromegaly  . adrenalinsufficiencyB  pharm.dochctzi/  pharm.doclithium . pthrpmm . mmcw} . pagetsz .  hyperthyroidw .  hyperpthnkt . sarcoidq .  osteoporosisKWn pics/ecgpotassium.gif. KWk pics/ecgpotassium.gif. 4bh pics/f-hypokalemia.jpg. dke . dka b .  hypoglycemia_ . hypophosphatemia{f\ . hypomagnesemiaY .  hypocalcemiar{V .  hypokalemia S .  hyponatremiaP . hyperphosphatemia{M . hypermagnesemiaJ . hypercalcemiaG .  hyperkalemia D . hypernatremiaA .  phosphate > .  magnesiumfw; . calcium8 .  potassiumbk5 . sodiuma~2 pics/calciphylaxis.jpg. }`/ . renaltransplant, .  hyperkalemia\)  pharm.docifnaq7&  pharm.docil2fu# . fuoP_ .http://www.ajkd.org/cgi/content/full/35/1/154. TR -http://www.ajkd.org/cgi/content/full/35/1/58. ^  pharm.doc cyclosporineG  pharm.doc steroids .  hemodialysis`p . homocystinuria T  pharm.doc indinaviron .  leschnyhan . bladdercanceraa . aaa|p . diverticulitispi . pide .  proximalrta  . diabetesinsipidus  .  hyponatremia . ttkg  . hypoaldosteronismS  pharm.docacetazolamidej} .  renalstonesje . sepsisHW pics/plasmaosmolality.gif. cl . multiplemyeloma .  dialysisrv . rvtep . rhabdomyolysisg%  pharm.docaminoglycosidess2  pharm.docnsaids .  fanconisdi . dirt . rtaat . atnrc . rccE . rta1jt . mercuryvm . copper  . leadny . cadmiumut . utic'  pharm.docdapsone .  hemodyalysis  pics/hsp.jpg. cv . iganephropathyX  micro.doc shigellaQ  micro.doceheci9  micro.docviralhepatitisit . itp .  appendicitisdi . dic .  preeclampsiaA  pharm.docactivatedproteinc_ pics/schizocytes-dic.jpg. D pics/rbcfragments-dic.jpg. Z  psycdrug.doc lamictal  . hellpje~ . sepsis{n{ . transfusionreactionmrx 3http://content.nejm.org/cgi/content/full/341/8/586. >>u 3http://dermis.net/dermisroot/en/42784/diagnose.htm. <gr pics/livedoreticularis-bad.jpg. peo . pel 1http://www.annals.org/cgi/content/full/146/3/211. i 1http://www.annals.org/cgi/content/full/146/3/211. G f pics/thrombophlebitis-apa.gif. poc . acutearterialocclusion{{` pics/riskofthromboembolism.jpg. hs] . hsphuZ . husttW . ttp T . hellpQ .  renaldicafN . systemicthrombosisyyK .  fatembolismpvH . pvtdvE . dvtpeB . pec? . focalthrombosis V< ddx.dochypercoagulabilityts9 . hypercoagulability{a6 .  scleroderma 3 .  wegenerspa0 . pansl- . sle* .  endocarditis' . goutcl$ . multiplemyeloma`5! ddx.doc mononeuritisX pics/eye-amyloidosis.jpg. qc 4http://content.nejm.org/cgi/content/full/344/12/917.   .  diabetescr . crfrt . rta .  acidbasews . renalarterystenosis . renalhypertensionpc . renalmechanicalhg . hydronephrosis . transplantglomerulopathy. cryoglobulinemia . nephroticsyndrome . mpgnmg. mgn. fsgsmc. mcd.  churgstrauss .  wegeners. complementstudies.  hcvrenal.  goodpastures . apkd . apkdE. rta1.  drugacidbase . drugpostrenal .  drugrenal.  drugprerenalyy.  fatembolismep. rhabdomyolysisy+ pharm.doc allopurinolep. rhabdomyolysisal. all .  burkitts.  dialysisya. tumorlysissyndromenw. arfaids.  bladderca|d.  prostatecaym.  sarcoidosisgipics/fattycast.jpg.  pics/hyalinecast.jpg. pics/wbccast.jpg. pics/rbccast.jpg. erpics/tubularepithelialcell.jpg.  .  nephroticj}.  renalstones=c labs.doc creatininepics/nephron.gif. .  dialysisii. renalneoplasms}`. renaltransplant . apkdco|. renalmalformationswsy. renalarterystenosisv. renalhypertensionj}s.  renalstonesaqp.  renalotherodm. balkanj. interstitialnephritiscwg. alportsd. renalendocarditishsa. hsptt^. ttphu[. husX.  renaldicaiU. renalthromboticrtR. rtaatO. atn L.  renaltubularI. renalsclerodermaF. renalwegenersC.  renalpan@. gout`n=.  amyloidosis:.  hypertension 7. mpgnmg4. mgn1. fsgsmc.. mcd +.  nephrotic(. cryoglobulinemiagb%. gbm". anca. rpgncv. iganephropathy. psgn .  nephriticcr. crfep. rhabdomyolysis  . renaldrugtoxicityar . arf. lytes.  hematuriafs.  proteinuria.  renalstudies.& pics/fibromusculardysplasia.jpg. mm. mm  micro.dochhv8.  fanconis.  breastcancerre.  carcinogens . tumorsuppressorsgj. paraneoplasticpemphigusfa. fap .  PeutzJeghersTpics/cowden2.jpg. Wpics/cowden1.jpg. ch.  coloncancerid. idats. ts .  wegenerspa. pangc. gcahs. hspss. acanthosisnigricans=53http://dermis.net/dermisroot/en/19683/diagnose.htm.  . nsgct 1drugs/chemotherapy.doc. . ovary.  breastcaga. female|d.  prostateca. male .  cnsneoplasmsrl. epidermaltumorsgi. gius. liverneoplasiav{. pulmonaryneoplasia.  lymphoma.  leukemia. neutropenicfeverbm. bmt~z.  tumorspread .  tumorbiology.  associationszx. markersigpics/infectiousmyocarditis.jpg. NR}5http://content.nejm.org/cgi/content/full/356/11/1153. J^z6http://content.nejm.org/cgi/content/full/343/19/1388?. wow. pulsusparadoxusXt"pics/jhid-pericardialeffusion.jpg. qpics/pleuraleffusion.jpg. Unpics/ekg-pericarditis.jpg.  k.  melanomarah. rasle. slejrb. uremicpericarditis_.  dresslersgl\. tbpericarditisY. viralpericarditiscmV. InfectiousPericarditis S. acutepericarditislwP. pericardialeffusionM. cardiactamponadeaiJ. restrictivepericarditis%{Gpics/ekg-jwave.jpg. 90D3http://dermis.net/dermisroot/en/37635/diagnose.htm. NA pharm.doc procainamide{f>. hypomagnesemiar{;.  hypokalemiaT8 pharm.doc theophyllineS5 pharm.doc digitalis 2. copdg{/3http://content.nejm.org/cgi/content/full/356/9/935. vt,. vt ). atrialflutterpa&. patpi#. hyperthyroidismS  pharm.doc digitalis. npjt. avnrtwp. wpw. afib . atrialflutterma. mat . sinustachycardia .  torsadesgs.  pacemakers . sicksinussyndromeS pharm.doc digitalisr{.  hypokalemia.  hyperkalemia . localizationofinfarct . avconductiondelay .  torsadesqt. qtvt. vtel.  ventricularma. matsv. svt . atrialflutter. afibrq. atrialcp.  hemiblocks. rbbb. lbbbrq.  heartblockn.  bradycardiaas. asj{.  thalassemia . postpartumcardiomyopathyp* pharm.doc gentamicin . !antibioticprophylaxisbonesurgeryt~pics/dukescriteria.jpg. >p pics/endocarditis-petechiae.jpg. <z pics/endocarditis-rothspots.jpg.  Lpics/oslersnodes3.jpg.  Lpics/oslersnodes2.jpg. Lpics/oslersnodes1.jpg.  pics/oslersnodes.jpg. B&pics/endocarditis-culturenegative.jpg. B micro.doc rhusiopathae|. micro.doc groupbstrepQ micro.doc pneumococcusA micro.doc EnterococcusQ micro.doc coxiella^ micro.dochacekBX5http://content.nejm.org/cgi/content/full/345/18/1318. fu3http://content.nejm.org/cgi/content/full/348/9/834. p2pics/esophagus1.jpg. sv. svcs. horners ~ pics/jvp.jpg. sp{. endocarditisprophylaxisBQx5http://content.nejm.org/cgi/content/full/355/19/2022. mvu. mvpbdr. papillarymuscleo.  endocarditiszzlpics/fn-esophagus1.jpg. i.  anorexiavf. ascites Ocddx.docsyncope{g`. bicuspidaorticvalveRMZ2http://content.nejm.org/cgi/content/full/337/1/32.  W. methemoglobinemiammT. mm{rQ. thrombocytosisbmN. digiamiuiK. ventricularaneurysmH. cardiactamponadevsE. vsdB. papillaryrupture?.  dresslers R< pharm.doc thrombolysisA9 labs.docckmb,~6 labs.docck 3.  thrombolysisr`0. othercausesofmi}m-.  mifollowupoz*.  miprognosiswy'. micomplicationsmy$.  mitreatmentc{!. milabsgb. gbsS pharm.doc clonidineus.  stresstest.  syndromexgi.  prinzmetalsc{. unstableangina .  stableangina .  chestpain .  pancreatitis. sdes. gerdpe. pe. aorticdissectionk'ddx.doc chestpain.  xanthomas~k. folate2http://www.annals.org/cgi/content/full/139/10/824. mi. mihf. angina.  chestpaindm. dmc5 pharm.docstatins'q labs.dochdl#q labs.docldlw%pics/pad-surgeryorstent.jpg. j? pharm.doc cilostazol.  takayasusbx. fibromusculardysplasiamq. buergerdiseaseJpics/pad-ddx.jpg. Jpics/pad-imaging.jpg. LS5http://content.nejm.org/cgi/content/full/356/12/1241. ca. caddm. dme~. Atherosclerosisfs.  proteinuriarc. rccuq.  acromegaly. pheochromocytoma.  cushings. primaryhyperaldosteronismpi. hyperthyroidism . apkd. pulmonaryhypertensionAddx.docorthostatichypotension . connsmi. mi. cardiactransplantQ pharm.docacei-{ labs.docbnpie. cardiacenzymesbe. pulmonaryedemajv. jvpcm. cm|.  diastolicary3http://content.nejm.org/cgi/content/full/348/3/243. div. dic s.  corpulmonalehtp. htnchm. chf j. shockoug.  Hypovolemiaded.  hypothermia a. edemala^. lad [.  thrombolysisc4X pharm.docdigoxinusU.  stresstest R.  torsadesGOpics/ekg-lqts.gif. #<Lpics/ekg-tuwave-cnsdisease.gif. 5jIpics/ekg-potassium.gif. pyF. hypokalemiaecgi-C pharm.docclassic4@ pharm.docdigoxinpy=. hypokalemiaecgCV:"pics/stelevationsandchestpain.jpg. ur7pics/stchanges.jpg. KW4pics/ecgpotassium.gif. AW1pics/twavechanges.jpg. wp.. wpwB +"pics/fn-heartvesselsposterior.jpg. H(!pics/fn-heartvesselsanterior.jpg. hh%pics/limbleads.jpg. S" pharm.doc digitalisl8 pharm.doctcaD pharm.doc classiiii- pharm.docclassi .  torsadesKWpics/ecgpotassium.gif. . lytestm .  ekgischemiaho .  hypertrophy. axisdeviation.  intervalsat.  heartrhythm.  heartrate more/ekg.html. hhpics/limbleads.jpg.  Oddx.docsyncope. constrictivepericarditis  pics/jvp.jpg. . afib5;_http://www.uni-duesseldorf.de/WWW/MedFak/Herz-Kreislauf-Physiologie/lehre/sounds/html/asd.html. pv. pvcSPpics/diastolicmurmurs.jpg.  pics/systolicmurmurs.jpg. XP9http://home.mdconsult.com/das/book/view/882?sid=21483771. .  swanganz  pics/jvp.jpg. WJpics/cardiaccycle.jpg. c{. milabsek. ekgce. cardiacphysical. cardiacphysiology.  cardiacpreop.  pedheart. cardiactumors. cardiactamponadeai. restrictivepericarditisjr. uremicpericarditis.  dresslerscm. InfectiousPericarditis . acutepericarditislw. pericardialeffusion.  pericarditissh.  myocarditis.  endocarditis. aorticdissectionaa. aaa . antibioticprophylaxismw. rheumaticfevertr. trmr. mrar. arhm. mitralstenosisas. as .  valvular .  torsadesqt}. qtvtz. vtmaw. matsvt. svt q. atrialfluttern. afibrqk.  heartblocknh.  bradycardiakbe.  Arrhythmias b. hocm _. restrictivecardiomyopathysn\. cardiomyopathymiY. mimiV. mihfS. anginacaP. cadpvM. pvde~J. atherosclerosisfhG. hyperlipidemia D.  corpulmonalechA. chf >. shockdi;. dicpe8. peme5.  thrombosis 2. edemaht/. htnj`,.  circulatory)y)cardiology.html. vw&. vwffd#. niacinh2  pharm.doc amiodarone|~. arsenicks. cyanide~n. ethyleneglycol. malignanthyperthermiaep. rhabdomyolysism3 pharm.doc misoprostolq(  pharm.dochydroxychloroquineP pharm.docgoldQ pharm.docpenicillamineu/ pharm.docmtxs2 pharm.docnsaids*7pics/psoriasishands.jpg. !pics/psoriaticarthritishands.jpg.  .  psoriasisai. aiib. ibd~c. reiters .  psoriasis{v.  ankylosingF@pics/rcvs.jpg. #50http://www.annals.org/cgi/content/full/146/1/34. ms. msUCpics/bsl-hla1.jpg. .  hypopyon .  retinitis pics/behcets.gif.  pics/behcets.jpg. .dhttp://content.nejm.org/cgi/content/full/341/17/1284?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=%22oral+ulcers%22&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jour. hs. hsp. eosinophilicpneumoniaqnhttp://content.nejm.org/cgi/content/full/343/13/953?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=churg&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nejm. xhttp://content.nejm.org/cgi/content/full/343/12/864?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=buerger&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&journalcode=nej. da. dahr}pics/wegeners-chestCT3.jpg. r|pics/wegeners-chestCT2.jpg. rpics/wegeners-chestCT1.jpg. . rpgn.  hematuria[ddx.doc hemoptysis.  typefouruc. ucsb. feltys[ddx.doc hemoptysisQ labs.docpanca~c. livedo.  typethreepm. pmrW micro.docLeptospirosis_"pics/primarycnsvasculitismri4.jpg. _"pics/primarycnsvasculitismri3.jpg. _"pics/primarycnsvasculitismri2.jpg. _"pics/primarycnsvasculitismri1.jpg. uy. vasculitisinfection~. rcvsX{ micro.dochtlvl>x micro.doc rickettsiaq;u pharm.doccocaineucr. paraneoplastico. cryoglobulinemiahsl. hspi.  buergers f.  wegenersc. churg`.  kawasakispa]. panZ.  takayasusgcW. gcahsT. hspgcQ. gca N.  hodgkins K.  wegeners H. hairycellleukemiapaE. pan`wB. erythemanodosumy7? pharm.docdmards_<pics/neurosarcoidmri1.jpg. af9.  langerhans 6.  vitiligo`w3. erythemanodosum1003http://dermis.net/dermisroot/en/17039/diagnose.htm. -. porphyriacutaneatarda4?*3http://dermis.net/dermisroot/en/33886/diagnose.htm. >v'pics/raynauds-scars.jpg. AB$pics/dm-calcinosis-elbow.jpg. 4;!3http://dermis.net/dermisroot/en/37886/diagnose.htm. ABpics/dm-calcinosis-elbow.jpg. {>pics/dm-telangiectasia.jpg. Epics/dm-shawl.jpg. ib. ibmsn. cardiomyopathy. pfts . gerdAn http://content.nejm.org/cgi/content/full/344/22/1701?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=0&volume=344&firstpage=1701&journalcode=nejm. .{ labs.docanaht. htn.  schistocytespics/cnslesion-lupus-ddx.jpg. jb.  lungcancerqg. pleuraleffusionap. apaz;ddx.doc alopeciaV micro.doctineara. rawa.  irradiationg$pics/chondroma-hand.jpg. |d.  prostateca.  breastcaas. lungcal8 pharm.doctca`n.  amyloidosis5 . _hemochromatosisy+ pharm.doc allopurinoln" pharm.doc probenecidr2 pharm.doc colchicine`y. infectiousmonoarthritis . diabetesinsipidus . adrenalinsufficiency .  psoriasisJ micro.doc borreliaq8 micro.doctb T.http://content.nejm.org/cgi/video/354/19/e19/. ^ micro.docHACEKT micro.doc syphilis@ micro.doc neisseria[ labs.doc ferritin.  legulcersQ pharm.docpenicillamineP pharm.docgoldn" pharm.docimmuran O pharm.doc rituximabE pharm.doc tnfalphau/ pharm.docmtxG pharm.doc steroidsdr. dr4ay. anemiaofchronicdiseasesh.  myocarditis.  pericarditissp. spnAhttp://content.nejm.org/cgi/content/full/344/13/997?maxtoshow=&HITS=20&hits=20&RESULTFORMAT=&fulltext=rheumatoid+nodules&searchid=QID_NOT_SET&stored_search=&FIRSTINDEX=20&sortspec=PUBDATE_SORTDATE+desc+Score+desc&fdate=1/1/1975&tdate=7/31/2001&jou.  |. peripheralneuropathy Rypics/boutonniere1.jpg.  vpics/boutonniere.jpg. A[spics/swanneck.jpg. Bppics/ra-hands.jpg. m. synovialfluidcwj. pagets gpics/oahands.jpg. #+dpics/oa-dip-pip.jpg. a.  menopause^.  osteoporosisVU[)http://mdtruth.com/pics/hoa-bonescan.jpg. nX. bronchogeniccay%U micro.doc gonococcusFR micro.doclymeorO. behcets~jL. hemochromatosisI.  fibromyalgiaf7F micro.doccmvLC micro.doc coxsackiem9@ micro.dochcvy&= micro.docrubellat:: micro.doc parvovirusuc7. ucbi4. crohns 1.  whipples..  gauchers~c+. reiters{v(.  ankylosing %.  psoriatic ". spondylarthropathiesjr. jrara. raoa. oa . caoxj{. hydroxyapetitecr.  pseudogout . goutcy . infectiousarthritis. polyarticularbb. testes.  referredpain.  referredpainuo.  hemophiliama. hypothyroidism .  whipples. cppdmw. rheumaticfeverRSpics/raynauds.gif. os. osapm. pmrg{. hlaassociationszu. rheumhpct. cts . kneepw.  lowbackpainxm.  orthopedics.  buergers. churg .  wegenerspa. pan.  kawasakis.  takayasus.  giantcell .  vasculitides myopathyother.  . eosinophilicmyositis . eosinophilicfasciitisA. rs3pepm. pmrf~. dermatomyositis.  polymyositis.  Fibromyalgia~c. reiters .  psoriatic{v.  ankylosingcy. infectiousarthritiscr.  pseudogout. goutoa. oaym.  sarcoidosisjr. jra.  sjogrens{a.  sclerodermasl. slera}. raz. jointw. osteomyelitisdzt.  bonecancerq.  fracturesn. bonemalformations k. bonernh. conjunctivitishbe. hbsb. comate_. tensj\. sjssrY. erythemamultiforme OVddx.docsyncopeS.  endocarditisslP. sle M. mpgnJ. cryoglobulinemiac+Gpics/bsl-complement.jpg. .~D labs.doc complementsbA. feltys>.  liverabscess;.  pneumoniaam8. amlzb5.  cellulitisHR25http://content.nejm.org/cgi/content/full/343/23/1703. I/1http://www.ubriaco.com/sounds/air-biological.wav. ,.  lymphoma).  lymphomab &. asepticmeningitisN# pharm.doc pneumovaxwt .  pernicious.  sinusitiscm. cmc . cvidcl. cllsl. sleym.  sarcoidosism3  micro.dochiv<63http://dermis.net/dermisroot/en/33214/diagnose.htm. A_pics/hymes-gvhd1.jpg. bm. bmt . serumsickness. typethreederm. epidermolysisbullosa . herpesgestationis. bullouspemphigoid}w. hemolyticanemia .  pemphigusz}.  typetwoderm. atopicdermatitiskd.  typeonederm-;pics/bsl-antibody1.jpg. Gpics/bsl-tcellsurface.jpg. Gpics/bsl-tcellsurface.jpg. . churg.  buergers .  wegenerspa. pan.  kawasakis.  takayasus.  giantcell .  vasculitidesym.  sarcoidosis{a.  scleroderma.  polymyositis.  sjrogrenssl. slera. rajn.  connectivedx. chediakhigashi. jobsR\. cd18. cyclicneutropeniabk.  phagocytes . ataxiatelangiectasiabr. wiskottaldrichad. ada. scidsbt. btkx. duncansxh. brutons . cvidk|. bcellscm. cmc ~.  digeorge}|{. tcellshfx. immunodeficienciesaku.  complement~{r. immunoglobulinsaao.  immunologyXlpics/icu2.jpg. Xipics/icu1.jpg. p:fprocedurevids/. x%cddx.doc. Z` micro.doc. [] pharm.doc.  Z.  emergencyklW.  developmentT.  nutrition Q. environmentalN. ophthalmologyK.  electrolytesH.  metabolicE.  acidbasexmB.  orthopedicsd`?. surgeryww<.  dermatologyaa9.  immunologyn6. allergyga3. female0. male -.  myopathy*. joint '. bone$.  Rheumatology !. livergi. gi. lungs. renal. neuropc.  infectious .  endocrine .  oncologyz} .  hematologyxj. cardiowt.  disclaimers!http://www.mdtruth.com/.   !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~                            ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~        !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~     !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~      !"#$%&'()*+,-./0123456789:;<=>?@ABCDEFGHIJKLMNOPQRSTUVWXYZ[\]^_`abcdefghijklmnopqrstuvwxyz{|}~                           ! " # $ % & ' ( ) * + , - . / 0 1 2 3 4 5 6 7 8 9 : ; < = > ? @ A B C D E F G H I J K L M N O P Q R S T U V W X Y Z [ \ ] ^ _ ` a b c d e f g h i j k l m n o p q r s t u v w x y z { | } ~  !!!!!!!!! ! ! ! ! !!!!!!!!!!!!!!!!!!! !!!"!#!$!%!&!'!(!)!*!+!,!-!.!/!0!1!2!3!4!5!6!7!8!9!:!;!!?!@!A!B!C!D!E!F!G!H!I!J!K!L!M!N!O!P!Q!R!S!T!U!V!W!X!Y!Z![!\!]!^!_!`!a!b!c!d!e!f!g!h!i!j!k!l!m!n!o!p!q!r!s!t!u!v!w!x!y!z!{!|!}!~!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!""""""""" " " " " """"""""""""""""""" "!"""#"$"%"&"'"(")"*"+","-"."/"0"1"2"3"4"5"6"7"8"9":";"<"=">"?"@"A"B"C"D"E"F"G"H"I"J"K"L"M"N"O"P"Q"R"S"T"U"V"W"X"Y"Z"["\"]"^"_"`"a"b"c"d"e"f"g"h"i"j"k"l"m"n"o"p"q"r"s"t"u"v"w"x"y"z"{"|"}"~""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""""######### # # # # ################### #!#"###$#%#&#'#(#)#*#+#,#-#.#/#0#1#2#3#4#5#6#7#8#9#:#;#<#=#>#?#@#A#B#C#D#E#F#G#H#I#J#K#L#M#N#O#P#Q#R#S#T#U#V#W#X#Y#Z#[#\#]#_#`#a#b#c#d#e#g#h#i#j#k#l#m#n#o#p#q#r#s#t#u#v#w#x#y#z#{#|#}#~##################################################################################################################################$$$$$$$$$ $ $ $ $ $$$$$$$$$$$$$$$$$$$ $!$"$#$$$%$&$'$($)$*$+$,$-$.$/$0$1$2$3$4$5$6$7$8$9$:$;$<$=$>$?$@$A$B$C$D$E$F$G$H$I$J$K$L$M$N$O$P$Q$R$S$T$U$V$W$X$Y$Z$[$\$]$^$_$`$a$b$c$d$e$f$g$h$i$j$k$l$m$n$o$p$q$r$s$t$u$v$w$x$y$z${$|$}$~$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$$%%%%%%%%% % % % % %%%%%%%%%%%%%%%%%%% %!%"%#%$%%%&%'%(%)%*%+%,%y%Root Entry FL {%Data 1Table GWordDocument9t#SummaryInformation(^#DocumentSummaryInformation8f#CompObjq  FMicrosoft Office Word Document MSWordDocWord.Document.89q