ࡱ > I} bjbjBrBr ' J K!
U! a! a! a! T ! ! ! M" $ d ! 5, ~ - : - - - . T 00 l 0 8 4 6 6 6 6 6 6 խ w R 6 a a! 0 . . 0 0 6 a! a! - - t7 t7 t7 0 f a! - a! - 4 t7 0 4 t7 t7 * $ l D - a ! :2 R < b ɱ 5 6 ɱ D D ɱ a! ̠ T 0 0 t7 0 0 0 0 0 6 6 V6 0 0 0 0 0 0 0 ɱ 0 0 0 0 0 0 0 0 0 : T a p e n t a d o l E x t e n d e d R e l e a s e ( N u c y n t a E R "!)
N a t i o n a l P B M A b b r e v i a t e d D r u g R e v i e w
D e c e m b e r 2 0 1 2
V H A P h a r m a c y B e n e f i t s M a n a g e m e n t S e r v i c e s , M e d i c a l A d v i s o r y P a n e l , a n d V I S N P h a r m a c i s t E x e c u t i v e s
T h e P B M p r e p a r e s a b b r e v i a t e d r e v i e w s t o c o m p i l e i n f o r m a t i o n r e l e vant to making formulary decisions. The manufacturers labeling should be consulted for detailed drug information. VA clinical experts may provide input on the content. Wider field review is not sought. Documents no longer current will be placed in the Archive section.
Executive Summary:
Tapentadol extended-release (ER) is a new formulation of tapentadol, a Schedule II, long-acting central analgesic with a dual mechanism targeting both mu-opioid receptors and norephinephrine reuptake.
Tapentadol ER is approved by the U.S. Food and Drug Administration for the management of moderate to severe chronic pain and neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults. Tapentadol ER is the only opioid FDA-approved for the treatment of neuropathic pain associated with peripheral diabetic neuropathy.
Other opioids, including tramadol and other forms of tapentadol, should be discontinued when starting and during tapentadol ER therapy due to the risk of adverse reactions including serotonin syndrome and respiratory depression.
The concurrent use of tapentadol ER and alcohol should be avoided since alcohol causes an increase in the plasma concentration of tapentadol ER by approximately 40%.
The recommended initial dose in opioid-nave patients is 50 mg twice daily. This may be titrated upward by 50 mg no more than twice daily every three days and not exceeding 250 mg twice daily.
Initial dose in patients already taking opioids is not established; however, an estimated conversion ratio of 5:1 for tapentadol ER to oxycodone CR has been suggested. The product information suggests a general approach of beginning with half of the estimated daily tapentadol requirement as the initial dose and managing inadequate analgesia by supplementation with immediate-release rescue medication (nonopioid or opioid without serotonergic effects).
Patients can be converted from tapentadol IR to tapentadol ER using the equivalent total daily dose of the IR formulation; however, the maximum recommended daily dose of the IR formulation is 600 mg, whereas it is 500 mg for tapentadol ER.
No dose adjustments are required in patients with mild hepatic impairment. Dose reduction is recommended for moderate hepatic impairment. Use is not recommended in severe hepatic impairment.
No dose adjustments are required for mild to moderate renal impairment. Use in severe renal impairment is not recommended.
Although clinical trial results showed that tapentadol ER produced statistically significant analgesic relief in patients with chronic pain associated with back pain and peripheral neuropathy when compared to placebo, the effect size was small. Two trials failed to show efficacy for tapentadol ER in knee osteoarthritis.
In a meta-analysis included in a pooled analysis of osteoarthritis and lower back pain trials, tapentadol ER (100250 mg twice daily) was shown to be noninferior to oxycodone CR (2050 mg twice daily) in terms of the change from baseline in average pain intensity over a 12-week period, while oxycodone CR had a less robust analgesic effect, suggesting a less than equianalgesic effect, at the doses studied.
The pooled analysis showed that, relative to oxycodone CR, tapentadol ER had a lower rate of and longer time to discontinuation due to adverse events and lower rate of gastrointestinal adverse events. These findings suggested better tolerability with tapentadol ER in comparison with oxycodone CR.
The most common adverse effects associated with tapentadol ER are nausea, constipation, dizziness, headache, and somnolence.
Major adverse events include respiratory depression, hypotensive effects and serotonin syndrome. Caution should be used in elderly, cachectic and debilitated patients and patients with pulmonary disease.
External validity of clinical trial results to VA patients is uncertain, as many tapentadol studies excluded patients characteristic of the Veteran population.
Look-alike, sound-alike medications include tapazol, tramadol, thiopental, Neulasta and Nucynta IR.
Daily cost of tapentadol ER ranges from $3.28 to $9.78 per day and $1198 to $3570 per year. Tapentadol ER is unlikely to be more cost-effective than most alternative formulary oral opioids.
Conclusions:
REF Conclusions \h \* MERGEFORMAT Tapentadol extended-release (ER) is a long-acting, dual-mechanism opioid analgesic that has been shown to provide small analgesic effects in patients with chronic pain associated with lower back pain and diabetic peripheral neuropathy, but it was not better than placebo in knee osteoarthritis. Overall, it is pharmacologically similar to tramadol and is similar in efficacy and safety to other oral opioids and immediate-release tapentadol. A potential advantage is a lower risk of gastrointestinal adverse events, a safety benefit seen relatively consistently across studies. This difference in tolerability may make tapentadol an alternative for patients who do not tolerate oxycodone CR.
The clinical studies tended to exclude patients representative of the population served at the VA which limited the external validity of the results. Considering the number of relatively safe, effective, and cost effective VA alternatives for the treatment of chronic pain, tapentadol ER will have a limited role in the treatment of chronic pain in the VA.
Introduction
Tapentadol ER is the tenth long-acting opioid analgesic and first long-acting dual-mechanism opioid analgesic marketed in the U.S. for chronic pain conditions. The immediate-release formulation of tapentadol was approved for acute pain in November 2008 and reviewed by VA Pharmacy Benefits Management Services in May 2010. Tapentadol ER was approved by the U.S. Food and Drug Administration (FDA) for the treatment of moderate to severe chronic pain in August 2011 and for neuropathic pain associated with diabetic peripheral neuropathy in adults in August 2012. Tapentadol is classified as a schedule II controlled substance.
The purposes of this monograph are to (1) evaluate the available evidence of safety, tolerability, efficacy, cost, and other pharmaceutical issues that would be relevant to evaluating for possible addition to the VA National Formulary; (2) define its role in therapy; and (3) identify parameters for its rational use in the VA.
Pharmacology/Pharmacokinetics1.8
Tapentadol is a centrally acting opioid analgesic believed to act through a dual mechanism as a mu-opioid receptor agonist and an inhibitor of norepinephrine reuptake. Tramadol, a widely utilized analgesic, works by a similar mechanism as a mu-opioid agonist (parent drug and M1 metabolite) and a weak inhibitor of serotonin and norepinephrine reuptake.
In-vitro studies have shown that tapentadol inhibits the reuptake of serotonin, though this inhibition was five times weaker than the inhibition of norepinephrine reuptake. The analgesic effects associated with tapentadol therapy are not believed to be related to the inhibition of serotonin reuptake, but use of tapentadol with medications that increase serotonin levels can result in increased risk of serotonin syndrome (see adverse events section).
Pharmacokinetics1,8
Table SEQ Table \* ARABIC 1: Pharmacokinetics of tapentadol ER
Mean absolute bioavailability32% (fasting)Time to maximum concentration*3-6 hoursVolume of distribution540 +/- 98LProtein Binding~20%Terminal half-life5 hoursMetabolismApproximately 97% of parent drug is metabolized
Primarily metabolized by glucuronic acid conjugation (70%)Elimination99% of active drug and inactive metabolites eliminated renally.*Determined after a single oral dose administration; Information obtained from product package insert dated August 2012
FDA Approved Indication(s) and Off-label Uses1
Tapentadol ER is FDA approved for the management of moderate to severe chronic pain and neuropathic pain associated with diabetic peripheral neuropathy (DPN) in adults.
Current VA National Formulary Alternatives
Table SEQ Table \* ARABIC 2: Formulary Alternatives for Chronic Pain
Drug ClassFormulary AgentsRestrictionsNon-Opioid AnalgesicsAcetaminophenNoneNSAIDSDiclofenac
Etodolac
Ibuprofen
IndomethacinMeloxicam
Naproxen
SulindacNoneSNRIVenlafaxineDuloxetineTCANortriptyline
DesipramineAmitriptylineNoneAntiepilepticGabapentin NoneOpioid Analgesics, Long-actingFentanyl Patch
MethadoneMorphine SAFentanyl Patch
Oxycodone SA
MethadoneDosage and Administration1
Dosing should be individualized based on patients past analgesic treatment experience.
Initial dose in patients not currently taking opioid analgesics (including tramadol and other forms of tapentadol) is 50 mg twice a day.
Titrate patients to adequate analgesia with dose increases of 50 mg no more than twice daily every three days. In clinical trials, efficacious doses ranged from 100 to 250 mg twice daily.
Discontinue tramadol and other forms of tapentadol when starting and during tapentadol ER therapy because of the risk of serotonin syndrome. Initial dose in patients already taking opioids is not established because of the lack of evidence for opioid conversions to tapentadol ER. The product information suggests a general approach of beginning with half of the estimated daily tapentadol requirement as the initial dose and managing inadequate analgesia by supplementation with immediate-release rescue medication (nonopioid or opioid). Note that the immediate-release rescue opioid should not be tapentadol or tramadol [or other opioids with serotonin effects].
Lange, et al. suggested using an estimated conversion ratio of 5:1 for tapentadol ER to oxycodone CR (50 mg tapentadol ER for every 10 mg oxycodone CR). REF _Ref341103236 \r \h \* MERGEFORMAT 6
Patients can be converted from tapentadol IR to tapentadol ER using the equivalent total daily dose of the IR formulation and dividing it into two equal doses of the ER formulation given 12 hours apart.
Do not exceed a total daily dose of 500 mg of tapentadol ER. Note that, when converting patients from tapentadol IR to ER, the maximum recommended daily dose of tapentadol IR is 600 mg. (Therefore, to stay within the maximum recommended dosing limits, a 100-mg reduction in the total daily dose would have to be made in the event that a switch is made from tapentadol IR at a total daily dose of 600 mg to tapentadol ER (500 mg total daily dose), possibly resulting in reduction in analgesic effect.)
Must be taken whole, one tablet at a time. ER tablets should not be cut, crushed, dissolved or chewed because of the risk of rapid release and absorption of a potentially fatal dose of tapentadol.
Hepatic impairment
No dose adjustment recommended in mild impairment (Child-Pugh Score 5 to 6).
In patient with moderate hepatic impairment (Child-Pugh Score 7 to 9) initiate treatment of 50 mg no more frequently than every 24 hours. The maximum recommended dose for these patients is 100 mg once daily.
Use of tapentadol ER in severe hepatic impairment (Child-Pugh Score 10 to 15) is not recommended.
Renal impairment
No dosage adjustment is recommended in patients with mild or moderate renal impairment.
Use of tapentadol ER is not recommended in patients with severe renal impairment because there is a risk of accumulation of a metabolite formed by glucuronidation of tapentadol.
Elderly patients
Consider starting with the lower range of recommended doses because elderly patients are more likely to have decreased renal and hepatic function.
Dosage Forms/Strengths1
50 mg, 100 mg, 150 mg, 200 mg, and 250 mg extended release tablets
Efficacy2,3,4,5,7
Primary Efficacy Measures
Mean pain intensity scores using the 11-point pain intensity numerical rating scale. Treatments were compared using the least square mean of the difference (LSMD) in the change in average pain intensity score from baseline to week 12 (primary outcome measure for the U.S. marketing submission) and the change in pain intensity score overall for the entire 12-week maintenance period (European primary outcome measure).
Responder rates were analyzed using the distribution of the percentage of responders for any degree of improvement from baseline and included the percentages of p a t i e n t s a c h i e v i n g e"3 0 % a n d e"5 0 % i m p r o v e m e n t i n p a i n i n t e n s i t y f r o m b a s e l i n e t o w e e k 1 2 .
S e c o n d a r y E f f i c a c y M e a s u r e s
Q u e s t i o n n a i r e s : W e s t e r n O n t a r i o a n d M c M a s t e r U n i v e r s i t i e s I n d e x o f O s t e o a r t h r i t i s Q u e s t i o n n a i r e ( W O M A C ) 2 4 q u e s t i o n s c o n c e r n i n g p a i n , d i sability and joint stiffness-minimal perceptible clinical improvement = reduction of 9.7 mm on OA pain subscale
Patient Global Impression of Change (PGIC)a measure of the patients perceived change in overall health status on a scale of 1= very much improved to 7= very much worse; clinically significant measures include very much improved and much improved.
EuroQol-5 Dimension (EQ-5D) and Short Form-36(SF-36) Health Survey, which evaluate health outcomes and physical, social, and mental well-being
A sleep study includingsleep latency comparison, amount of sleep, quality of sleep
Summary of efficacy findings
Four randomized placebo-controlled trials evaluated tapentadol ER (50250 mg twice daily, titrated over 3 weeks) in the treatment of patients with moderate to severe chronic pain associated with osteoarthritis, chronic lower back pain, and painful diabetic neuropathy ( REF _Ref343519186 \h Table 3). Three of the four trials used oxycodone CR (2050 mg twice daily, titrated) as an active comparator in the treatment of patients with osteoarthritis (2 trials) and low back pain (1 trial). The patient populations were predominantly white, female, and under 65 years of age.
In the LBP and DPN studies, tapentadol ER was shown to produce statistically significant improvement in pain scores when compared with placebo in terms of the least squared mean difference (LSMD; i.e., change from baseline) in average pain intensity at week 12 (applicable to LBP study only) and overall for the 12-week maintenance period. T h e c l i n i c a l r e l e v a n c e o f t h e i m p r o v e m e n t i n p a i n w a s q u e s t i o n a b l e a s t h e e f f e c t s i z e w a s s m a l l ( p l a c e b o - c o r r e c t e d r e d u c t i o n s o f d" 0 . 8 f o r L B P a n d 1 . 3 f o r P D N o n a n 1 1 - p o i n t n u m e r i c a l r a t i n g s c a l e ) . T h e N N T s f o r p a i n i m p r o v e m e n t o f e"3 0 % a n d e"5 0 % r a n g e d f r om 8-16. The FDA considered the results from the LBP and DPN trials to be sufficient evidence to support the approved chronic pain indication.
In the two knee OA trials, tapentadol ER failed to show a statistically significant benefit in LSMD in pain intensity both at 12 weeks and overall for the maintenance period. Oxycodone CR was not statistically significantly different from placebo in terms of pain improvement at 12 weeks (both trials REF _Ref341089189 \r \h \* MERGEFORMAT 2, REF _Ref341089195 \r \h \* MERGEFORMAT 4) and was not significantly different from (1 trial REF _Ref341089195 \r \h \* MERGEFORMAT 4) or inferior to (1 trial REF _Ref341089189 \r \h \* MERGEFORMAT 2) placebo in terms of pain improvement overall (NNTH for 30% pain improvement was 10).
A Johnson-and-Johnson and Grnenthal GmbHsponsored pooled analysis of the two OA trials and one LBP trial, however, showed a statistically significant but small improvement in average pain. NNTs for 30% and 50% pain improvement were both 16. Oxycodone CR also showed statistically significant pain improvement for both primary efficacy measures but 30% and 50% responder rates were lower than those for placebo. Tapentadol ER was statistically superior to oxycodone CR at the doses studied for both 30% and 50% responder rates (p<0.001). Higher discontinuation rates with oxycodone CR may have affected the responder rates since patients who discontinued therapy were considered nonresponders.
The same pooled analysis of trials comparing tapentadol ER and oxycodone CR in OA and LBP included a meta-analysis that showed tapentadol to be noninferior to oxycodone CR in terms of the co-primary efficacy measures by using the 50% retention of the oxycodone CR effect as the noninferiority hypothesis. REF _Ref341103236 \r \h \* MERGEFORMAT 6
In the pooled analysis of the percentage of patients with PGIC improvement of much improved or very much improved at end point, tapentadol ER (421/742, 56.7%) was shown to be significantly better than oxycod o n e C R ( 3 1 0 / 6 2 2 , 4 9 . 8 % ) a n d p l a c e b o ( 3 0 4 / 8 1 2 , 3 7 . 4 % ) ( p < 0 . 0 0 1 f o r b o t h c o m p a r i s o n s ) . R E F _ R e f 3 4 1 1 0 3 2 3 6 \ r \ h \ * M E R G E F O R M A T 6 7
I n t w o l o n g - t e r m ( d"2 4 m o n t h s ) t o l e r a b i l i t y s t u d i e s i n p a t i e n t s w i t h m o d e r a t e t o s e v e r e c h r o n i c p a i n a s s o c i a t e d w i t h k n e e and hip osteoarthritis or with lower back pain, tapentadol ER provided sustained analgesic effects.8,9
Table SEQ Table \* ARABIC 3: Tapentadol ER Clinical Studies
Maintenance Treatment Dose
(Mean TDD-mg/d)NLSMD in Avg PI at Wk 12
(Active vs. PBO)LSMD in Avg PI Overall 12 Wks
(Active vs. PBO) e"3 0 % ! i n A v g P a i n ,
% o f p t s N N T - 3 0 e"5 0 % ! i n A v g P a i n , % o f p t s N N T - 5 0 S t u d y 1
A f i l a l o e t a l . 2 ( 2 0 1 0 ) - O A
P h a s e I I I M N M C D B P C / A C R C T
T A P E R 1 0 0 - 2 5 0 m g b . i . d . ( 2 9 9 . 3 )
O X Y C R 2 0 - 5 0 m g b . i . d . ( 4 8 . 2 )
P B O
3 4 4
3 4 2
3 3 7 - 0 . 7 ( - 1 . 0 4 , - 0 . 3 3 )
- 0 . 3 ( - 0 . 6 8 , 0 . 0 2 ) -0.7 (-1.00, -0.33)
-0.3 (-0.67, 0.00)b43.0a
24.9b
35.9NSD
NNTH 10
--32.0b
17.3b
24.313
NNTH 14
--Study 2
Buynak et al.3 (2010)-LBP
Phase III MC DB PC/AC RCT
TAP ER 100-250 mg b.i.d (313.2)
OXY CR 20-50 mg b.i.d (53.0)
PBO
315
326
317-0.7 (-1.06,-0.35)b
-0.8 (-1.16,-0.46)b-0.8 (-1.22,-0.47)b
-0.9 (-1.24,-0.49)b39.7b
30.4
27.18
NSD
--27.0b
23.3
18.913
NSD
--Study 3 Grnenthal4 GmbH-NCT00486811 (2010)-OA
Phase III MC DB PC/AC RCT
TAP ER 100-250 mg b.i.d (315.2)
OXY CR 20-50 mg b.i.d (54.1)
PBO
319
331
336-0.2 (-0.55, 0.07)
-0.3 (-0.61, 0.09)0.1 (-0.18, 0.44)
0.2 (-0.16, 0.54)41.1
26.0
40.9dNSD
NNTH 7
--31.0
22.1
27.0NSD
NSD
--Study 4
Schwartz et al.5 (2011)-PDPN
MC PC RWDCT
TAP ER 100-250 mg b.i.d
PBO
196
193N/A-1.3 (-1.70,-0.92)b53.6b
42.2937.8b
27.610Study 5
Lange et al.6 (2010)-
(OA x 2, LBP)
Pooled AnalysisTAP ER 100-250 mg b.i.d
OXY CR 20-50 mg b.i.d
PBO
978
999
991-0.6 (-0.80,-0.39)c
-0.3 (-0.53,-0.12)c-0.5 (-0.73,-0.34)c
-0.3 (-0.52,-0.14)c41.3bd
27.0c
34.816
NSD30.1bd
20.8
23.516
NSDThis table has been modified from Hoy SM. Tapentadol extended release: in adults with chronic pain. Drugs. 2012 Feb 12;72(3):375-93.
Last observation carried forward for the intent-to-treat analysis. All comparisons were between tapentadol ER and placebo. There was no comparison between tapentadol and oxycodone.
AC=Active-controlled; CR=continuous release; ER=extended release; LBP=lower back pain; LSMD = least squares mean difference; MN=Multinational; OXY=oxycodone; NNT=number needed to treat; NNT-30 or -50=Number needed to treat for at least 30% or 50% reduction in pain, respectively (calculated); NNTH=NNT for harm; PC=Placebo-controlled; PD=Period; PEM=primary efficacy measure; PGIC=patient global impression of change; PI=Pain intensity; PL=Placebo; OA=osteoarthritis; RCT=Randomized clinical trial; RWDCT=Randomized withdrawal clinical trial; TDD = total daily dose of medication
a p=0.058 vs PBO; b p<0.05 vs PBO; c p<0.001 vs PBO; d p<0.005 vs. OXY CR Adverse Events (Safety Data)1,2,3,4,6,7
Long-term safety experience with tapentadol ER is limited, with 227 patients treated for at least 1 year in one long-term study. REF _Ref340852128 \r \h \* MERGEFORMAT 8
Table SEQ Table \* ARABIC 4: Withdrawals Due to Adverse Events Osteoarthritis and Low Back Pain Trials
TAP ER
n/N (%)OXC CR
n/N (%)PBO
n/N (%)Lange et al. (2010)9 Pooled analysis of 12-wk trials2-4179/978 (18.3)394/999 (39.4)65/991 (6.6)Wild et al. (2010)8 1-y RD MC OL AC Phase III 198/894 (22.1)82/223 (36.8)N/A
Table SEQ Table \* ARABIC 5: Total Patient Discontinuation from Trials Osteoarthritis and Low Back Pain Trials
TAP ER
n/N (%)OXC CR
n/N (%)PBO
n/N (%)Lange et al. (2010)9 Pooled analysis2-4425/978 (43.5)616/999 (61.7)402/991 (40.6)Wild et al. (2010)8 RD MC OL AC Phase III 481/894 (53.8)145/223 (65.0)N/A
In the pooled analysis of OA and LBP trials, the time to discontinuation was significantly shorter with oxycodone CR (39 days) than with tapentadol ER (118 days) and placebo (124 days) (p<0.001 for both comparisons). REF _Ref341103236 \r \h \* MERGEFORMAT 6
Common Adverse Events
The most common adverse events reported by >10% of patients treated with tapentadol ER therapy at any dose and at rates greater than that in placebo-treated patients were primarily gastrointestinal and nervous system related and included:
nausea (21%), constipation (17%), dizziness (17%), headache (15%) and somnolence (12%) in OA and LBP trials; and
nausea (27%), dizziness (18%), somnolence (14%), constipation (13%), vomiting (12%) and headache (10%) in diabetic neuropathy trials.
Tapentadol ER also had a significantly more tolerable gastrointestinal adverse effect profile when compared to oxycodone ( REF _Ref343519347 \h Table 6).8,9
Table SEQ Table \* ARABIC 6: Treatment-emergent adverse events reported e"5 % o f p a t i e n t s i n a n y t r e a t m e n t g r o u p
A d v e r s e E v e n t W i l d e 2 0 1 0 8
n ( % ) J o h n s o n c 2 0 1 0 9
n ( % ) L a n g e b 2 0 1 0 7
n ( % ) T A P
N = 8 9 4 O X Y
N = 2 2 3 T A P
N = 1 1 5 4 P B O
N = 9 9 3 T A P
N = 9 8 0 O X Y
N = 1 0 0 1 G a s t r o i n t e s t i n a l D i s o r d e r s 4 6 5 ( 5 2 . 0 ) 1 4 3 ( 6 4 . 1 ) - - 2 6 4 ( 2 6 . 6 ) 4 2 0 ( 4 2 . 9 ) 6 57(65.6)Nausea162(18.1)74(33.2)135(11.7)73(7.4)203(20.7)362(36.2)Constipation202(22.6)86(38.6)128(11.1)69(6.9)166(16.9)330(33.0)Vomiting63(7.0)30(13.5)71(6.2)29(2.9)80(8.2)210(21.0)Dry Mouth81(9.1)10(4.5)--22(2.2)67(6.8)40(4.0)Diarrhea71(7.9)12(5.4)110(9.5)58(5.8)51(5.2)51(5.1)Nervous system disorders406(45.4)89(39.9)--223(22.5)394(40.2)463(46.3)Dizziness132(14.8)43(19.3)98(8.5)63(6.3)169(17.2)210(21.0)Headache119(13.3)17(7.6)151(13.1)131(13.2)14 6 ( 1 4 . 9 ) 1 3 2 ( 1 3 . 2 ) S o m n o l e n c e 1 3 3 ( 1 4 . 9 ) 2 5 ( 1 1 . 2 ) 6 1 ( 5 . 3 ) 3 5 ( 3 . 5 ) 1 1 4 ( 1 1 . 6 ) 1 6 8 ( 1 6 . 8 ) S k i n a n d s u b c u t a n e o u s t i s s u e d i s o r d e r s 1 5 1 ( 1 6 . 9 ) 4 8 ( 2 1 . 5 ) - - 5 0 ( 5 . 0 ) 1 3 2 ( 1 3 . 5 ) 2 3 7 ( 2 3 . 7 ) P r u r i t u s 4 8 ( 5 . 5 ) 2 3 ( 1 0 . 3 ) - - 1 6 ( 1 . 6 ) 5 1 ( 5 . 2 ) 1 3 4 ( 1 3 . 4 ) I n c i d e n c e b a s e d o n t h e n u m b e r o f p a t i e n t s e x p e r i e n c i n g e"1 T E A E , n o t t h e n u m b e r o f e v e n t s . b L a n g e 2 0 1 0 i n c l u d e s 3 s t u d i e s i n p o o l e d a n a l y s i s , A f i l a l o 2 0 1 0 , B u y n a k 2 0 1 0 , a n d G r n e n t h a l 4 G m b H - N C T 0 0 4 8 6 8 1 1 ( 2 0 1 0 ) . c J o h n s o n 9 2 0 1 0 i s a P h a s e I I I l o n g t e r m t r i a l ( e v e n t s w e r e c o l l e c t e d b y n o n - s y s t e m a t i c a s s e s s m e n t )
O t h e r A d v e r s e E v e n t s
A d d i t i o n a l a d v e r s e e v e n t s r e p o r t e d i n c l i n i c a l t r i a l s e"1 % b u t < 1 0 % i n c l u d e f a t i g u e , v o m i t i n g , d r y m o u t h , h y p e r h i d r o s i s , p r u r i t u s , i n s o m n i a , d y s p e p s i a , l e t h a r g y , a s t h e n i a , a n x i e t y d e c r e a s e d a p p e t i t e , v e r t i g o , hot flush, disturbance in attention, tremor, chills, abnormal dreams, depression, blurry vision and erectile dysfunction.
Contraindications1
Use of tapentadol ER is contraindicated in the following patient populations:
Significant respiratory depression
Acute or severe bronchial asthma or hypercarbia in an unmonitored setting or in the absence of resuscitative equipment
Known or suspected paralytic ileus or gastrointestinal obstruction
Current or recent use (within the last 14 days) of monoamine oxidase inhibitors (because of potential additive effects on norepinephrine and serotonin levels)
Warnings and Precautions1
Tapentadol can cause life threatening respiratory depression; caution should be used in patients with risk for hypoxia or patients that have decreased respiratory reserve.
Risk for misuse and abuse exists with tapentadol, which is a Schedule II controlled substance; thus caution should be used in patients who may be at risk.
Accidental ingestion of tapentadol ER, particularly in children, can result in a fatal overdose.
Elderly, cachectic and debilitated patients may be more likely to develop respiratory depression; monitor such patients closely.
Patients with chronic pulmonary disease are at risk of respiratory depressant effects of tapentadol and may develop apnea. Consider the use of nonopioid analgesics.
Tapentadol may cause severe hypotension. Avoid use in patients with circulatory shock. Use with caution in patients in patients whose ability to maintain blood pressure has already been compromised by a reduced blood volume or concurrent administration of certain CNS depressant drugs.
Tapentadol has the potential to cause increases in intracranial pressure by depressing respiratory drive, resulting in CO2 retention. Tapentadol should be used cautiously in patients with evidence of head injury or increased intracranial pressure.
Tapentadol should be used with caution in patients with a predisposition to or history of seizure disorders as tapentadol may aggravate convulsions in patients with convulsive disorders and may induce or aggravate seizures in some clinical settings. Use has not been assessed in this patient population.
Life-threatening serotonin syndrome has been reported with concurrent use of tapentadol and serotonergic agents. Tapentadol should be used cautiously in patients taking other medications that can increase serotonin levels..
Spasm of the sphincter of Oddi may occur with tapentadol; monitor for worsening symptoms in patients with biliary tract disease including acute pancreatitis.
Withdrawal symptoms may occur with abrupt discontinuation of tapentadol; dose tapering should be considered. Avoid use of opioid agonist/antagonists and partial agonists with tapentadol because concomitant use may precipitate withdrawal symptoms.
Tapentadol use may result in impaired ability to operate machinery or drive.
Concomitant use of alcohol/drugs of abuse and tapentadol may result in additive side effects (sedation, respiratory depression, and hypotension) and should be avoided.
Caution with use in hepatic and renal impairment (see dosing recommendations).
Caution with use in the elderly due to increased risk of impaired hepatic and renal impairment.
Tapentadol is not approved for use in adolescents and children less than 18 years old.
Pregnancy/Lactation1
Tapentadol is pregnancy category C.
Information regarding excretion of tapentadol in breast milk is limited; use is not recommended during breast feeding.
Postmarketing Safety Experience1
The following reactions have been reported in post-approval use of tapentadol ER:
Gastrointestinal: diarrhea
Psychiatric disorders: hallucination, suicidal ideation
Cardiac disorders: palpitations
Sentinel Events11
In August 2012 the Joint Commission issued a Sentinel Event Alert on the safe use of opioids in hospitals. Dosing errors, improper monitoring of patients and drug interactions may result in serious adverse effects such as respiratory depression. The Joint Commission recommends that effective, safe practices are implemented for appropriate monitoring of patients receiving opioids.
Look-alike / Sound-alike (LA / SA) Error Risk Potential
As part of a JCAHO standard, LA/SA names are assessed during the formulary selection of drugs. Based on clinical judgment and an evaluation of LASA information from four data sources (Lexi-Comp, USP Online LA/SA Finder, First Databank, and ISMP Confused Drug Name List), the following drug names may cause LA/SA confusion:
LA/SA for generic name tapentadol: Tapazol, Thiopental, Tramadol
LA/SA for brand name Nucynta: Neulasta, Nucynta IR
Drug Interactions1
Tapentadol is primarily metabolized by Phase 2 glucuronidation. In vitro studies did not reveal potential of tapentadol to inhibit or induce the cytochrome P450 enzyme system, therefore interactions mediated by the cytochrome P450 system are unlikely to occur.
Concomitant use with alcohol may result in an increase in tapentadol AUC by 17% and Cmax by 48%. This may result in a potentially fatal overdose. Patients should not consume alcohol while taking tapentadol.
CNS depressants (i.e. sedatives, general anesthetics, phenothiazines) when co-administered with tapentadol may increase the risk for respiratory depression and hypotension.
Serotonergic medications including MAOIs, SSRIs, SNRIs when administered with tapentadol may increase the risk for serotonin syndrome.
Mixed agonist/antagonist opioid analgesics (i.e. butorphanol, nalbuphine and pentazocine) and partial agonists (buprenorphine) may precipitate withdrawal syndrome when used with tapentadol.
Anticholinergics when used concurrently with tapentadol may increase the risk for urinary retention and/or severe constipation.
Acquisition Costs
Drug acquisition costs for sustained action oral opioids on VHA formulary (methadone, morphine SA) and not on formulary (oxycodone CR, tapentadol ER, tramadol ER)
Table SEQ Table \* ARABIC 7: Relative Drug Acquisition Costs
Tapentadol ER Dose
(twice daily dosing)Cost/Day/patient ($) Cost/Year/patient ($)50 mg 3.281198100 mg6.062212150 mg 7.542752200 mg 9.743555250 mg9.783570Tramadol ER Dose
(once daily dosing)100mg 1.43522200mg2.11770300mg 3.551296Methadone Dose
(TID dosing)5 mg0.124410 mg 0.1866Morphine SA Dose
(twice daily dosing)15 mg0.1451100 mg0.68248Oxycodone CRa
(twice daily dosing)20 mg4.26155540 mg7.56275960 mg11.424168aOxycodone CR is a non-formulary alternative for patients who have failed methadone or morphine SA. Lange, et al. suggested using an estimated conversion ratio of 5:1 for tapentadol ER to oxycodone CR (50 mg tapentadol ER for every 10 mg oxycodone CR). REF _Ref341103236 \r \h \* MERGEFORMAT 6
Pharmacoeconomic Analysis
No pharmacoeconomic studies relevant to the VA.
Table SEQ Table \* ARABIC 8: Indirect Comparisons of Cost-effectiveness Based on NNT for Benefit
NNT-30DoseCost per 12 weeks to benefit one patient ($)Tapentadol ERAfilalo et al.2 (2010), Grnenthal4 GmbH-NCT00486811 (2010) OANSD250mg BIDN/ABuynak et al.3 (2010)-LBP8250 mg BID6572Schwartz et al.5 (2011)-PDPN9250 mg BID7393Alternative Opioids with NNT Data for Chronic Pain DisordersTramadol ER
CepedaMS17(2006) OA6300mg QD298 NNT data from Cochrane meta-analyses
Conclusions
Tapentadol extended-release (ER) is a long-acting, dual-mechanism opioid analgesic that has been shown to provide small analgesic effects in patients with chronic pain associated with lower back pain and diabetic peripheral neuropathy, but it was not better than placebo in knee osteoarthritis. Overall, it is pharmacologically similar to tramadol and is similar in efficacy and safety to other oral opioids and immediate-release tapentadol. A potential advantage is a lower risk of gastrointestinal adverse events, a safety benefit seen relatively consistently across studies. This difference in tolerability may make tapentadol an alternative for patients who do not tolerate oxycodone CR.
The clinical studies tended to exclude patients representative of the population served at the VA which limited the external validity of the results. Considering the number of relatively safe, effective, and cost effective VA alternatives for the treatment of chronic pain, tapentadol ER will have a limited role in the treatment of chronic pain in the VA.
References:
Nucynta Extended-Relase (tapentadol ER) prescribing information. Ortho-McNeil-Janssen, Inc; August 2012.
Afilalo M, Etropolski MS, Kuperwasser B, et al. Efficacy and safety of tapentadol extended release compared with oxycodone controlled release for the management of moderate to severe chronic pain related to osteoarthritis of the knee: a randomized, double-blind, placebo- and active-controlled phase III study. Clin Drug Investig. 2010;30(8):489-505.
Buynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the management of chronic low back pain: results of a prospective, randomized, double-blind, placebo- and active-controlled Phase III study. Expert Opin Pharmacother. 2010 Aug;11(11):1787-804.
Grnenthal GmbH. A study to evaluate the efficacy and safety of CG5503 prolonged release(PR) in subjects with moderate to severe chronic pain due to osteoarthritis of the knee [Clinical Trials.gov identifier NCT00486811]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from http://clinicaltrials.gov/ct2/show/results/NCT00486811?term=NCT00486811&rank=1 --Non-Peer Review
Schwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial. Curr Med Res Opin. 2011 Jan;27(1):151-62
Lange B, Kuperwasser B, Okamoto A, et al. Efficacy and safety of tapentadol prolonged release for chronic osteoarthritis pain and low back pain. Adv Ther 2010 Jun; 27(6):381-99
Zhou Y, Price D, Permutt T. Statistical review and evaluation: clinical studies for NDA/serial number 200-533 Nucynta ER for management of moderate to severe chronic pain. Division of anesthesia and analgesia. http://www.accessdata.fda.gov/drugsatfda_do
cs/nda/2011/200533Orig1s000StatR.pdf [Accessed 31 Aug 2012]
Wild JE, Grond S, Kuperwasser B, Gilbert J, McCann B, Lange B., et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Practice. 2010; 10 (5) 416-427.
Johnson & Johnson Pharmaceutical Research & Development, LLC. An open-label extension study with flexible extended-release (ER) tapentadol to treat patients with moderate to severe chronic pain. US National Institute of Health. ClinicalTrials.gov. Accessed October 8, 2012.
Vadivelu N, Timchenko A, Huang Y, Sinatra R.. Tapentadol extended-release for treatment of chronic pain: a review. Journal of Pain Research. 2011: 4. 211-218.
Sentinel Event Alert Issue 49: Safe use of opioids in hospitals. August 9, 2012. http://www.jointcommission.org/sentinel_event.aspx
http://www.causascientia.org/math_stat/ProportionCI.html --used to calculate 95% interval
Hoy SM. Tapentadol extended release: in adults with chronic pain. Drugs. 2012 Feb 12;72(3):375-93.
Dworkin RH, Turk DC, Wyrwich KW. et. al. Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations. J Pain. 2008 Feb;9(2):105-21. Epub 2007 Dec 11.
Dworkin RH, Turk DC, McDermott MP. et al. Interpreting the clinical importance of group differences in chronic pain clinical trials: IMMPACT recommendations. Pain. 2009 Dec;146(3):238-44. Review.
Farrar JT, Young JP Jr, LaMoreaux L, et al. Clinical importance of changes in chronic pain intensity measured on an 11-point numerical pain rating scale. Pain. 2001 Nov;94(2):149-58.
CepedaMS, CamargoF, ZeaC,et al.Tramadol for osteoarthritis.Cochrane Database Syst Rev.2006;(3):CD005522.
NueschE, RutjesAW, HusniE,et al.Oral or transdermal opioids for osteoarthritis of the knee or hip.Cochrane Database Syst Rev.2009;(4):CD003115
Prepared December 2012 by:
Jeremy Boehme,Pharm.D., Pharmacy Practice Resident
Kathleen Wallace, Pharm.D., Pharmacy Practice Resident
Contact person:
Francine Goodman, PharmD, BCPS
Clinical Pharmacy Specialist, VA Pharmacy Benefits Management Services (119D)
Appendix: Clinical Trials
A literature search was performed on PubMed/Medline (1996-2012) using the search terms Tapentadol ER and Nucynta ER. The search was limited to studies performed in humans and published in the English language. Reference lists of current articles, review articles, and the manufacturers AMCP dossier were searched for relevant clinical trials. Food and Drug Administration materials, and data from clinicaltrials.gov were also accessed. All randomized controlled trials published in peer-reviewed journals were included.
Trial 1Trial of chronic pain in osteoarthritis of the knee2
CitationAfilalo M, Etropolski MS, Kuperwasser B, et al. Efficacy and safety of Tapentadol extended
release compared with oxycodone controlled release for the management of moderate
to severe chronic pain related to osteoarthritis of the knee: a randomized,
double-blind, placebo- and active-controlled phase III study. Clin Drug Investig.
2010;30(8):489-505.Study GoalsEvaluate efficacy and safety of tapentadol extended release (ER) compared with oxycodone controlled release (CR) for management of moderate to severe chronic osteoarthritis-related knee pain.MethodsStudy Design
Randomized, double-blind, placebo-, active- controlled, parallel arm, multicenter, phase III study
Primary endpoint: Change in average daily pain intensity (11-point numerical scale) over the last week of maintenance and over the entire 12-week maintenance period (entered electronic diary).
Screening, washout, randomization (1:1:1 BID TAP ER 100-250mg, OXY CR 20-50mg, or PBO), titration, maintenance, and follow-up trial design
Responder analysis to determine percentage o f p a t i e n t s a c h i e v i n g e"3 0 % a n d e"5 0 % i m p r o v e m e n t f r o m b a s e l i n e t o w e e k 1 2 . I f p t d i s c o n t i n u e d m e d i c a t i o n p r i o r t o 1 2 w e e k s = n o n - r e s p o n d e r
Q u e s t i o n n a i r e s : W e s t e r n O n t a r i o a n d M c M a s t e r U n i v e r s i t i e s I n d e x o f O s t e o a r t h r i t i s Q u e s t i o n n a i r e ( W O M A C ) 2 4 q u e s t i o n s c o ncerning pain, disability and joint stiffness
Patient Global Impression of Change(PGIC)a measure of perceived change in overall health status1=very improved, 7=very much worse
EuroQol-5 Dimension (EQ-5D) and Short Form-36(SF-36) Health Survey, which evaluate health outcomes and physical, social, and mental well-being
Data Analysis
90% power w/p=0.05 and CI 95% required 314 pts per treatment arm
Intent-to-treat-all randomized pts who took one or more doses of study medication. Last observation carried forward (LOCF) to impute missing measurement w/early discontinuation
Primary endpoint: analysis of covariance (ANCOVA) with treatment and pooled analysis center as factors, and baseline pain intensity score as a covariate was applied.
Pairwise treatment difference estimated using least squares mean (LSM) compared to placebo.
Cochran-Mantel-Haenszel used to analyze difference in response rates and rates of adverse reactions. w/ p values for pairwise differences between arms.CriteriaInclusion criteria
e"4 0 y e a r s o f a g e w / D x o s t e o a r t h r i t i s o f k n e e f u n c t i o n a l c l a s s I - I I I
P a i n a t t h e r e f e r e n c e j o i n t r e q u i r i n g t h e u s e o f a n a l g e s i c s ( d"1 6 0 m g m o r p h i n e / d a y e q u i v a l e n t s ) f o r m o r e t h a n o r e q u a l t o 3 m o n t h s
P t s d i s s a t i s f i e d w / c u r r e n t a n a l g e s i c t h e r a p y a n d a n a v e r a g e b a s e l i n e p a i n i n t e n s i t y e"5 f o r 3 d a y s
E x c l u s i o n c r i t e r i a
P r e s e n c e o f u n s t a b l e m e d i c a l o r p s y c h i a t r i c d i s e a s e o r c l i n i c a l l y s i g n i f i c a n t d i s e a s e .
R e q u i r e m e n t o f p a i n f u l p r o c e d u r e s o r s u r g e r y d u r i n g t h e s t u d y t i m e p e r i o d
H i s t o r y o f s u b s t a n c e a b u s e , e pilepsy/seizure disorder, stroke/transient ischemic attacks, malignancy in the past 2 years, HIV infection, chronic hepatitis b or C, uncontrolled hypertension
Diseases that affect the assessment of osteoarthritis painanatomical, fibromyalgia, gout, infectious or autoimmune disease affecting the knee
No other analgesics could be used during the study period, except specific paracetamol dose.
Neuroleptics, antiparkinsonian drugs, tryciclic antidepressants, anticonvulsants, serotonin-norepinephrine reuptake i n h i b i t o r s , a n d m o n o a m i n e o x i d a s e i n h i b i t o r s p r o h i b i t e d w i t h i n 1 4 d a y s o f s t u d y , a n d d u r i n g t h e s t u d y .
M o d e r a t e t o s e v e r e r e n a l i n s u f f i c i e n c y o r h e p a t i c i m p a i r m e n t
O t h e r d r u g s o t h e r t h a n t h o s e l i s t e d a b o v e w e r e a l l o w e d i f o n s t a b l e d o s e e"3 m o n t h s p r i o r .
Systemic steroid therapy within 4 weeks to 6 months prior to screening depending on administration rate, or if used during the trial.
History of sensitivity to tapentadolResultsBaseline characteristics similar in the 1030 randomized patients; 1023 intent-to-treat patients.
Efficacy Measure
Tapentadol ER
(299.3mg)g
N = 344
Oxycodone HCl CR
(48.2mg)g
N =342
Placebo
N = 337
LSMD- At 12 wksa
[95% CI]
-0.7
[-1.04, -0.33]f
-0.3
[-0.68, 0.02]
--
LSMD- Including titrationa
[95% CI]
-0.7
[-1.00, -0.33]f
-0.3
[-0.67, 0.00]f
--
BOCFb-LS mean(SE)
p-value vs PBO
-2.0(0.1)
0.082
-1.2(0.1)
0.002
-1.7(0.1)
30% reduction in pain
intensity at week 12 c
43.0
ARR 7.1
NSD
24.9 d,f
ARR 11.0
NNTH 10
35.9
50% reduction in pain
intensity at week 12 c
32.0
ARR 7.7
NNT 13
p=0.027
17.3
ARR 7.0
NNTH 14
p=0.023d
24.3
Completionc
Rate (n=N(%))
197/344(42.7)
121/342(64.6)
207/337(38.6)
n
VMI
MI
MiI
NC
MiW
MW
VMW
PGICe
Tapentadol ER
258
20.2
38.4
20.9
12.8
3.1
3.9
0.8
Oxycodone CR
200
13.5
33.5
26.5
9.5
10
6.5
0.5
Placebo
273
8.4
27.1
23.4
24.2
11
4
1.8
a least squares mean difference (LSMD) vs placebo [95% CI]
b Baseline observation carried forwardnew analysis numbers FDA7
c Percent
d-placebo statistically favorable vs oxycodone HCl CR
e Patients Global Impression of Change (PGIC) percentages:7- VMI-very much improved, MI-much improved, MiI-minimally improved, NC-no change, MiW-minimally worse, MW-much worse, VMW-very much worse
f p<0.05
gGroup average of individual mean total daily doses over 15 weeks
A d v e r s e e v e n t s
T r e a t m e n t e m e r g e n t a d v e r s e e v e n t s ( T E A E ) w e r e m i l d t o m o d e r a t e . T a p e n t a d o l E R h a d a s i g n i f i c a n t l y l o w e r i n c i d e n c e o f c o n s t i p a t i o n a n d n a u s e a / v o m i t i n g c o m p o s i t e v e r s u s o x y c o d o n e C R .
D u r i n g d o u b l e - b l i n d t r e a t m e n t a n d d"3 0 d a y s o f l a s t d o s e o f medication, 20 patients experienced serious AEs. One patient died due to MI 90 days after receiving first dose of oxycodone CR. This was considered to be unrelated to study medications as patient had history of morbid obesity.
Treatment emergent adverse effect measure
Tapentadol ER n(%)
N = 344
Oxycodone HCl CR n(%)
N =342
Placebo
n(%)
N = 337
Constipation
65 (18.9)a
NNTH 8
126 (36.8)
NNTH 3
22 (6.5)
Nausea/Vomiting
Composite
92(26.7) a
NNTH 6
186(54.4)
NNTH 2
34(10.1)
Discontinuations due to TEAE , %
6 6 ( 1 9 . 2 ) a
N N T H 8
1 4 6 ( 4 2 . 7 )
N N T H 3
2 2 ( 6 . 5 )
S e r i o u s a d v e r s e e v e n t s
4 ( 1 . 2 )
1 0 ( 2 . 9 )
6 ( 1 . 8 )
a p < 0 . 0 0 1 c o m p a r e d t o o x y c o d o n e C R A u t h o r s
C o n c l u s i o n s T a p e n t a d o l E R h a d a s i g n i f i c a n t l y h i g h e r p e r c e n t a g e o f p a t i e n t s a c h i e v i n g e"5 0 % i m p r o v e m e n t i n p a i n i n t e n s i t y c o m p a r e d t o p l a c e b o , r e s p e c t i v e l y ( 1 1 0 / 3 4 4 ( 3 2 % ) a n d 8 2 / 3 3 7 ( 2 4 . 3 % ) ) .
A s i g n i f i c a n t l y l o w e r p e r c e n t a g e o f p a t i e n t s a c h i e v e d e"5 0 % i m p r o v e m e n t i n p a i n i n t e n s i t y c o m p a r e d t o p l a c e b o i n t h e o x y c o d o n e C R g r o u p ( 5 9 / 3 4 2 ( 1 7 . 3 % ) )
T a p e n t a d o l E R h a d a s i g n i ficant reduction in average pain intensity at week 12 compared to placebo, whereas oxycodone CR did not.
Treatment with tapentadol ER 100-250mg twice daily was associated with a clinically significant decrease in pain intensity compared with placebo at the termination of the study based on accepted clinical measures.
Tapentadol ER and oxycodone CR both had significant improvements in PGIC ratings vs PBO
Tapentadol has a significantly better gastrointestinal tolerability versus oxycodone IR. CritiqueStren g t h s
R a n d o m i z e d , d o u b l e b l i n d , p l a c e b o - a c t i v e - c o n t r o l l e d , m u l t i - a r m t r i a l
S t u d y u s e o f c l i n i c a l l y r e l e v a n t m e a s u r e s ( e"3 0 % p a i n r e d u c t i o n , e"5 0 % p a i n r e d u c t i o n , u s e d n u m e r i c a l p a i n s c a l e 0 - 1 0 )
I n c l u d i n g a n i n t e n t - t o - t r e a t a n a l y s i s a n d w e l l - d e s i g n e d p r o t ocols and procedures
Limitations
A very restricted patient population due to multiple inclusion and exclusion criteria
Study funded by makers of tapentadol; researchers are employees and shareholders
With a LOCF method for ITT, patients who discontinued due to adverse events may have good pain scores carried forward even though they werent successfully treated.7
The sample size was only calculated to assess the analgesic efficacy of tapentadol ER to placebo
There is only external validity to a very small population of individuals
Trial 2Trial in chronic low back pain3
CitationBuynak R, Shapiro DY, Okamoto A, et al. Efficacy and safety of tapentadol extended release for the
management of chronic low back pain: results of a prospective, randomized, double-blind, placebo-
and active-controlled Phase III study. Expert Opin Pharmacother. 2010 Aug;11(11):1787-804.Study GoalsTo evaluate the efficacy and safety of tapentadol extended release(ER) for the management of moderate to severe chronic low back pain (LBP).MethodsStudy Design
Prospective, randomized, double-blind, placebo- and active- controlled, parallel group multicenter, Phase III study conducted in the United States, Canada, and Australia.
Primary endpoint: change from baseline in mean overall pain (11-point numerical scale(NRS) twice daily) until the end of the prospective study (US requirement: included titration phase, European requirement: change in entire 12 week maintenance period
Secondary endpoints : R e s p o n s e r a t e e"3 0 % a n d e"5 0 ; P G I C , B P I , E Q - 5 D , S F - 3 6 , a n d a s l e e p q u e s t i o n n a i r e .
S t u d y t i m e l i n e : 2 - w e e k s c r e e n i n g , a w a s h o u t p e r i o d , r a n d o m i z a t i o n 1 : 1 : 1 , 3 - w k d o u b l e b l i n d t i t r a t i o n , f o l l o w e d b y 1 2 w e e k m a i n t e n a n c e p e r i o d . 4 d a y p o s t t e r m i n a t i o n f o l l o w - u p / p h o n e c a l l
P a t i e n t s g i v e n o p t i o n t o c o n t i n u e t r e a t m e n t i n a n o p e n l a b e l e x t e n s i o n s t u d y .
N o o t h e r a n a l g e s i c s a l l o w e d , u n l e s s f o r r e a s o n s u n r e l a t e d t o l o w b a c k p a i n ; a n d t h e n A P A P d"1 0 0 0 m g / d a y x 3 d a y s .
D a t a A n a l y s i s
P o w e r : 3 1 4 p a t i e n t s / t r e a t m e n t g r o u p , 9 4 2 enrolled and randomized to provide 90% power. Assuming a mean treatment group difference of -0.7 with standard deviation (SD) of 2.7 in change from baseline in pain intensity on 11-point NRS
Primary analysis population is the ITT and safety populations-last observation carried forward(LOCF) to input missing pain scores after early discontinuation
Treatment effects were estimated based on least mean squares difference (LSMD) from placebo. Active treatments were compared to placebo using analysis of covariance (ANCOVA) with factors treatment, pooled center, and baseline pain intensity as a covariate.
Robustness of primary efficacy results evaluated using: baseline observation carried forward(BOCF); worst observation carried forward(WOCF); placebo mean imputation (PMI)
Responder rates, PGIC, and sleep study compared between active treatment and placebo using Cochran-Mantel-Haenszel w/a p value calculated at 5% significance.
Distribution of percentage of improvement in pain score at week 12 and time to treat disc o n t i n u a t i o n d u e t o l a c k o f e f f i c a c y w e r e e s t i m a t e d u s i n g K a p l a n - M e i e r m e t h o d s a n d c o m p a r e d u s i n g t h e l o g - r a n k t e s t
B P I , S F - 3 6 , E Q - 5 D , a n d P A C - S Y M w e r e a l l a n a l y z e d u s i n g A N C O V A m o d e l s C r i t e r i a I n c l u s i o n c r i t e r i a
e"1 8 y e a r s o l d w i t h h i s t o r y o f n o n - m a l i g n a n t l o w b a c k p a i n f o r e"3 m o n t h s p r i o r t o r a n d o m i z a t i o n
T a k i n g a n a l g e s i c s f o r L B P f o r e" 3 m o n t h s p r i o r t o s c r e e n i n g , a n d b e d i s s a t i s f i e d w i t h c u r r e n t t r e a t m e n t w / a b a s e l i n e p a i n o f e"5 o n a n 1 1 - p o i n t N R S a f t e r a 3 - 7 d a y w a s h o u t p e r i o d
P a t i e n t s c u r r e n t o p i o i d a n a l g e s i c s d"1 6 0 m g o r a l m o r p h i n e e q u i v a l e n t s
E x c l u s i o n c r i t e r i a
P a r t i c i p a t i o n i n o t h e r c l i n i c a l s t u d i e s o r p r e v i o u s p a r t i c i p a t i o n i n o t h e r t a p e n t a d o l s t u d i e s .
T a k i n g n e u r o l e p t i c s , t r i c y c l i c a n t i d e p r e s s a n t s , a n t i c o n v u l s a n t s , a n t i p a r k i n s o n i a n , s e r o t o n i n n o r e p i n e p h r i n e r e u p t a k e i n h i b i t o r s , a n d M A O - I s d u r i n g & w / i n 1 4 d a y s o f t h e s t u d y .
P t s w / d i a g n o s e d p s y c h i a t r i c o r n e u r o l o g i c c o n d i t i o n s c o u l d p a r t i c i p a t e i f t r e a t e d w i t h m e d i c a t i o n s n o t l i s t e d a b o v e a t a c o n t r o l l e d , s t a b l e d o s e e"3 m o n t h s p r i o r t o r a n d o m i z ation.
Corticosteroids prohibited within 4 weeks(IM), within 8 weeks(SQ), within 3 months (intra-articular), and within 6 months(depot-injected).
The use of Transcutaneous electrical nerve stimulation, acupuncture, physical therapy, packs, and massages we r e p e r m i t t e d i f s t a r t e d e"1 4 d a y s p r i o r t o e n r o l l m e n t a n d c o n t i n u e d t h r o u g h o u t .
P r e s e n c e o f c l i n i c a l l y s i g n i f i c a n t m e d i c a l o r p s y c h i a t r i c d i s e a s e , i f a p a i n f u l p r o c e d u r e o r s u r g e r y w a s r e q u i r e d d u r i n g t h e s t u d y , s u r g e r y i n l o w b a c k a r e a w i t h i n 3 m o n t h s o f s creening.
History of drug or alcohol abuse, epilepsy/seizure disorder, stroke/transient ischemic attack, HIV, chronic hepatitis B or C, malignancy w/in 2 years, uncontrolled hypertension >160/95, moderate to severe renal and hepatic impairment., or history of hypersensitivity or allergies to study meds
Fibromyalgia, gout, infectious or autoimmune diseases
ResultsBaseline characteristics were similar between the 981 patients who were randomized, 73% white, 58% female, and the mean age was 50.
14 randomized patients had data excluded due to not taking study medication, also excluded were two patients who were randomized twice. 965 patients received one dose of medication, and seven patients at study sites with major audit findings were excluded from intent-to-treat population (ITT) prior to unblinding. ITT population=958 patients; PBO=317; TER=315; OCR=326
Efficacy Measure a
Tapentadol ER
(313.2 mg)f
N = 315
Oxycodone HCl CR
(53.0 mg)f
N =326
Placebo
N = 317
LSMD- 12 wks
[95% CI]
-0.8
[-1.22, -0.47] g
-0.9
[-1.24, -0.49] g
--
LSMD- 15 wks
[95% CI]
-0.7
[-1.06, -0.35] g
-0.8
[-1.16, -0.46] g
--
BOCFb LS mean(SE)
p-value vs PBO
-1.8(0.1)
0.002
n=312
-1.5(0.1)
0.213
n=323
-1.3(0.1)
30% reduction in pain
Intensity at week 12 c
39.7
NNT 8
p=0.016
30.4
NSD
p=0.365
27.1
50% reduction in pain
intensity at week 12 c
27.0
NNT 13
p=0.016
23.3
NSD
p=0.174
18.9
PGIC at 12 weeks c
55.5
(n=236)
60.0
(n=210)
32.7
(n=245)
BPI at 12 weeks a,e
Total score
-0.7(0.18) g
-0.5(0.17) g
--
SF-36a,e
Physical functioning
Role-physical
Bodily pain
vitality
4.1 (1.65)g
9.9 (2.87) g
5.5 (1.56) g
3.2 (1.43) g
2.6 (1.64) g
--
6.3 (1.54) g
--
--
--
--
--
EQ-5Da,e
0.0 (0.02)**
0.1 (0.02)**
Study completion c
Rate (n=N (%))
166/315 (52.7)
133/326(40.8)
152/317(47.9)
a least squares mean difference(LMSD) vs placebo [95% CI]
b Baseline observation carried forwardthe analysis provided is from the FDA7
c Percentage
d Patients Global Impression of Change (PGIC) percentages: Composite of clinically significant measure of VMI-very much improved, MI-much improved
e Using last observation carried forward for imputation with Brief Pain Intensity (BPI), EuroQol-5(EQ-5D), Short Form-36 (SF-36)
f Group average of individual mean total daily doses over 15 weeks
g p<0.05
Adverse events
Treatment emergent adverse events (TEAE) were mild to moderate. Tapentadol ER had a significantly lower incidence of constipation and nausea/vomiting composite versus oxycodone CR.
Of the Serious TEAEs in the tapentadol group 3 were possibly related to study drug including: decreased level of consciousness, mental confusion, and one had atrial fibrillation.
Treatment emergent adverse event (TEAE) Measurea
Tapentadol ER
(313.2 mg)*
N = 318c
Oxycodone HCl CR
(53.0 mg)*
N =328c
Placebo
N = 319c
Constipation
44(13.8b)
NNH 12
88(26.8)
NNH 5
16(5.0)
Nausea/Vomiting Composite
93(29.2 b)
NNH 6
176(53.7)
NNH 3
34(10.7)
TEAE caused discontinuation rates
16.7 b
31.7
4.4
Serious adverse eventsd
2.2
(n=7)
3.4
(n=11)
0.9
(n=3)
a RR
b p<0.001compared to OXY CR
c total population before exclusion of 7 patients just prior to unblindingAuthors
ConclusionsTapentadol ER 100-250 mg twice daily over 15 weeks significantly more effective for management of moderate to severe chronic low back pain than placebo.
Significant reductions in mean pain intensity and si g n i f i c a n t l y h i g h e r p e r c e n t a g e s o f p a t i e n t s w i t h e"3 0 % a n d e"5 0 % i m p r o v e m e n t s , a n d w a s g e n e r a l l y w e l l t o l e r a t e d .
T a p e n t a d o l E R h a d i m p r o v e d G I t o l e r a b i l i t y a n d l o w e r i n c i d e n c e o f s t u d y d i s c o n t i n u a t i o n d u e t o T E A E s t h a n o x y c o d o n e C R a t s i m i l a r a n a l g e s i c d o s e s.
Tapentadol ER may contribute to more consistent and improved relief of chronic pain.CritiqueStrengths
Properly powered, prospective, randomized, double-blind, placebo- and active- controlled, parallel group multicenter trial.
Analyzing multiple forms of measure and effectiveness to quantify the subjective nature of pain.
Appropriate measurement scales for statistical and clinical significance.
Limitations
Study was funded by makers of tapentadol; the majority of researchers were employees and shareholders.
With a LOCF method for ITT, patients who discontinued due to adverse events may have good pain scores carried forward even though they werent successfully treated.7
The study limited patients with severe renal impairment and moderate to severe hepatic impairment without defining parameters. This limits the generalization possible with this study.
Removal of 7 patients for unknown reasons immediately prior to unblinding, and then including these patients in some statistical analysis and not others.
Only powered to find a statistical difference between tapentadol ER and placebo, when possibly could have evaluated for non-inferiority compared to oxycodone CR.
Study lacks external validity and therefore does not have a place in therapyPatient Global Impression of Change(PGIC)a measure of perceived change in overall health status1=very much improved, 7=very much worsetwice in maintenance period and at end
Brief Pain Inventory (BPI)-assesses pain intensity(pain subscale score) and degree to which pain interferes with function(pain interference sub score), and a total score.weeks 1,3,5,7,9, 11, end
EuroQol-5 Dimension (EQ-5D) and Short Form-36(SF-36) Health Survey, evaluate health outcomes and physical, social, and mental well-being: administered at baseline and weeks 1,5,9, and the end.
Sleep questionnaireevaluated sleep latency, time slept, number awakenings, sleep quality from the night before----once per week
Trial 3Knee osteoarthritis study4
CitationGrnenthal GmbH. A study to evaluate the efficacy and safety of CG5503 prolonged release(PR) in subjects with moderate to severe chronic pain due to osteoarthritis of the knee [Clinical Trials.gov identifier NCT00486811]. US National Institutes of Health, ClinicalTrials.gov [online]. Available from URL: http://clnicaltrials.gov/ [31]Study GoalsEvaluate effectiveness and tolerability of tapentadol prolonged release (PR) 100-250mg twice daily in patients with moderate to severe chronic pain due to osteoarthritis of the knee compared to placeboMethodsStudy Design
A prospective randomized double blind, placebo- and active-control, parallel arm, phase III trial in Europe.
Primary efficacy endpoint: change from baseline of the average pain intensity over the last week (12) of the maintenance period based on 11 point numerical rating scale (NRS) least squares mean difference (LSMD)
Secondary efficacy endpoint: Patient global Impression of change; Western Ontario McMaster Questionnaire(WOMAC) Global Score; Time to treatment discontinuation due to lack of efficacy. Scores Form 36(SF-36), EuroQol-5; sleep questionnaire; patient assessment of constipation symptoms (PAC-SYM)
Schedule of study:screening, washout, titration, maintenance, and follow up (2 weeks post-)
Intent to treat (ITT) used last observation carried forward (LOCF)
Data Analysis
Intent-to-treat population-all randomized patients who took one or more doses of study medication. Last observation carried forward (LOCF) to impute missing measurement w/early discontinuation
Primary endpoint: analysis of covariance (ANCOVA) with treatment and pooled analysis center as factors, and baseline pain intensity score as a covariate was applied.
Pairwise treatment difference estimated using least squares mean (LSM) compared to placebo.
Cochran-Mantel-Haenszel used to analyze difference in response rates and rates of adverse reactions. w/ p values for pairwise differences between arms.Primary analysis CriteriaInclusion criteria
M e n a n d w o m e n e"4 0 y e a r s o f a g e w i t h d i a g n o s i s o f o s t e o a r t h r i t i s o f t h e k n e e p e r A m e r i c a n C o l l e g e o f R h e u m a t o l o g y c r i t e r i a f u n c t i o n a l c a p a c i t y c l a s s I - I I I
P a i n a t t h e r e f e r e n c e j o i n t r e q u i r i n g t h e u s e o f a n a l g e s i c s ( d"1 6 0 m g m o r p h i n e / d a y e q u i v a l e n t s ) f o r m o r e t h a n o r e q u a l t o 3 m o n t h s
P a t i e n t s n e e d e d t o b e d i s s a t i s f i e d w i t h c u r r e n t a n a l g e s i c t h e r a p y a n d h a v e a n a n a v e r a g e b a s e l i n e p a i n i n t e n s i t y e"5 f o r 3 d a y s p r i o r t o r a n d o m i z a t i o n . W r i t t e n c o n s e n t w a s r e q u i r e d .
E x c l u s i o n c r i t e r i a
H i s t o r y o f a l c o h o l a n d / o r d rug abuse in Investigator's judgment;
Chronic hepatitis B or C, or HIV, presence of active hepatitis B or C within the past 3 months;
Life-long history of seizure disorder or epilepsy;
History of malignancy within past 2 years, with exception of basal cell carcinoma that has been successfully treated;
Uncontrolled hypertension;
Patients with severely impaired renal function;
Patients with moderate to severely impaired hepatic function or with laboratory values reflecting inadequate hepatic function,
Treatment with neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitors (SNRI), tricyclic antidepressants, anticonvulsants, or anti-parkinsonian drugs, treatment with any other analgesic therapy than investigational medication or rescue medication during the trial.ResultsEfficacy Measure a
Tapentadol ER
N = 319
Oxycodone HCl CR
N =331
Placebo
N = 336
LSMD- 12 wks
[95% CI]
(-0.2)
[-0.55, 0.07]
(-0.3)
[-0.61, 0.09]
--
LSMD- 15 wks
[95% CI]
(0.1)
[-0.18, 0.44]
(0.2)
[-0.16, 0.54]
--
30% reduction in pain
Intensity at week 12 c
41.1
NSD
26.0
NNTH 7
40.9
50% reduction in pain
intensity at week 12 c
31.0
NSD
22.1
NSD
27.0
Baseline characteristics were similar between groups, 61% of the population was between 18-65 years of age, 72% of the population was female.
a least squares mean difference(LMSD) vs placebo [95% CI]
b Baseline observation carried forwardthe analysis provided is from the FDA4
c Percentage
d Patients Global Impression of Change (PGIC) percentages: VMI-very much improved, MI-much improvedtapentadol ER 139/248 and oxycodone CR 90/212 and placebo 127/294
e Using last observation carried forward for imputation with Brief Pain Intensity (BPI), EuroQol-5(EQ-5D), Short Form-36 (SF-36)
()standard deviation (SD)
* Group average of individual mean total daily doses over 15 weeks
** p<0.05
Adverse events
Treatment emergent adverse effect measurea
Tapentadol ER
n = 319
Oxycodone CR
n=331
Placebo
n = 337
Constipationa
56(17.6)
NNH 12
114(34.4)
NNH 4
31(9.2)
Nausea/Vomitinga Composite
97(30.4)
NNH 5
209(63.1)
NNH 2
34(10.1)
Serious adverse events
2(0.63)
13(3.93)
4(1.19)
a n(%)ConclusionsThere was not a significant difference between tapentadol ER and placebo.
Tapentadol ER compared to placebo was associated with significantly better functional and health status outcomes. CritiqueStrengths
Randomized, double blind, placebo controlled, multi-center trial
The methodology was improved to account for patient discontinuation
Limitations
Study was sponsored by makers of tapentadol
The study concluded that there wasnt statistical difference between tapentadol and placebo
The inclusion and exclusion criteria were so broad that many possible patients would have been excluded from this study.
Study lacks external validity and therefore does not have a place in therapy.
Trial 4Chronic diabetic neuropathic pain5
CitationSchwartz S, Etropolski M, Shapiro DY, et al. Safety and efficacy of tapentadol ER in patients with
painful diabetic peripheral neuropathy: results of a randomized-withdrawal, placebo-controlled trial.
Curr Med Res Opin. 2011 Jan;27(1):151-62. PubMed PMID: 21162697.Study GoalsEvaluate efficacy, safety, and tolerability of tapentadol ER 100-250 mg twice daily compared to placebo in patients with moderate to severe pain due to chronic, painful diabetic peripheral neuropathy(DPN) who tolerated tapentadol ER and have initial improvement in pain after a three week open-label titration period.MethodsStudy Design
A prospective randomized withdrawal, placebo-controlled multi-center study
Primary efficacy endpoint: change in average pain intensity from double-blind baseline over the last week (12) of the maintenance period based on 11 point numerical rating scale (NRS) least squares mean difference (LSMD)
Secondary efficacy endpoint: Responder analysis: e"5 0 % i m p r o v e m e n t i n a v e r a g e p a i n i n t e n s i t y N R S f r o m b a s e l i n e t o a t t h e w e e k 1 2 e n d p o i n t ; P G I C a t w e e k 1 2 e n d p o i n t ; P a i n i n t e n s i t y s u b s c a l e o f t h e b r i e f p a i n i n v e n t o r y - c h a n g e f r o m b a s e l i n e o f o p e n - l a b e l a t w e e k 1 2 e n d p o i n t ; E Q - 5 D - c h a n g e i n b a s e l i n e a t w e e k 12 endpoint
Only patients that have initial to response in open-label 13 day screening period will advance to randomization, the 5-day washout, a three-day pre-titration pain intensity evaluation (where twice daily pain intensity is documented), and a three-week open label titration starting with tapentadol ER 50mg twice daily to patients optimal dose between 100-250 mg.
Then a 12 week double blind maintenance phase, and a 10-14 day posttreatment phase
Total duration of study drug will be 15 weeks where all doses of study medication will be taken with at least 120mL of water with or without food.
Safety and tolerability will be evaluated by vital signs, physical exam, clinical laboratory tests, ECGs, neurologic exams, and monitoring for adverse events
Baseline characteristics were similar between groups
Data Analysis
144 patients per treatment arm estimated to provide proper power to show that tapentadol ER is statistically different from placebo.
Intent to treat (ITT) population= last observance carried forward(LOCF) to impute pain score after discontinuation
Pairwise treatment differences were estimated based on the least squares mean difference
Least mean square difference was analyzed using ANCOVA with treatment, dose level, and pooled analysis as factors and baseline pain intensity score as a covariateCriteriaInclusion criteria
Men and women e"1 8 y e a r s o l d w i t h D M - I o r D M - I I w i t h a d o c u m e n t e d c l i n i c a l d i a g n o s i s o f d i a b e t i c p e r i p h e r a l n e u r o p a t h y w i t h s i g n s a n d s y m p t o m s f o r a t l e a s t 6 m o n t h s , a n d p a i n p r e s e n t a t t h e t i m e o f s c r e e n i n g .
D i a g n o s i s m u s t i n c l u d e p a i n p l u s a r e d u c t i o n o r a b s e n c e o f p i n sensitivity and/or vibration sensitivity on total neuropathic score-nurse examination in lower and/or upper extremities.
Blood glucose is controlled by diet, hypoglycemics, or insulin for at least 3 months prior to study
Taking analgesics for at least 3 months prior to screening for condition and dissatisfied with either the treatment or the current analgesia.
Current daily doses of opioid therapy must be d"1 6 0 m g o f e q u i v a l e n t o r a l m o r p h i n e .
E x c l u s i o n c r i t e r i a
H i s t o r y o f s e i z u r e o r i n c r e a s e d r i s k o f s e i z u r e
S e v e r e l y i m p a i r e d r e n a l f u n c t i o n
H i s t o r y o f m o d e r a t e t o s e v e r e h e p a t i c f u n c t i o n
S i g n i f i c a n t h i s t o r y o f p u l m o n a r y , g a s t r o i n t e s t i n a l , e n d o c r i n e , m e t a b o l i c (except DM), neurological, psychiatric disorders(resulting in disorientation, memory impairment, or inability to report accurately as in schizophrenia)
Clinically significant laboratory abnormalities
Clinically significant cardiac disease
History of any other clinically significant disease that in the investigators opinion may affect efficacy or safety assessments or may compromise patient safety during the study.
ResultsEfficacy Measure a
Tapentadol ER
N = 196
Placebo
N = 192
LSMD- 15 wks
[95% CI]
(-1.3)
[-1.70, -0.92]**
--
BOCFb
LS mean(SE)
p-value vs pbo
2.0 (0.4)
n=179
0.015
2.6 (0.4)
n=188
30% reduction in pain
Intensity at week 12
53.6
NNT9
42.2
50% reduction in pain
intensity at week 12
37.8
NNT 10
27.6
a least squares mean difference(LMSD) vs placebo [95% CI]
b Baseline observation carried forwardthe analysis provided is from the FDA7
c Percentage
Adverse events
Treatment emergent adverse effect measurea
Tapentadol ER
N = 196
Placebo
N = 192
Constipationa
6.1
NNH 20
1.0
Nausea/Vomitinga Composite
20.4
NNH 8
7.3
Serious adverse events
10(5.1)
3(1.6)
a RR ConclusionsTapentadol ER 100-250 mg twice daily over 15 weeks significantly more effective for management of moderate to severe chronic low back pain than placebo.
Significant reductions in mean pain intensity and significantly higher perce n t a g e s o f p a t i e n t s w i t h e"3 0 % a n d e"5 0 % i m p r o v e m e n t s , a n d w a s g e n e r a l l y w e l l t o l e r a t e d . C r i t i q u e S t r e n g t h s
R a n d o m i z e d , d o u b l e b l i n d , p l a c e b o c o n t r o l l e d , m u l t i - c e n t e r t r i a l
T h e m e t h o d o l o g y w a s i m p r o v e d t o a c c o u n t f o r p a t i e n t d i s c o n t i n u a t i o n
H a s e x t e r n a l N P T ~ $
`
e
& J k A
B
& ' i n % 5 K W g k ʿشzqhbh
hx
o ^J ha h+Q ^J ha ha ^J ha ha ^J aJ ha hQM ^J aJ hg hLx ^J hg hf ^J hg hQM ^J hg hWu| ^J hi~ hf CJ aJ hf 6CJ ]aJ hb hf 6CJ ]aJ hb hf 6CJ aJ
hf CJ hu hf hf CJ ^J
hf CJ % T & B
' W G
& F( ^`gdg gdf gdf ^ ` gdn+; " ( ( $d &d -D M
N P gdf " ( ( $d &d -D M
N P gdf k z 5 6 S U W F G w ! " 1 J N S u ' E F R S [ \ ] 廲 hg h U ^J
h ^J
hx
o ^J hg h5 ^J hg hb3 ^J hg hZU ^J hg hWu| ^J hg ht ^J aJ hg hb3 ^J aJ hg hQM ^J aJ hg hf ^J hg ht ^J hg hzH ^J 4 ^ v j! " " 6$ 7$ % ^ ` gdf gdf ^ ` gdf gdR gdR o s ' gdK gd gd/<
& F( ^`gdg % & 6 = ? @ F T g ; < P g i v 5 |xq| h h h h h ^J hR hg 5^J "j hR hb3 5U^J hR hb3 ^J j hR hb3 5U^J h<4 hf hg hf 5^J hg hLx ^J hg hL5 ^J hg hf ^J hg hWu| ^J hg h5 ^J hg hEU ^J + ! ! " " " " " " # # # $ 4$ 5$ $ $ % & & & & & & .& /& 0& 1& ƿƿʵyumumdm h% mH nH uj hu Uhu hf 5>* H*^J hq3 hf 5>* H*^J h8w9 hf ^J
hf aJ hCZ hf aJ hCZ hf B*H*ph hf B*H*ph h$qt hf hf hf B*ph hR hR 5j hR hb3 5U h h h ^J h h H*^J $% & V& t& & & & & e kdy $$If l 0 @
t 0 6 4 4
l a p yt.d $If gd.d gdf gdf 1& R& U& V& & & & & & & & & ' ' =' >' z' {' ' ' ' ' @( m( n( o( ) ) D) J) K) `) a) b) c) p) q) {) ) ) ) ) ) ) 6* 7* T* U* * * * ǿ hf2 h6b hf2 h6b CJ hf2 hf hf2 hf CJ h% mH nH uj hu Uhu h~ hh hf hCZ hf H* hf H*hf CJ aJ hi~ hf CJ aJ
hf CJ hp;X hf h hf CJ hf h hf 2& & & & x o o $If gd.d kd# $$If l 0 @
t 0 6 4 4
l a p yt.d & & & & x o o $If gd.d kd $$If l 0 @
t 0 6 4 4
l a p yt.d & & & ' x o o $If gd.d kdw $$If l 0 @
t 0 6 4 4
l a p yt.d ' ' ' ?' z' x o o o $If gd.d kd! $$If l 0 @
t 0 6 4 4
l a p yt.d z' {' ' ' x o o $If gd.d kd $$If l 0 @
t 0 6 4 4
l a p yt.d ' ' @( o( ) D) ) ) x k f Y f T I
$$If gdp gdu ^ ` gdf gdf ^ ` gdf kdu $$If l 0 @
t 0 6 4 4
l a p yt.d ) ) ) ) ) ) ) ) W N N N N $If gd6b kd $$If l F ," h $
t 0 4 4
l a yt.d
$$If gdp
$$$If a$gdp ) ) ) ) ) * * * (* 1* ] T T T T T T T T $If gd.d kd $$If l \ H ," h L
t 0 4 4
l a yt6b 1* 6* 7* <* H* I* T* T K K K K $If gd6b kd $$If l \ H ," h L
t 0 4 4
l a yt.d $If gd.d T* U* Y* j* v* * * ] T T T T T $If gd6b kd $$If l \ H ," h L
t 0 4 4
l a yt6b * * * * * * ] T T T T $If gd6b kd $$If l \ H ," h L
t 0 4 4
l a yt6b * * * * + + /+ 0+ 1+ 3+ 4+ + + + + + , , , , - - - - '- Y- [- . . . . . . // 2/ * CJ ^J mH sH h=) hf 5>* CJ ^J h<4 hf h6b hCZ hf H* hf H*hf hf2 hf hf2 hf CJ hf2 h6b hf2 h6b CJ
h6b CJ &* * * * * * * + + ] T T T T T T T $If gd.d kd` $$If l \ H ," h L
t 0 4 4
l a yt6b + + 1+ + , ] X H 5 $
& F h ^hgdp m$
& F h ^hgdf m$ gdf kd=
$$If l \ H ," h L
t 0 4 4
l a yt.d , , g/ .0 0 2 3 3 4 4 F5 W5 5 a6 r6
& F h 7$ 8$ H$ ^hgdQi m$
& F 8 7$ 8$ H$ ^8gdf m$
& F 8^8gdf m$
& F h^hgdc m$
& F) 8^8gd1j m$
& F h^hgd m$
& F h^hgdf m$ @/ d/ e/ f/ g/ / 0 0 0 *0 +0 ,0 -0 .0 0 0 0 0 0 0 0 0 0 0 0 #1 41 51 1 1 62 I2 P2 X2 ^2 o2 2 2 2 2 ˼˗ːxxriiiiir hE9 h] aJ
h] aJ h hf aJ
hc aJ hc hc aJ h1j hp 5 h1j hb3 B*H*^J ph +j( h1j hp 5 B*H*U^J ph h1j hp 5 B*H*^J ph %j h1j hp 5 B*H*U^J ph h1j hp 5 B*^J ph
h aJ
hE9 aJ hE9 h: aJ '2 2 3 3 3 4 "5 05 W5 5 5 6 6 `6 a6 7 7 7 7 7 `7 a7 i7 r7 s7 {7 7 7 A8 I8 o8 8 8 .9 09 19 ;9 ƹzztznh] h hQ ^J aJ
h aJ
h8R aJ
hL5 aJ
hSV aJ
h aJ hEK hEK aJ h~S h
hCZ h~S H* hCZ H*hCZ h6b hf 5>* h6b hf hCZ hf 5>*H*^J hf 5>*H*^J h,9 hf 5>*^J h hQi aJ
hQi aJ
hb+ aJ h hf aJ
hf aJ $r6 7 7 a7 s7 7 19 : : p< i= = L> j> @ D G
& F! gd9
& F! gd&;V gd&;V
& F
gdD
& F
gdM gdf
& F
gdZ
& F gdZ gd1j x gdzH
& F 8 7$ 8$ H$ ^8gdQi m$ ;9 A9 9 9 9 9 : D: Z: : : : : : < X< Y< o< p< < < < < < < < < < < = = =
= H= M= U= h= i= = K> L> i> z> > > > > ¹{{w h;1p hL h&;V h~S h\ hG hG h9 h&e hIE h<; h,h h9 hEK
hEU aJ
hl aJ h hEK aJ
hf aJ hf h h aJ h hQ ^J aJ h8R ^J aJ hSV ^J aJ h[ ^J aJ h,h ^J aJ .> > > ;? Y? a? u? w? x? ? ? ? ? ? ? ? ? ? ? X@ n@ o@ p@ u@ @ @ @ @ @ @ A !A &A 3A HA LA kA oA A A A A A A B B
B B .B 0B VB lB nB B B B C C C C C C ļ켸 hCh hy hCh hCh
hCh ^J hy hf h6b h9 hB h|> hL hu mH nH uj hu Uhu j hu Uh,h hN^ h&;V h;1p hCh =C C C C D D D D D D D D E E E E E E E E E E E F F F F F F F "F KF LF eF fF vF wF xF yF ~F F F F F F F F ǿǥǿǿǥǿǥǿu j
h A h A H*U j
h A h A H*U j h A h A H*U hb3 H* h A H* j" h A h A H*U h A h A H*j h A h A H*U h A h+ h : h : h : h9 hCh hCh hCh hy hCh h U .F F F F G 3G 4G KG G G G G G G G H
H H H >H H H I 1I 2I I I I I )J 1J AJ MJ zJ J J K K K *K +K ,K -K .K 1K 5K BK CK 屪|x hCh h., hl H* j hl hl H*U hl hl H*j hl hl H*U h h h hX h
T hX h k hX j h
0J3 Uh
h : h : OJ QJ h : h+ h A j h A h A H*U hb3 H* /G I .K M gN hN iN N N N N N N O !O 2O *P N FN cN fN gN iN oN pN N N N N ضر𥠙 h% mH nH uj hu Uhu hnj hnj hs hJ H*h9 h|> hJ hnj H* hb3 H* hl H* j hl hl H*U hl hl H*j hl hl H*U h., h., hy hN^ h
T h., hCh 0N N N N N N N N N N N N N N N N N O O
O O O O !O 0O P
P P P $P (P *P :P
hx CJ H*^J aJ h!f CJ H*^J aJ hx CJ ^J aJ hP hx CJ ^J aJ h$vU CJ ^J aJ hX CJ ^J aJ *R R R R S S 0S DS JS OS TS VS ZS ]S cS hS mS pS tS wS
$If ^ ` gd[
$If gd[ $If ^ ` gd[ $ $If ^ ` a$gd[ wS xS S S S S T T T
T T T %T 8T JT \T aT fT lT pT wT zT
$If ^ ` gd[ $ $If ^ ` a$gd[ $If ^ ` gd[ Ff 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 7T 8T [T \T jT kT lT yT xnxncU h!f hx CJ H*^J aJ h!f CJ H*^J aJ h$vU CJ ^J aJ hX CJ ^J aJ hP hx CJ ^J aJ hb_ hu% CJ ^J aJ hx CJ ^J aJ h h CJ ^J aJ h hu} CJ ^J aJ hx CJ ^J hgN CJ ^J hf hgN CJ ^J aJ h#` hgN CJ H*^J hgN CJ ^J aJ hgN hgN CJ ^J aJ !yT zT T T T T T T T T T T T T T T T T T T T U U U
U U U U U U U U U U U U U !U "U 'U )U *U /U 0U 7U 8U 騚騌騌 h hx CJ ^J aJ hz> hx CJ H*^J aJ h hx CJ H*^J aJ h!f CJ H*^J aJ hx h9 CJ ^J aJ hX CJ ^J aJ h}t hx CJ H*^J aJ hx h8w9 hx CJ ^J aJ hx CJ ^J aJ hP hx CJ ^J aJ -zT T T T T T T T T T T T T T T T T T U U
$If ^ ` gd[ $ $If ^ ` a$gd[ $If ^ ` gd[ Ff0
$If gd[ U U U U U !U "U +U AU OU _U wU U U U U U U U $ $If ^ ` a$gd[ $If ^ ` gd[ Ffb"
$If gd[
$If gd[
$If ^ ` gd[ 8U 9U ?U @U IU JU NU ^U _U pU vU U U U U U U U U U U U U U U U U U U U U U U U U V V ڸڸڭڑڑڑڭxj\ڸhX hX CJ H*^J aJ hB hx CJ H*^J aJ h k CJ H*^J aJ h&> hx CJ H*^J aJ h!f h!f CJ H*^J aJ h!f hx CJ H*^J aJ h!f CJ H*^J aJ hP hx CJ ^J aJ hX CJ ^J aJ hb_ hx CJ aJ hx CJ ^J aJ h hx CJ ^J aJ h hx CJ H*^J aJ $U U U U U U V V V V V V V V V V )
2 - H $If ]H gd[ Ff&
$If gd[
$If ^ ` gd[ $If ^ ` gd[ $If ^ ` gdPQ V V V V V
V V V V V V V V V V !W [W \W W W 'X *X X X X X
Y Y ɻ߮ulflWlflfNH
hQ% CJ h hQ% CJ h hx CJ OJ QJ ^J
hx CJ h hx CJ #h8> hx CJ H*OJ QJ ^J aJ "hx CJ OJ QJ ^J aJ mH sH h8> hx CJ OJ QJ ^J aJ hx hB hx CJ ^J aJ hB hx CJ H*^J aJ h k CJ H*^J aJ h!f CJ H*^J aJ hx CJ ^J aJ h8w9 hx CJ ^J aJ ho2 CJ ^J aJ V \W Y Z Z Z H 3 $d N ^ ` gd., o kd( $$If l 3 x3
t 0 4 4
l a p
yt[
- H $If ]H ^ ` gd[
- H $If ]H ^ ` gd[ )
\'2 - H $If ]H gd[ Y Y Y !Y $Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Z Z Z µµui]PC hC hx CJ ^J aJ hX h!f CJ ^J aJ h!f @CJ ^J aJ hx @CJ ^J aJ hX @CJ ^J aJ hx CJ ^J aJ h hx CJ H*^J aJ h!f @CJ H*^J aJ h hx @CJ ^J aJ h hx CJ ^J aJ h!f CJ H*^J aJ
hx CJ
h#` CJ h hx CJ OJ QJ ^J h hx CJ
hQ% CJ hQ% hQ% CJ Z Z Z !Z ,Z -Z fZ gZ Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z Z [ H[ I[ J[ X[ Y[ g[ h[ s[ t[ u[ ȸЮ᪢tgYgYgYt *hW* hx CJ ^J aJ h&3 hx CJ ^J aJ h
hx CJ ^J aJ
h& aJ hJ hx aJ hJ hJ aJ h% mH nH uj hu Uhu hb3 H* h0 H* j) h0 hc H*U h0 hc H*j h0 hc H*U h hc hCZ hx H* hx H*hx CJ ^J aJ hx "Z -Z Z I[ J[ Q[ Y[ `[ h[ l[ t[ $ $If ^ ` a$gdx $If ^ ` gdx gdu ^ ` gdc ^ ` gdx
t[ u[ [ [ [ [ U D 0 0 0 $ $If ^ ` a$gdx $If ^ ` gd kd * $$If l \ x,"
t 0 6 4 4
l a p
yt& u[ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ [ \ \ \ \ $\ %\ (\ *\ +\ 1\ 2\ G\ H\ I\ J\ L\ R\ zzqze^ hu hK hJ hJ 5^J aJ h% mH nH uj hu Uhu hD hx ^J hK CJ ^J aJ hu% hx CJ ^J aJ hu% CJ H*^J aJ hu% CJ ^J aJ h
hx CJ ^J aJ hD hx CJ H*^J aJ hD CJ H*^J aJ h& CJ ^J aJ hlI CJ H*^J aJ hOB CJ ^J aJ "[ [ \ \ U D 0 $ $If ^ ` a$gdx $If ^ ` gd kd* $$If l \ x,"
t 0 6 4 4
l a p
yt& \ %\ )\ *\ +\ - & gdD kd+ $$If l \ x,"
t 0 6 4 4
l a p
yt& $ $If ^ ` a$gdx $ $If ^ ` a$gd@ R\ Z\ t\ u\ \ \ \ \ \ \ \ \ \ \ \ \ \ \ \ ] ] ] ] ] ] "] 4] 5] L] M] [] \] j] k] n] p] q] I^ sok h h5 hu% hK CJ ^J aJ hK CJ H*^J aJ he4 CJ ^J aJ hD hK CJ H*^J aJ hD CJ H*^J aJ hlI CJ H*^J aJ hK CJ ^J aJ *hW* hK CJ ^J aJ h&3 hK CJ ^J aJ h
hK CJ ^J aJ hu h& hu hK hu hlI %+\ \ \ \ \ \ \ \ \ $ $If ^ ` a$gd%C $If ^ ` gd%C gdu \ \ \ ] ] !] U D 0 0 0 $ $If ^ ` a$gd%C $If ^ ` gd kd>, $$If l \ x,"
t 0 6 4 4
l a p
yt& !] "] M] \] k] o] U D 0 0 0 $ $If ^ ` a$gd%C $If ^ ` gd kd, $$If l \ x,"
t 0 6 4 4
l a p
yt& o] p] q] y^ ^ _ U P C > 0 ^ ` gdx m$ gdx ^ ` gd gd5 kd- $$If l \ x,"
t 0 6 4 4
l a p
yt& I^ J^ c^ d^ t^ u^ v^ w^ x^ y^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ ^ 5_ t_ {_ |_ }_ ~_ _ _ _ _ _ _ _ _ _ _ ]` p` w` x` y` z` ` ` ` ` ǼΈ| j h% Uh\ hj@N h|3
hud aJ
h9$ aJ
hv* aJ
h 6 aJ
hx aJ
h[l+ aJ h hx aJ h hx OJ QJ h hx h|3 h h|3 H* j]. h|3 h|3 H*U h|3 h|3 H*j h|3 h|3 H*U/_ _ z` a Nb jb b b b b b b $ $If ^ ` a$gdP $
$If ^ ` a$gdP $If ^ ` gd gd% ^ ` gd\
& F% gd[l+ m$ ` a a
a a a a a a a a !a "a 7a 8a 9a :a ;a c Fc Vc ^c pc $ $If ^ ` a$gd[l+ $ $If ^ ` a$gd pc rc kd60 $$If l 4 ֞ w" ," ^
t 0 6 4 4
l a p
ytP rc c c c c c c d $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ d
d kd'1 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP
d d d $d .d 6d @d Jd $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If gd[l+ Jd Kd kd2 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP Kd Xd bd kd ud }d d d $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ d d kd2 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP d d d d d d d d $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ d d kd3 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP d d d d d d d e $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ d d d d d d d d e e e e e e e e &e 'e .e /e 6e 7e >e ?e @e Ye be ce ke le ne oe xe ye e e e e e e e e e e e e e e e e e e e e e e e &f (f f Pf Rf bf df rf tf f f g g g "g &g (g `g bg g g g g g g g g hv@ hD CJ ^J aJ hD hD CJ ^J aJ h
hD CJ ^J aJ Te e kd4 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP e e e e 'e /e 7e ?e $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ ?e @e kd5 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP @e Ye ce le oe ye e e $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ e e kd6 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP e e e e e e e e $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ e e kd7 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP e e e e e e f &f $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ &f (f kdo8 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP (f >f Rf df tf f f f $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ f f kdX9 $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP f f g "g (g 8g Lg `g $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ `g bg kdA: $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP bg tg g g g g g g $ $If ] ^ ` a$gdP $ $If ^ ` a$gdP $If ^ ` gd[l+ g g kd*; $$If l ֞ w" ," ^
t 0 6 4 4
l a p
ytP g h h h *i >i @i ni ti vi i i 6j 8j bj (k *k |l l l l m vm m m m m m n ʼʲ옍~zug^X^R^IX^ h hb+ aJ
h7 aJ
hb+ aJ h hRt aJ h9Y hRt H*OJ QJ aJ hRt H*hRt
hRt aJ h hRt aJ h hRt CJ aJ hx hud CJ H*^J aJ hv* CJ H*^J aJ hv* CJ ^J aJ hC hC CJ H*^J aJ hC hC CJ ^J aJ hC CJ ^J aJ hC CJ H*^J aJ hud CJ ^J aJ h&3 CJ ^J aJ g 8j bj |l l l m wm m Yn sn o o p p Aq _r Ws t hu v v
& F* gdM
& F" gdRt m$ ^ ` gdRt m$ gdRt ^ ` gdRt gdRt ^ ` gdud n Cn Qn Xn Yn qn rn sn n n n n o o p Fp p p @q Aq jq q r r r r r r s s s s s Rt t t du eu gu hu u v v *v rv sv v v x ¾ºº«««««««§£º h h :& h?G h :& h?G hRt h?G h?G h7 h4F h :& h{ h h?G h!!
hRt h?G h hRt hCZ hRt >*CJ H*aJ hRt >*CJ H*aJ hRt >*CJ aJ h hRt aJ
h7 aJ
hb+ aJ 0v Jw w Ax x x x y 2y y y y z :z rz z z $| \| ^ ` gdRt gdRt
& F
gdRt m$ gdRt m$ ^ ` gdRt h ^h` gdRt m$
& F gdRt m$ $gd9$ m$ gdRt
& F* gdM x x x y
y y 1y 2y yy zy y y y y y y z z z z #| $| \| } } ~ ~ '~ (~ )~ i~ |pggZR h> hRt H*hRt 6B*\]ph h hRt aJ ho2 hRt H*mH sH ho2 H*mH sH hF hRt hCZ hRt H* hRt H*hRt h ' hRt 5^J
hRt aJ h hRt 5aJ h hRt aJ hCZ hRt 5>*H*^J aJ hRt 5>*H*^J aJ h19 hRt 5>*^J aJ h ' hRt ^J aJ h hRt B*ph \| } } } ~ ~ )~ . 3 q & i }
$$If gd.d gd% ^ ` gdM gdjFW
& F h ^hgdjFW m$
& F h^hgdRt m$ ^ ` gdRt gdRt gdRt ^ ` gdRt i~ q~ % & , - B C D E G g h i Ѓ у $ ' , ? @ B C ȿ}}ob[ h hjFW hRt hjFW CJ ^J aJ hRt h% 5CJ ^J aJ h% 5CJ ^J aJ hjFW 5CJ ^J aJ hRt hRt CJ ^J aJ h hRt hRt hRt 5CJ \^J aJ hM h9$ h% mH nH uj h% Uh% h9$ h9$ tH
h9$ tH hRt mH sH h% mH sH hRt h,e hRt 6 # ƃ ˃ Ѓ f kd< $$If l F ," 0 6 4 4
l a ytRt
$$If gd.d Ѓ у ݃ o d d d
$$If gd.d kd< $$If l F ," 0 6 4 4
l a ytRt q f f f
$$If gd.d kdg= $$If l F ," 0 6 4 4
l a ytRt q h h h $If gd.d kd> $$If l F ," 0 6 4 4
l a ytRt q h h h $If gd.d kd> $$If l F ," 0 6 4 4
l a ytRt , @ A B q h h _ _ $If gd.d $If gdjFW kd_? $$If l F ," 0 6 4 4
l a ytRt B C J O S q h h h $If gd.d kd@ $$If l F ," 0 6 4 4
l a ytRt C J N O R S T Y Z ^ _ b c d k o p t u v ل ۄ ܄
! " 2 3 C D U V 黴զu hRt hRt 5CJ H*^J aJ hRt 5CJ H*^J aJ h hRt hRt hRt CJ ^J aJ hRt hRt 5CJ ^J aJ h hjFW hp 5 hjFW CJ ^J aJ hjFW hjFW CJ ^J aJ h h% hp 5 h% CJ ^J aJ hp 5 hp 5 CJ ^J aJ h% CJ ^J aJ -S T Z _ c q h h h $If gd.d kd@ $$If l F ," 0 6 4 4
l a ytRt c d k p u q h _ _ $If gd.d $If gd% kdWA $$If l F ," 0 6 4 4
l a ytRt u v q h h h h $If gd.d kdA $$If l F ," 0 6 4 4
l a ytRt q h h h $If gd.d kdB $$If l F ," 0 6 4 4
l a ytRt q h h h $If gd.d kdOC $$If l F ," 0 6 4 4
l a ytRt Ą ل ڄ ۄ q h h h h $If gd.d kdC $$If l F ," 0 6 4 4
l a ytRt ۄ ܄ q h h h $If gd.d kdD $$If l F ," 0 6 4 4
l a ytRt q h h h $If gd.d kdGE $$If l F ," 0 6 4 4
l a ytRt
! q h h h h $If gd.d kdE $$If l F ," 0 6 4 4
l a ytRt ! " ( - 2 q h h h $If gd.d kdF $$If l F ," 0 6 4 4
l a ytRt 2 3 9 > C q h h h $If gd.d kd?G $$If l F ," 0 6 4 4
l a ytRt C D J P U q h h h $If gd.d kdG $$If l F ," 0 6 4 4
l a ytRt U V ˆ 2 3 q b ] X S ; $$ $If ^ ` a$gdU gd% gdM gdRt ^ ` gdjFW kdH $$If l F ," 0 6 4 4
l a ytRt V W R S l m } ~ ʆ ˆ ц ҆ Ѻ}m_[T[MBMBMB; h% hRt j h% h% U h% h% hRt hRt hRt hjFW B*CJ ^J aJ ph hb3 B*CJ H*^J aJ ph hp 5 B*CJ H*^J aJ ph 3j7I hp 5 hp 5 B*CJ H*U^J aJ ph $hp 5 hp 5 B*CJ H*^J aJ ph -j hp 5 hp 5 B*CJ H*U^J aJ ph hp 5 B*CJ ^J aJ ph !hRt hRt B*CJ ^J aJ ph hRt B*CJ H*^J aJ ph $ ) * 0 1 2 6 9 l m z ~ ҇ Ӈ ӵyl^lQӵl^l hM h) CJ ^J aJ hM h K CJ H*^J aJ hM h K CJ ^J aJ hM h[{ CJ H*^J aJ hM h[{ CJ ^J aJ $hM hW' 6B*CJ ^J aJ ph hM hW' 6CJ ^J aJ hM hW' CJ ^J aJ !hM h K B*CJ ^J aJ ph !hM h[{ B*CJ ^J aJ ph h% hRt h% hb3 h% h9$ h% hU 3 : ? l m , kdI $$If l Y\
$ r [
t 0 6 4 4
l a p( ytW' $$ $If ^ ` a$gdU m { | } ~ $ $If ^ ` gdW' $If ^ ` gdW' ~ ? , $If ^ ` gdL0 kdJ $$If l Y\
$ r [
t 0 6 4 4
l a g ) 'p( ytW' ć · ҇ $ $If ^ ` a$gdU $ $If ^ ` a$gdL0 ҇ Ӈ D 1 $ $If ^ ` a$gdL0 $If ^ ` gdL0 kdK $$If l g\
$ r [
t 0 6 4 4
l a p( ytW' / 0 l m n o ͤtftYtH7H !hM ho B*CJ ^J aJ ph !hM h[{ B*CJ ^J aJ ph hM h) CJ ^J aJ hM h[{ CJ H*^J aJ hM h[{ CJ ^J aJ $hM hb3 6B*CJ ^J aJ ph hM hb3 6CJ H*^J aJ hM hb3 6CJ ^J aJ hM h K CJ H*^J aJ hM h K CJ ^J aJ hM hW' CJ ^J aJ !hM h K B*CJ ^J aJ ph 'hM h K h[{ B*CJ ^J aJ ph $ $If ^ ` a$gdU o t g $ $If ^ ` a$gd K D 1 $ $If ^ ` a$gdL0 $If ^ ` gdL0 kdL $$If l \
$ r [
t 0 6 4 4
l a p( ytW' * / $ $If ^ ` a$gdU o t g $ $If ^ ` a$gd K o " ' / 0 n ? * x $If ^ ` gdb3 kdM $$If l \
$ r [
t 0 6 4 4
l a g ) 'p( ytW' n o { y y e Q e $ $If ^ ` a$gdo $ $If ^ ` a$gdL0 $If ^ ` gdL0 s kdN $$If l $
t 0 6 4 4
l a p
ytb3 Ȉ Ɉ ʈ - H N X ` k l Ɖ ɉ a f K M V j e {r hV6 hX aJ hX hx aJ h; hEU aJ
hEU aJ h; hx aJ h *hj@N h5 h) h`$ h
hM h|3 h; hx ho hb3 hb3 hM hW' CJ ^J aJ !hM h[{ B*CJ ^J aJ ph !hM h) B*CJ ^J aJ ph + Ɉ ʈ ֈ D ? ? : - ^ ` gdM gdx gdb3 kdrO $$If l g\
$ r [
t 0 6 4 4
l a p( ytW' g ˎ x j k W J ^ ۗ A ԙ 2
& F -D M
gd;
& F gd; ^` gd;
& F gd; ^ ` gdx gdK e w x đ ő j k ! W G J [ ^ f ķ妟ueVG hM hx B*CJ aJ ph hM h9$ CJ OJ QJ aJ hM h9$ CJ OJ QJ \aJ hM hx B*aJ ph hM hBit aJ hM hx aJ hR hx B*ph hR hx hR hBit hBit B*aJ ph h; hx B*aJ ph hM h}t B*aJ ph hM hx CJ aJ h; h7`i aJ h; hx aJ hX hx aJ hX h7`i aJ ڗ @ ә ԙ ͚ e Û ě ś ) ǾzrzrzrzrerzaZ h; hx h; hG hx 5B*ph hx B*ph h; B*ph h~ 5B*ph hx 5B*ph hx B*CJ aJ ph h; hjFW ]aJ h; hjFW aJ h; hDL aJ h; h|q aJ h; hK. aJ h; hx aJ h; hx B*aJ ph hM hx aJ hM hx KH$ \aJ mH sH # ) H $If gdx ^ ` gd&3 ^ ` gdx gdx gd; $d &d N P gdx $d &d N P gdx m$ ^` gdx
& F gd; q u
j Ş n o p | ; < = E R ɡ [ v x ռՑ~qfXfMf hN 5CJ ^J aJ h8w9 hx 5CJ ^J aJ hx 5CJ ^J aJ h8w9 hx CJ ^J aJ $hm hx 5B*CJ ^J aJ ph hx 5B*CJ ^J aJ ph 4hd0 hx 5B*CJ ^J aJ mH nH ph sH tH 0hd0 hx CJ OJ QJ ^J aJ mH nH sH tH h8w9 hx CJ ^J hv* hx H* hv* H* h8w9 hx h&3 hhna hx _ X o p | < y p a
& F $If gdx $If gdx | kdeP $$If l 0 " @ 0 "6 4 4
l al ytx ) $If gdx < = E R x . y p a a R a a a
& F
$If gda
& F
$If gdx $If gdx $If gdx | kd Q $$If l 0 " @ 0 "6 4 4
l al ytx x Ϣ ' - @ A O v B B C D ܩ ݩ ´xj\O\A h:; hx 5CJ ^J aJ hF hx CJ ^J aJ hF hx 5CJ ^J aJ h hx 5CJ ^J aJ h6^ 5CJ ^J aJ hN hx 5CJ ^J aJ hN hN 5CJ ^J aJ h8w9 hx CJ ^J aJ hQ,I hx 5hQ,I hx 5CJ ^J aJ h* hx 5CJ ^J aJ hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ hN 5CJ ^J aJ ha 5CJ ^J aJ A O B D ݩ ީ Y P $If gdx | kdQ $$If l 0 " @ 0 "6 4 4
l al ytx
& F $If gdx $If gdx
& F
$If gdx ݩ ީ & . T X ^ t ʫ H X 0 2 g y ̰ L ֲ ڲ ǻǻǰyyynj hEj hx 5CJ ^J aJ hTO 5CJ ^J aJ h6^ hx 5CJ ^J aJ hOW hx ^J
hTO ^J h8w9 hx ^J
hx ^J hm hx CJ ^J hm hx 5CJ ^J h6^ 5CJ ^J h hx 5CJ ^J h&3 5CJ ^J hx 5CJ ^J h8w9 hx CJ ^J h8w9 hx & Z 2 ƭ / ΰ L
& F $If gdx $If ^ ` gdx
& F $If gdx $If gdx y j a a a a a a a a $If gdEj
& F
$If gdx $If gdx | kd6R $$If l 0 " @ 0 "6 4 4
l al ytx 0 1 < H I J N Q _ b c k l m n s t | ~ dz ȽȽȽȽȽȽȽș}odV h0r hx CJ H*^J aJ hz CJ H*^J aJ h8w9 hx CJ H*^J aJ #h8w9 h 5B*CJ H*^J ph hx CJ ^J aJ h8w9 hx h hx 5CJ H*^J aJ ho 5CJ H*^J aJ hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ #h8w9 hx 5B*CJ H*^J ph h8w9 hx 5B*CJ ^J ph hEj hEj 1 ? J R c m t | } $ $If a$gdo K$ $ $If a$gdo $If gdo K$
) $If gd=\; kdR $If K$L$l \ Xh T b
t ( 0 h 6 4 4
l a p( ytx ȳ ˳
$$If a$gdx K$ $ $If a$gd=\; K$ $ $If a$gdz K$ $ $If a$gd=\; $If gd=\; K$ dz ȳ ʳ ˳ ̳ ҳ ! " # % = > h i Ʒ鬞鬞⑃ؑvk]P hE[ hx CJ ^J aJ hC hx CJ H*^J aJ h=\; CJ H*^J aJ hUP hx CJ ^J aJ hz hx CJ H*^J aJ h=\; hx CJ ^J aJ h0r hx CJ H*^J aJ hz CJ H*^J aJ h=\; 5B*CJ H*^J ph #h8w9 h 5B*CJ H*^J ph h=\; CJ ^J aJ h8w9 hx hx CJ ^J aJ h8w9 hx CJ ^J aJ ˳ ̳ Z O B 4 $ $If a$gd=\; $If gd=\; K$ $If gd=\; kdT $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx
. kdT $If K$L$l \ Xh T b
t 0 h 6 4 4
l a yt=\;
$$If a$gdx K$ $ $If a$gd=\; $ $If a$gdz K$ / > H N X ^ h $ $If a$gdx K$ $ $If a$gd=\; K$ $ $If a$gdx $If gdx K$ $If gdx h i X M B 4 4 $ $If a$gd=\;
$If gdx K$ $If gdx kdU $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx ƴ Ǵ
$$If a$gdx K$ $$If a$gd=\; $ $If a$gd=\; $ $If a$gdo K$ ƴ Ǵ ȴ . / 0 6 7 8 B C D E H Q U ^ c l q z | } ü阼馋tgt hlI hx CJ ^J aJ hP hx CJ ^J aJ h=\; CJ ^J aJ h hx CJ ^J aJ h0r hx CJ H*^J aJ hx CJ H*^J aJ h=\; CJ H*^J aJ h8w9 hx h2PE hx CJ ^J aJ ho CJ H*^J aJ h=\; ho CJ H*^J aJ hx CJ ^J aJ h8w9 hx CJ ^J aJ %Ǵ ȴ ߴ X M @ 2 2 $ $If a$gd=\; $If gdx K$ $If gdx kdV $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx
' 0 7
$$If a$gd=\; K$ $ $If a$gd=\; K$ $ $If a$gd=\; 7 8 D R Z O : $If ^ ` gdx K$ $If gdx kdW $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx R ` n | } 0 kd\X $If K$L$l \ Xh T b
t 0 h 6 4 4
l a yt=\; $ $If a$gd=\; K$ $ $If ^ ` a$gd=\; K$ } ~ µ ǵ ˵ ϵ ӵ Ե յ Ff$^ FfZ $If ^ ` gdz K$ / 1 3 4 X l m n o * ڿvh[NCN ho CJ \^J aJ hx CJ H*\^J aJ h hx CJ ^J aJ hqUP hx CJ H*^J aJ h9= CJ H*^J aJ hqUP hx CJ ^J aJ hC hx CJ ^J aJ hx CJ H*^J aJ hx 5CJ ^J aJ hN hx CJ \^J aJ hx CJ \^J aJ h8w9 hx 5CJ H*^J aJ hx CJ ^J aJ hP hx CJ ^J aJ hz hz CJ H*^J aJ % ( * . / 0
$If gdx K$ Ff\e Ffa $If ^ ` gdz K$ 0 1 m u u j a $If gdx $If gdz $If ^ ` gdx $If gdx l kdg $If K$L$l h h
t 0 h 6 4 4
l a ytx * , t
xn`O> hG h 5B*CJ ^J ph h8w9 h 5B*CJ ^J ph h 5B*CJ ^J ph hS@ CJ ^J aJ hZ hx CJ ^J aJ hx 5CJ ^J aJ hZ hx 5CJ ^J aJ ha 5CJ ^J aJ hd< hx CJ ^J aJ hx CJ ^J aJ ho CJ H*^J aJ h7 hx CJ \^J aJ hz hz CJ H*\^J aJ hx CJ \^J aJ hlI CJ \^J aJ
( > E N S [ $ $If a$gd.d $ $If a$gd.d K$ $If gdx
$ ' 5 8 = ? D E L S T Z [ \ i j n r s t u w x { | ɿww h CJ H*^J aJ h8w9 h CJ ^J aJ h#5N h CJ H*^J aJ hz CJ H*^J aJ h.d CJ ^J aJ h\ h CJ ^J aJ h CJ ^J aJ h8w9 h h.d 5CJ ^J aJ hjS 5CJ ^J aJ h 5CJ ^J aJ h8w9 h 5CJ ^J aJ +[ \ i $If gd.d kd9h $If K$L$l \ Xh T b
t
6`/ ( 0 h 6 4 4
l a e4p( yt i j u | $ $If ^ ` a$gd.d $ $If a$gd.d K$ $ $If a$gd.d $If ^ ` gd.d K$ Q F 9 + $ $If a$gd.d $If gd.d K$ $If gd.d kdi $If K$L$l \ Xh T b
t
6`/ 0 h 6 4 4
l a e4yt » û Ż ƻ ǻ л ѻ Ի ջ ػ ٻ " * . 0 8 @ B D L P X ^ ` b d ײ졔↡ hD h CJ H*^J aJ h.d h.d CJ ^J aJ hS@ CJ ^J aJ h8w9 h hc h CJ ^J aJ h8w9 h CJ ^J aJ hz CJ H*^J aJ h CJ H*^J aJ h CJ ^J aJ h.d CJ ^J aJ hz CJ ^J aJ 4 ǻ һ ٻ $ $If a$gd.d $ $If a$gd.d K$ " Q < . $ $If a$gd.d $If ^ ` gd.d K$ kdzj $If K$L$l \ Xh T b
t
6`/ 0 h 6 4 4
l a e4yt " 0 D R b d 1 kdgk $If K$L$l \ Xh T b
t
6`/ 0 h 6 4 4
l a e4ytI8x $ $If a$gd.d $ $If a$gd.d K$ d ļ $ $If a$gdS@ K$ $ $If ^ ` a$gdS@ K$ ¼ ļ Ƽ ȼ ʼ ̼ $ < > X ̿ ο j @ A _ g Ȼzqhqzh_z_V h8w9 hx ^J h9 hx ^J h&e hx ^J h&e h&e ^J
h&e ^J
hx ^J
hz ^J h8w9 hx CJ ^J hx CJ ^J h8w9 hx hdC hx h hx 5CJ ^J aJ hC hx CJ ^J aJ hx 5CJ H*^J aJ h8w9 hx 5CJ H*^J aJ h8w9 h hS@ CJ ^J aJ h CJ ^J aJ !ļ Ƽ O D $If gdz kdXl $If K$L$l \ Xh T b
t
6`/ 0 h 6 4 4
l a e4ytS@ $ < ο j @ y y l l l l _ _
& F $If gdz
& F $If gdx $If gdx | kdCm $$If l 0 " @ 0 "6 4 4
l al ytx ! w o y y l l l c l l l l $If gdx
& F $If gdx $If gdx | kdm $$If l 0 " @ 0 "6 4 4
l al ytx ! m n o C D E N w x 軲pbTb h0f 5B*CJ ^J ph hx 5B*CJ ^J ph 0hd0 hx CJ OJ QJ ^J aJ mH nH sH tH hEj hx 5H* hEj hv* 5H* hEj hx 5hEj h8w9 hx ^J h'L hx ^J
h9= H*^J hrOb hx ^J hov hx ^J h8w9 hx 5^J h9 hx 5^J
hx ^J h8w9 hx CJ ^J h8w9 hx E N w u p k b Y Y Y ) $If gdx $If gdx gdEj gdx | kdn $$If l 0 " @ 0 "6 4 4
l al ytx
& F $If gdx w x y n $If gdx $If gdx | kd"o $$If l 0 " 4 @ 0 t"6 4 4
l a ytx ( - 9 ; 4 < . 2 Z d ] ^ ^ _ ɻɻɢɰ~~tjj` hz\ hx 5^J h4} hx 5^J h8w9 hx 5^J h0f 5CJ ^J aJ h8w9 hx 5CJ ^J aJ hx 5CJ ^J aJ h#m hlI 5CJ ^J aJ h#m 5CJ ^J aJ h#m h#m 5CJ ^J aJ h#m hx 5CJ ^J aJ
hx ^J h8w9 hx CJ ^J h8w9 hx h8w9 hx 5B*CJ ^J ph # ( y y l ] ] ] ] ]
& F
$If gdx
& F $If gdx $If gdx | kdo $$If l 0 " 4 @ 0 t"6 4 4
l a ytx ^ _
r t _ | kdXp $$If l 0 " 4 @ 0 t"6 4 4
l a ytx
& F $If gdlI
& F $If gdx $If gdx
p r t j l n F ^ ` B D T N Z n p x ﳪӐv h8w9 hx 5^J
ho ^J hV/ hx 5^J
h0f ^J h0f hx 5^J h0f h0f 5^J h0f hx ^J h0f h0f ^J
h ^J h8w9 hx 5B*CJ ^J ph h8w9 hx CJ ^J h8w9 hx hlI hx 5^J
hx ^J hOh hx 5^J .t l ` D
1 h
& F $If gdo
& F $If gdx $If gdx
0 1 g h i j r Q S h i j { } ּ|j\L ho ho 5CJ H*^J aJ h8w9 hx 5CJ ^J aJ #h8w9 hx 5B*CJ H*^J ph h8w9 hx 5B*CJ ^J ph hEj hEj hx 5CJ ^J aJ ho8 hx 5CJ ^J aJ h8w9 hx CJ ^J hEj h8w9 hx hDCv hx 5^J hDCv hx ^J h8w9 hx 5^J hV/ hx 5^J
h0f ^J h hx 5^J
hx ^J h i j r i j } w h h _ O $ $If a$gdo K$ $If gdEj
& F
$If gdx $If gdx | kdp $$If l 0 " 4 @ 0 t"6 4 4
l a ytx } $ $If a$gdo K$ $ $If a$gdo 0 4 C E F J Y [ \ _ ` d e wwl hx CJ H*^J aJ h}J CJ ^J aJ h8w9 hx CJ ^J aJ hjm hx CJ ^J aJ ho ho CJ H*^J aJ h8w9 hx CJ H*^J aJ hx CJ ^J aJ h8w9 hx ho ho 5CJ H*^J aJ hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ hjm hx 5CJ ^J aJ ) ) $If gdo kdq $If K$L$l \ Xh T b
t ( 0 h 6 4 4
l a p( ytx $ $If a$gdo K$ $ $If a$gdo $If gdo K$ ' 0 5 Z O B 4 $ $If a$gdo $If gdo K$ $If gdo kdr $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx 5 F K \ _ ` < kds $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdo $ $If a$gdo K$ e f
? A B V W ] ` h i r s t ˽˦˰r h hx CJ ^J aJ hgU hx CJ H*^J aJ hx CJ H*^J aJ h0r hx CJ H*^J aJ h$0 CJ ^J aJ h8w9 hx CJ ^J aJ hC hx CJ H*^J aJ h$0 CJ H*^J aJ h8w9 hx hUP hx CJ ^J aJ hx CJ ^J aJ h CJ H*^J aJ '` r $ $If a$gdo K$ $ $If a$gdo $If gdo K$ $If gdo Z O B 4 4 $ $If a$gdo $If gdo K$ $If gdo kdt $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdo $ $If a$gdo K$ + B H O X M @ 2 2 $ $If a$gdo $If gdo K$ $If gdo kdau $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx O W ] a i q r s $ $If a$gdo $ $If a$gdo K$ s t Z M ? / ? $ $If a$gdo K$ $ $If a$gdo $If gdo K$ kd@v $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx : / $If gdo kdw $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdo $ $If a$gdo K$ ; kd x $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdo K$ $If gdo K$ P Q \ ] h j u w x % ' ѿߥ鿘鿋 h$0 CJ ^J aJ h hx CJ ^J aJ hm[ hx CJ ^J aJ ho ho CJ ^J aJ h hx CJ ^J aJ hx CJ H*^J aJ h8w9 hx ho ho CJ H*^J aJ ho CJ ^J aJ hx CJ ^J aJ hS hx CJ ^J aJ 2 . A Q R ^ k y $ $If a$gdo K$ $ $If a$gdo $If gdo K$ $If gdo X K ; ; ; $ $If a$gdo K$ $If gdo K$ kdx $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx X M 8 $If ^ ` gdo K$ $If gdo kdy $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx ' ( 0 kdz $If K$L$l \ Xh T b
t 0 h 6 4 4
l a yt$0 $ $If a$gdo K$ $ $If ^ ` a$gdo K$ ' ( * + N b c d e ( R S Թߋ~qfqXH ho ho CJ H*\^J aJ h hx CJ \^J aJ h$( CJ \^J aJ hx CJ H*\^J aJ hC hx CJ ^J aJ hx CJ H*^J aJ h9= CJ H*^J aJ hqUP hx CJ ^J aJ hx 5CJ ^J aJ hx 5CJ H*^J aJ hN hx CJ \^J aJ hx CJ \^J aJ hx CJ ^J aJ h8w9 hx 5CJ H*^J aJ h8w9 hx ( c R /
' $ $If a$gdG $ $If a$gdG K$ $If gdx $If ^ ` gdx $If gdx . / Y o ¸saSES hjm hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ #h8w9 hx 5B*CJ H*^J ph hx 5B*CJ H*^J ph hx 5B*CJ ^J ph h8w9 hx 5B*CJ ^J ph h$( CJ ^J aJ hZ hx CJ ^J aJ hx CJ ^J aJ hx 5CJ ^J aJ hZ hx 5CJ ^J aJ htF4 hx 5CJ ^J aJ hx CJ \^J aJ ho CJ H*^J aJ
% & ' ( 5 6 9 = > ? @ F G J N O Q V W Z ] ^ ` a b } ʼ㵫|ooo h8w9 hx CJ ^J aJ h9= hx CJ ^J aJ hx CJ H*^J aJ h9= CJ ^J aJ h\ hx CJ ^J aJ hx CJ ^J aJ h8w9 hx hjm hx 5CJ ^J aJ hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ h~ hx 5CJ H*^J aJ hx 5CJ H*^J aJ +' ( 5 ) $If gdG kd|{ $If K$L$l \ Xh T b
t ( 0 h 6 4 4
l a p( ytx 5 6 @ G Q W ` a $ $If ^ ` a$gdG $ $If a$gdG K$ $ $If a$gdG $If ^ ` gdG K$ a b | } Z O B 4 $ $If a$gdG $If gdG K$ $If gdG kd| $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx 4 Ǻǥ鳕}pb h hx 5CJ ^J aJ hC hx CJ ^J aJ hx 5CJ ^J aJ hx 5CJ H*^J aJ h8w9 hx 5CJ H*^J aJ hD hx CJ H*^J aJ h8w9 hx hc hx CJ ^J aJ hx CJ H*^J aJ h9= CJ ^J aJ h8w9 hx CJ ^J aJ hx CJ ^J aJ h9= hx CJ ^J aJ " < kd} $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdG $ $If a$gdG K$ 3 kdt~ $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx $ $If a$gdG K$ $If ^ ` gdG K$
$ $If a$gdG K$ $ $If a$gdG $If ^ ` gdG K$ ; X M M D $If gdx $If gdx kdS $If K$L$l \ Xh T b
t 0 h 6 4 4
l a ytx 4 : ; < = X Y Z m " g ļxnx` h* hx 5CJ ^J aJ h hx 5^J h8w9 hx 5^J
h9= H*^J h9= hx ^J h9= h9= ^J h8w9 hx h8w9 hx ^J
hx ^J h8w9 hx CJ ^J hx CJ ^J hZ hx h~ hx hx CJ ^J aJ hx 5CJ H*^J aJ hx 5CJ ^J aJ h9= 5CJ ^J aJ % 5 Y y y l l l l
& F $If gdx $If gdx | kd2 $$If l 0 " 4 @ 0 t"6 4 4
l a ytx Y Z c m J g y y l l l y _ _ _
& F $If gdx
& F $If gdx $If gdx | kdۀ $$If l 0 " 4 @ 0 t"6 4 4
l a ytx
g f ' u k k k k f ] $If gdx gdx
& F
gdx | kdv $$If l _0 " 4 @ 0 t"6 4 4
l a ytx
& F $If gdx
f & ' # $ % 1 + S q z { + ǿ{t{{{{i[ h h' 5CJ ^J aJ h' 5CJ ^J aJ hm7A h' h' hI4 h' #hd0 h' 5CJ OJ QJ ^J aJ h\ h' CJ OJ QJ ^J aJ h' CJ OJ QJ ^J aJ hI4 h' 5hv* hx H* hv* H*hx hk)X hx 5CJ ^J aJ hk)X hx 5hQ,I hx 5CJ ^J aJ hx 5CJ ^J aJ $ % 1 y p g $If gdL0 $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx ) $If gdL0 T { + y y l l l l _ y
& F $If gd'
& F $If gdx $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx + 4 f ] ] N
& F $If gdx $If gdx | kdG $$If l 0 " 0 t"6 4 4
l a ytx
& F $If gdx
& F $If gdx 4 : " # $ , = ? J M Q T b e g ˺n\NCNCNCNh' 5CJ ^J aJ h8w9 h' 5CJ ^J aJ #h8w9 h' 5B*CJ H*^J ph h8w9 h' 5B*CJ ^J ph h' h' CJ aJ hR h' CJ ^J aJ hm h' CJ ^J hm h' 5CJ ^J h h' 5CJ ^J h' 5CJ ^J hI4 h' 5 hI4 h' ha h' ha h' ^J aJ hF h' CJ ^J aJ hF h' 5CJ ^J aJ 4 : & / J z #
& F $If gd'
& F $If gdx $If ^ ` gdx
& F $If gdx # $ , ? M U f m u } y k _ k _ k _ k $$If a$gdx
$$If a$gdx K$ $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx g l m t v | } ~ . 0 1 : ; G H M N O z | } ǺպխպխպխխբպպՆբպպՆ h0r h' CJ H*^J aJ hC h' CJ H*^J aJ h' CJ H*^J aJ hjm h' CJ ^J aJ h8w9 h' CJ ^J aJ h8w9 h' CJ H*^J aJ h' CJ ^J aJ h8w9 h' h8w9 h' 5CJ ^J aJ h' 5CJ ^J aJ 0} ~ " $If gdx kd} $If K$L$l \ Xh T b
t ( 0 h 6 4 4
l a e4p( yt'
$$If a$gdx K$ $$If a$gdx
$If gdx K$ R I > 2 $$If a$gdx
$If gdx K$ $If gdx kd΅ $If K$L$l \ Xh T b
t 0 h 6 4 4
l a e4yt' 8 kd $If K$L$l \ Xh T b
t 0 h 6 4 4
l a e4yt' $$If a$gdx
$$If a$gdx K$ 1 7 ; A H N $ $If a$gdlh K$ $ $If a$gdlh $If gdlh K$ $If gdx N O f } P E 8 * $ $If a$gd$0 $If gdx K$ $If gdx kd $If K$L$l \ Xh T b
t 0 h 6 4 4
l a e4yt' $ $If a$gd$0 K$ $ $If a$gd$0 $ $If a$gdlh K$ $ % ` b R G G G G G G $If gdx kd $If K$L$l \ Xh T b
t 0 h 6 4 4
l a e4yt' " # $ % ' ( K _ ` a b a b c C K ̼鱣̘sf[fM h h' CJ \^J aJ h)t@ CJ \^J aJ h' CJ H*\^J aJ hC h' CJ ^J aJ h' CJ H*^J aJ hqUP h' CJ ^J aJ h' 5CJ ^J aJ hN h' CJ \^J aJ h' CJ \^J aJ h8w9 h' 5CJ H*^J aJ h' 5CJ H*^J aJ h' h' 5CJ H*^J aJ h' CJ ^J aJ h' h' CJ ^J aJ b A K L [ $ $If a$gd[ $ $If a$gd[ K$ $If gdx $If gdx $If ^ ` gdx K L [ ~ ij~pcYYK>h8w9 h' CJ ^J aJ h#5N h' CJ H*^J aJ h[ CJ ^J aJ h\ h' CJ ^J aJ hs h' CJ H*^J aJ h' CJ H*^J aJ h' CJ ^J aJ h8w9 h' h' 5CJ ^J aJ h8w9 h' 5CJ ^J aJ hG h' 5B*CJ ^J ph h' 5B*CJ H*^J ph h8w9 h' 5B*CJ ^J ph h' 5B*CJ ^J ph hI4 h' 5 h' 5 ) $If gd[ kd $If K$L$l \ 9l E 3 3
t ( 0 6 4 4
l a p( ytx $ $If ^ ` a$gd[ K$ $ $If ^ ` a$gd[ $ $If a$gd[ K$ $ $If a$gd[ $If ^ ` gd[ K$
#
$
(
,
-
4
<
=
>
T
U
W
[
\
]
`
d
e
f
h
l
m
n
o
p
q
u
v
w
͢|u hI4 h' hs h' 5CJ ^J aJ h)t@ 5CJ ^J aJ h' 5CJ H*^J aJ h8w9 h' 5CJ H*^J aJ hD h' CJ H*^J aJ hc h' CJ ^J aJ h8w9 h' h8w9 h' CJ ^J aJ h' CJ H*^J aJ h' CJ ^J aJ h[ CJ ^J aJ -
$
.
Z M ? / ? $ $If a$gd[ K$ $ $If a$gd[ $If gd[ K$ kd $If K$L$l \ 9l E 3 3
t 0 6 4 4
l a ytx .
4
=
>
U
]
f
J 5 $If ^ ` gd[ K$ kd $If K$L$l \ 9l E 3 3
t 0 6 4 4
l a ytx $ $If a$gd[ K$ f
n
o
v
H = $If gdx kdT $If K$L$l \ 9l E 3 3
t 0 6 4 4
l a ytx $ $If a$gd[ K$ v
w
A y l l
& F $If gdx $If gdx | kd% $$If l 0 " 0 t"6 4 4
l a ytx w
> B U m n 4
5
6
7
>
`
a
b
k
} ~ + F %
3 A Žʵʵ{uʵ
hx ^J hm7A hx 3hd0 hx 5CJ OJ QJ ^J aJ mH nH sH tH 0hd0 hx CJ OJ QJ ^J aJ mH nH sH tH hI4 hx 5hv* hx H* hv* H* hI4 hx hx hI4 h)t@ h)t@ h' hI4 h'
h)t@ ^J
h' ^J hI4 h' 5 -A B K U n 5
y y l l y _ _ _ _
& F $If gdx
& F $If gdx $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx
5
6
7
b
k
: ~ } } t k k k ) $If gdx $If gdx gdx | kdi $$If l 0 " 0 t"6 4 4
l a ytx ~ y y $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx +
z ` 3 A y y l l l l l l l l y
& F $If gdx $If gdx | kd $$If l 0 " 0 t"6 4 4
l a ytx A 9 5 6 ? R z u l l _ _ _
& F $If gdx $If gdx | kd: $$If l 0 " 0 t"6 4 4
l a ytx
& F $If gdx
A 4 5 6 Q R H n l n ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! ! " " zphx CJ ^J aJ hj hx CJ ^J aJ hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ #h8w9 hx 5B*CJ H*^J ph h8w9 hx 5B*CJ ^J ph hEj hDCv hx 5hm7A hx 5
hx ^J h hx ^J hI4 hx hI4 hx 5hx h7 ; hx , l H n n ! ! $If gdEj
& F $If gdx $If gdx
& F $If gdx ! ! ! ! ! ! ! ! ! ! w g Y g Y g $ $If a$gd> $ $If a$gd> K$ $If gdx | kdՐ $$If l 0 " 0 t"6 4 4
l a ytx ! ! ! " G < / $If gd> K$ $If gd> kdp $If K$L$l F X T b
t 0 6 4 4
l a p ytx " " " " " "" ." O D D $If gdx kd $If K$L$l F X T b
t 0 6 4 4
l a ytx $ $If a$gd> K$ $ $If a$gd> " " !" c" d" " " " " " " " " " " " " " " " " " # # # # # f# g# h# i# ͻ۠zmbmX h)t@ CJ ^J aJ h)t@ CJ H*^J aJ hqUP h)t@ CJ ^J aJ hx 5CJ ^J aJ hx 5CJ H*^J aJ hN hx CJ \^J aJ hx CJ \^J aJ h8w9 hx 5CJ H*^J aJ hx H*h8w9 hx CJ ^J aJ h0r hx CJ H*^J aJ hx CJ ^J aJ hj hx CJ H*^J aJ hj hx CJ ^J aJ ." =" G" M" S" ]" c" $ $If ^ ` a$gdx K$ $ $If a$gdx K$ $ $If a$gdx $ $If ^ ` a$gdx $If gdx K$ c" d" z" " " " " m b W I 9 I $ $If a$gdx K$ $ $If a$gdx
$If gdx K$ $If gdx kdQ $If K$L$l F X T b
t 0 6 4 4
l a ytx " " " " " " " [ P C 5 $ $If a$gdx $If gdx K$ $If gdx kd $If K$L$l F X T b
t 0 6 4 4
l a ytx $ $If a$gdx K$ " " " " # i# v# w# ] T I I > T $If gd)t@ $If gdx $If gdx kdٔ $If K$L$l F X T b
t 0 6 4 4
l a ytx $ $If a$gdx K$ i# j# n# u# v# w# # # # # # # # # # # # # # # # # # # # # ŷxmxmxmxmxfXK h\ hx CJ ^J aJ hs hx CJ H*^J aJ h8w9 hx hx 5CJ ^J aJ h8w9 hx 5CJ ^J aJ hG hx 5B*CJ ^J ph hx 5B*CJ H*^J ph h8w9 hx 5B*CJ ^J ph hx 5B*CJ ^J ph hI4 hx 5 hx 5hx CJ \^J aJ hx CJ ^J aJ hC hx CJ ^J aJ hx CJ H*^J aJ w# # # # # # # $ $If a$gd)t@ $ $If a$gd)t@ K$ $If gdx # # # # G < ' $If ^ ` gd)t@ K$ $If gd)t@ kd $If K$L$l F 2k
t 0 6 4 4
l a p ytEj # # # # # # 9 kd $If K$L$l F 2k
t 0 6 4 4
l a ytEj $ $If ^ ` a$gd)t@ $ $If a$gd)t@ K$ $ $If a$gd)t@ # # # # # # # # $ $ $ $ $ !$ $$ &$ '$ ($ >$ ?$ B$ E$ F$ H$ J$ M$ N$ P$ Q$ R$ S$ V$ W$ X$ d$ ϻ筣ȓxjc[ hI4 hx 5 hI4 hx hs hx 5CJ ^J aJ hH hx 5CJ ^J aJ hx 5CJ H*^J aJ h8w9 hx 5CJ H*^J aJ h)t@ CJ ^J aJ hD hx CJ H*^J aJ hc hx CJ ^J aJ h8w9 hx hx CJ H*^J aJ h8w9 hx CJ ^J aJ hx CJ ^J aJ h#5N hx CJ H*^J aJ "# $ $ $ !$ &$ '$ $ $If a$gd)t@ K$ $ $If a$gd)t@ $If gd)t@ K$ $If gd)t@ '$ ($ ?$ G$ H$ O$ P$ m X J : J : $ $If a$gd)t@ K$ $ $If a$gd)t@ $If ^ ` gd)t@ K$ kdY $If K$L$l F 2k
t 0 6 4 4
l a ytEj P$ Q$ W$ k ` $If gdx kd $If K$L$l F 2k
t 0 6 4 4
l a ytEj W$ X$ d$ $ & y l _
& F $If gd)t@
& F $If gdx $If gdx | kdǘ $$If l 0 " 0 t"6 4 4
l a ytx d$ & & & \' ^' ' ( X X ,X XX X X Y Y Y [Y dY Y #Z GZ JZ KZ WZ Z Z Z Z
[ 5[ 6[ 7[ L[ [ [ [ [ αٱ}tf`
h4 ^J hTC: h4 5CJ ^J aJ h* h4 ^J h* h4 5CJ ^J aJ $h* h4 5B*CJ ^J aJ ph $h* h4 5B*CJ ^J aJ ph h4 5B*CJ ^J aJ ph h4 56CJ ^J aJ h4 5CJ ^J aJ h4 CJ ^J h4 Uhx hI4 hx 5 hI4 hx
hx ^J %& & & & ^' ' X ,X XX X Y y y l l l y _ _ _
& F $If gdx
& F $If gdx $If gdx | kdp $$If l 0 " 0 t"6 4 4
l a ytx
validity for the VA population
Limitations
Study was sponsored by makers of tapentadol
The inclusion and exclusion criteria were so broad that many possible patients would have been excluded from this study.
Study lacks external validity and therefore does not have a place in therapy.Trial 5Long term safety and tolerability of tapentadol ER
CitationWild, James, Grond, Stefan, Kuperwasser, Brigitte, et al. Long-term safety and tolerability of tapentadol extended release for the management of chronic low back pain or osteoarthritis pain. Pain Practice. 2010; 10 (5) 416-427. Study GoalsAssess the long-term safety and tolerability of tapentadol ER in patients with chronic knee or hip osteoarthritis pain or low back pain.
Primary endpoint: Number of Participants with Treatment-emergent Adverse Events (TEAE)
Secondary endpoints: Change From Baseline in Average Pain Intensity Scores at Week 52 Using the Numerical Rating Scale (NRS)MethodsStudy Design
Randomized, multicenter, parallel-group, open-label, active-controlled phase 3 trial
1,117 patients were included in the study after screening. Patients were assigned to treatment based on a computer-generated randomization
Patients were randomized 4:1 to receive controlled, adjustable twice-daily doses of tapentadol ER (100 to 250 mg) or oxycodone HCL controlled release (CR; 20 to 50 mg).
Study consisted of a screening period, a 3-7 day washout period, 1-week titration period and a 51-week maintenance period.
Safety and tolerability was evaluated by treatment group. Assessments included adverse event (AE) reporting, vital signs measurements, physical examinations, clinical laboratory tests, Patients Assessment of Constipation Symptoms (PAC-SYM), the Clinical Opiate Withdrawal Scale (COWS) and the Subjective Opiate Withdrawal Scale (SOWS) questionnaires.
Concomitant use other analgesics was not allowed during the study. NSAIDs could be used occasionally for fever or pain other than chronic pain (i.e. toothache), and aspirin <325 mg could be used for cardiac prophylaxis.
Efficacy was assessed using patient ratings of their average pain intensity over the previous 24 hours on the 11-point NRS at each study visit.
Data Analysis
Safety population included all randomized patient who received at least 1 dose of study medication and the intended to treat (ITT) population
Distribution of time to first incidence of TEAEs were determined using Kaplan-Meier estimatesCriteriaInclusion criteria
Men and nonpregnant, nonlactating women 18 years of older.
Clinical diagnosis of knee or hip osteoarthritis with history of pain at the reference joint for at least 3 months or clinical diagnosis of low back pain of benign origin for at least 3 months
Must be dissatisfied with their current analgesic therapy (e.g. Non-steroidal anti-inflammatory drugs NSAIDS, COX-2 inhibitors, opioids, acetaminophen
Have a pain intensity >4 on Numerical Rating Scale
Exclusion criteria
Life-long history of seizure disorder or epilepsy
Any of the following within one year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, and brain neoplasm
Severe traumatic brain injury within 15 years (consisting of more than one of the following: brain contusion (injuries resulting in hemorrhage), intracranial hematoma, unconsciousness or post traumatic amnesia lasting for more than 24 hours) or residual sequelae suggesting transient changes in consciousness
History of malignancy within past 2 years, with exception of a successfully treated basal cell carcinoma
Presence of significant pain associated with conditions other than osteoarthritis or low back pain that could confound the assessment or self-evaluation of pain
ResultsSafety Measure a
Tapentadol ER
N = 894
Oxycodone CR
N=223
NNH
TEAE (at least 1)
766 (85.7%)
202 (90.6%)
20
Efficacy
Tapentadol ER
Oxycodone CR
Baseline pain intensity score (mean)
7.6 (0.05)
7.6 (0.11)
Endpoint pain intensity score (mean)
4.4 (0.05)
4.5 (0.17)
Patients completing treatment in the tapentadol ER and oxycodone CR groups were 46% (413/894) and 35% (78/223) respectively.
TEAE requiring discontinuation was 22.7% (203/894) for the tapentadol ER group and 36% (82/223) in the oxycodone CR group. P <0.001
The most common TEAEs reported were constipation, nausea, dizziness, somnolence, vomiting, headache, fatigue and pruritus.
Gastrointestinal TEAEs were reported in 52% of the patients in tapentadol ER group and 64.1% of patients in the oxycodone CR group.Authors
ConclusionsTapentadol ER was associated with a lower incidence of gastrointestinal adverse effects than oxycodone CR including nausea, vomiting, and constipation despite the median duration of treatment being substantially longer with tapentadol ER than with oxycodone CR.
The favorable GI tolerability profile observed for tapentadol ER over the 1-year treatment period may improve patient compliance with long-term analgesic treatment, as indicated by the reduction in TEAD-related discontinuations. CritiqueStrengths
Long-term study (one-year), randomized controlled trial
Limitations
The study excluded patients with renal insufficiency and patients with hepatic dysfunction which limits its generalizability.
Study and editorial was sponsored by the makers of tapentadol.
Baseline characteristics were do not extrapolate well to VA population, majority of patients were females and <65 years of age
Study was open-label meaning the investigators knew randomization of patients
Trial 6Long term Phase III extended trial safety and tolerability of tapentadol ER
CitationJohnson & Johnson Pharmaceutical Research & Development, LLC. An open-label extension study with flexible extended-release (ER) tapentadol to treat patients with moderate to severe chronic pain. US National Institute of Health. ClinicalTrials.gov. Accessed October 8, 2012. Study GoalsAssess the long-term safety and tolerability of tapentadol ER in patients with chronic pain, osteoarthritis or lower back pain.
Primary endpoint: Number of Participants with Treatment-emergent Adverse Events (TEAE)
Secondary endpoints: Change From Baseline in Average Pain Intensity Scores at Week 52 Using the Numerical Rating Scale (NRS)MethodsStudy Design
Open-label extension, single-arm, flexible dosing phase 3 trial
1,154 patients were included in the study.
Patients received adjustable twice-daily doses of tapentadol ER (100 to 250 mg) for 52 weeks
Visits were schedule every 4 weeks at which dose adjustments and adverse effects were assessed
Efficacy was assessed using patient ratings of their average pain intensity over the previous 24 hours on the 11-point NRS at each study visit.
Analysis was intention to treatCriteriaInclusion criteria
Non-lactating female subjects (Sexually active women must be postmenopausal, surgically sterile, or practicing an effective method of birth control [e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double barrier method, contraceptive patch, male partner sterilization] before entry and throughout the trial. Female patients of childbearing potential must have a negative pregnancy test at screening.)
Completion of the expected double-blind treatment period of the pivotal Tapentadol Phase 3 trials in osteoarthritis or low back pain, or completion of the 1-year treatment period of the safety Phase 3 trial in the non-European sites
Must be willing to take Tapentadol extended release (ER) and the rescue medication supplied for the duration of the trial
Exclusion criteria
History of alcohol and/or drug abuse, life-long history of seizure disorder or epilepsy, any of the following within the past year: mild/moderate traumatic brain injury, stroke, transient ischemic attack, or brain neoplasm
Severe traumatic brain injury within the past 15 years
Uncontrolled hypertension (repeated systolic blood pressure >160 mmHg or diastolic blood pressure >95 mmHg)
Severely impaired renal function
Moderately or severely impaired hepatic function
Patients taking neuroleptics, monoamine oxidase inhibitors, or tricyclic antidepressants within 14 days prior to screening.Results
Safety Measure
Tapentadol ER (N = 1154)
TEAE (at least 1)
907 (78.6%)
Efficacy
Tapentadol ER
Change from baseline on numerical rating scale (mean)
-0.26 (2.129)
Patients completing treatment of tapentadol ER at 52 weeks was 669/1154 (57%)
TEAE requiring discontinuation was 12.7% (146/1154) .
The most common TEAEs reported were nausea, constipation, diarrhea, vomiting, fatigue, headache and dizziness.CritiqueStrengths
Long-term study (one-year)
Limitations
The study excluded patients with renal insufficiency , hepatic dysfunction, history of alcohol abuse and patient on concurrent neuroleptic medications which account for a large portion of the VA population.
Study and editorial was sponsored by the makers of tapentadol.
Did not compare again active control.
These findings are consistent with the reported effects of opioids for patients with osteoarthritis of the knee and hip; a Cochrane systematic review of placebo-controlled trials showed that opioids were associated with an NNT of 25 and an NNTH of 12 over a median treatment duration of 4 weeks (range, 3 days to 3 months).18
Tapentadol ER Monograph
Updated version may be found at HYPERLINK "http://www.pbm."www.pbm.va.gov or vaww.pbm.va.gov PAGE 6
Tapentadol ER Monograph
PAGE \* MERGEFORMAT 22
Tapentadol ER Monograph
Y Y [Y dY JZ { r i $If gdL0 $If gdL0 gd4 | kd $$If l 0 " 0 t"6 4 4
l a ytx JZ KZ WZ Z 7[ [ ~ u f f f
& F $If gdL0 $If gdL0 kd $$If l 0 F" FF F
t 0 " 4 4
l B al ytL0 [ [ [ [ \ \ T] ] /_ ~ u l ] ] ] ] ]
& F
$If gdL0 $If gdL0 $If gdL0 kdX $$If l 0 F" FF F
t 0 " 4 4
l B al ytL0 [ [ /_ ` ` ` 8a a a a a a #c 8c yc c e e f f f f f f f f f f f g g g g żŧŊ{pbRb h^d h4 5CJ H*^J aJ h^d h4 5CJ ^J aJ h4 CJ H*^J aJ h4 5B*CJ H*^J ph h4 5B*CJ ^J ph ho$7 h4 ^J
h4 ^J hTC: h4 ^J hTC: h4 5CJ ^J h4 5CJ ^J h4 CJ ^J h4 hH] h4 CJ ^J aJ hdWC h4 CJ ^J aJ h4 5CJ ^J aJ h4 CJ ^J aJ /_ ` ` ` 8a a a F kd
$$If l 0 F" FF F
t 0 " 4 4
l B al ytL0
& F $If gdL0 m$
& F $If gdL0 $If gdL0
& F
$If gdL0 m$ a a a a b Fc yc c c @d ue e f
& F $If gd4
& F $If gd4 m$
& F $If gd4 m$ $If gdL0 f f f f f f f f f ~ u u e W e J W $If gd~ K$ $ $If a$gd~ $ $If a$gd~ K$ $If gdL0 kd $$If l 0 F" FF F
t 0 " 4 4
l B al ytL0 f f f $ $If ^ ` a$gd~ K$ $ $If a$gd~ K$ f f kdn $If K$L$l r J
F FT F8 FT F;
t 2 0 4 4
l B a p2 ytL0 f f f f f f
$$If a$gd% K$ $$If a$gdL0 m$K$ $ $If ^ ` a$gdL0 m$K$ $If ^ ` gd~ m$K$ f f g g g H = = * $If ^ ` gdL0 K$
$If gd% K$ kd $If K$L$l r J
F FT F8 FT F;
t 0 4 4
l B a ytL0 g g g g Dg Og Pg [g \g
$$If a$gdL0 K$
$If gdL0 K$ $If ^ ` gdEj K$ Ff]
$$If a$gd% K$ $If ^ ` gd% K$ g g Cg Dg \g ]g g g g g i i i i k k k k k k k k k k m m m m m m m n n n o o {kk h4 5B*CJ ^J aJ ph hjS hjS 5hpU h4 ^J hM h4 5^J
h4 5^J hU%} h4 ^J
h4 ^J h4 CJ ^J h4 5CJ ^J aJ hyi h4 CJ ^J aJ h% hEj CJ ^J aJ h% CJ ^J aJ h
h4 CJ ^J aJ h4 CJ ^J aJ h4 #\g ]g g g g g H 5 5 5 5 $If ^ ` gdL0 K$ kdE $If K$L$l r J
F FT F8 FT F;
t 0 4 4
l B a ytL0 g g g h h i : - - -
& F $If gdL0 kdB $If K$L$l r J
F FT F8 FT F;
t 0 4 4
l B a ytL0
$$If a$gdL0 K$ i i i i i j k q h h [ [
& F $If gd4 $If gdL0 kd? $$If l 0 F" FF
t 0 " 4 4
l B al ytL0
& F $If gdL0 k k k k k k k xl l 6m ~ u u h _ _ h R R
& F $If gdL0 $If gdL0
& F$ $If gd4 $If gdL0 kd $$If l 0 F" FF F
t 0 " 4 4
l B al ytL0 6m m m m m m n q d ] T K $If gdL0 $If gdL0 gdjS ^ ` gdx kd $$If l 0 F" FF
t 0 " 4 4
l B al ytL0
& F $If gdL0 n n o o o Xp v g g g
& F $If gdL0 $If gdL0 kdU $$If l 0 F" FF F
t 0 "6 4 4
l B al yt% o o o o o o o o o Wp Xp Yp ap np 9q Hr Ir Jr fr Yt qt t t t t t t u
u u .u u u w w w ⪤⎁ululululululuc h8Q h4 ^J h4 5CJ ^J h8Q h4 5CJ ^J h~? h4 CJ ^J aJ h4 CJ ^J aJ h4 CJ ^J h4
h4 ^J hTC: h4 5CJ ^J aJ h* h4 ^J h* h4 5CJ ^J aJ $h* h4 5B*CJ ^J aJ ph h4 5CJ ^J aJ $h* h4 5B*CJ ^J aJ ph #Xp Yp ap np p p 9q q )r v m ^ ^ ^ N N
& F
$If gdL0 m$
& F
$If gdL0 $If gdL0 $If gdL0 kd $$If l 0 F" FF F
t 0 "6 4 4
l B al yt% )r Ir Jr Sr fr t u u u o f f X X X f
& F $If gd4 m$ $If gdL0 kd $$If l 0 F" FF F
t 0 "6 4 4
l B al yt%
& F
$If gdL0 m$ u xv v w y y y y y ˨ˀsisisisi\XP h4 CJ ^J h4 h>2 h4 CJ ^J aJ h4 CJ ^J aJ hyi h4 CJ ^J aJ h4 5CJ ^J aJ h
h% CJ ^J aJ h^d h% 5CJ H*^J aJ h^d h% 5CJ ^J aJ h% CJ H*^J aJ h% CJ ^J aJ h% h% 5CJ ^J aJ h% 5B*CJ H*^J ph h% 5B*CJ ^J ph h% h4 CJ /x ;x #v 2#v9#v>:V l
t 0 6 , ,5 /
p ytEj $If K$L$l !v h5 2595>#v 2#v9#v>:V l
t 0 6 , 5 /
ytEj $If K$L$l !v h5 2595>#v 2#v9#v>:V l
t 0 6 , 5 /
ytEj $If K$L$l !v h5 2595>#v 2#v9#v>:V l
t 0 6 , 5 /
ytEj $$If !v h5 5 #v #v :V l 0 t"6 5 5 / a ytx $$If !v h5 5 #v #v :V l 0 t"6 5 5 a ytx $$If !v h5 5 #v #v :V l 0 t"6 5 5 a ytx $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 r$If K$L$l !v h5 5T585T5;#v #vT#v8#vT#v;:V l
t 2 0 , 5 5T585T5;/ /
B p2 ytL0 $If K$L$l !v h5 5T585T5;#v #vT#v8#vT#v;:V l
t 0 , 5 5T585T5;/ /
B ytL0 |$If K$L$l !v h5 5T585T5;#v #vT#v8#vT#v;:V l
t 2 0 , ,5 5T585T5;/ /
B p2 ytL0 kdߟ $If K$L$l r J
F FT F8 FT ;
t 2 0 4 4
l B a p2 ytL0 $If K$L$l !v h5 5T585T5;#v #vT#v8#vT#v;:V l
t 0 , 5 5T585T5;/ /
B ytL0 $If K$L$l !v h5 5T585T5;#v #vT#v8#vT#v;:V l
t 0 , 5 5T585T5;/ /
B ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 " 5 F5 / B al ytL0 $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% $If K$L$l !v h5 <5]#v <#v]:V l
t 0 6 , 5 / /
B p yt% $If K$L$l !v h5 <5]#v <#v]:V l
t 0 6 , 5 / /
B yt% $If K$L$l !v h5 <5]#v <#v]:V l
t 0 6 , 5 / /
B p yt% $If K$L$l !v h5 <5]#v <#v]:V l
t 0 6 , 5 / /
B yt% $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% $$If l !v h5 F5 #v F#v :V l
t 0 "65 F5 / B al yt% s $$If !v h5 5 5i
#v #v #vi
:V l 6 5 |
5 5ytM $$If !v h5 %5
5f#v %#v
#vf:V l
t 0 65 S5 5 $$If !v h5 %5
5f#v %#v
#vf:V l
t 0 65 S5 5s $$If !v h5 %55|#v %#v#v|:V l 6 5 |
5 5ytM s $$If !v h5 5 5i
#v #v #vi
:V l 6 5 |
5 5ytM ^5 0 0 2 0 @ P ` p 2 ( 0 @ P ` p 0 @ P ` p 0 @ P ` p 0 @ P ` p 0 @ P ` p 0 @ P ` p 8 X V ~ _HmH nH sH tH T ` T 1j N o r m a l Ex ^ `E OJ QJ _HmH sH tH N ` N ' ;0 H e a d i n g 1 $x @& 5>*CJ mH sH tH L @ L ` H e a d i n g 2 $x @& 5CJ OJ QJ 8 8 ` H e a d i n g 3 $@& 5 @ @ ` H e a d i n g 4 $@& 6B*ph L @ RL ` H e a d i n g 7 $< @& 5CJ OJ QJ 8 8 ` H e a d i n g 8 $@& 5 D A` D D e f a u l t P a r a g r a p h F o n t R i@ R 0 T a b l e N o r m a l 4
l 4 a ( k (
0 N o L i s t > >@ > ` T i t l e a$ 5B*OJ QJ ph D J@ D ` S u b t i t l e a$ 5B*OJ QJ ph : B@ : ` B o d y T e x t CJ OJ QJ : @ ": `
F o o t n o t e T e x t CJ 6 U`16 ` H y p e r l i n k >*B*ph 4 @ B4 ` H e a d e r
! 8 OR8 ` T a b l e
B*CJ ph J 6@ bJ
/<
L i s t B u l l e t 2 x ^ ` @ @ r@ 4 ` 0 F o o t e r
! CJ OJ QJ . )@ . ` P a g e N u m b e r H H % B a l l o o n T e x t CJ OJ QJ ^J aJ 6 OQ6 `
T a b l e F o o t n o t e D "@ D ` C a p t i o n $x 5CJ OJ QJ \T ^ T z N o r m a l ( W e b ) d d [$\$ B* CJ aJ ph D + D qv E n d n o t e T e x t ^ ` CJ : : qv E n d n o t e T e x t C h a r X X ,9 L i s t P a r a g r a p h ^` m$ CJ aJ j O j >q S t y l e H e a d i n g 1 + B l a c k x ^ ` B*\ph F V F xt] F o l l o w e d H y p e r l i n k >*B* ph ~ # ] T a b l e G r i d 1 z :V" 0 j j
" Ex ^ `E 6] 6]D 3D T a b l e C o n t e m p o r a r y :V# 0 j%@
j%
j%
4 # Ex ^ `E< @ B* `J ph B* `J ph 5B* \`J ph C T a b l e W e b 1 h :V$ 0 3 j
$ Ex ^ `E B* `J ph S T a b l e T h e m e 7 :V% 0 % Ex ^ `E j cj
T a b l e G r i d 7 :V& 0 & R /qR ;0 H e a d i n g 1 C h a r 5>*CJ OJ QJ mH sH tH 2 /2 *
l i - c o n t e n t ph e` * L 0 H T M L P r e f o r m a t t e d K )
2 (
Px 4 #\'*.25@9 ^ ` OJ QJ mH sH tH P /P ) L 0 H T M L P r e f o r m a t t e d C h a r OJ QJ ^J B ' B V* C o m m e n t R e f e r e n c e CJ aJ 8 8 - V* C o m m e n t T e x t , CJ : : , V* C o m m e n t T e x t C h a r T j T / V* C o m m e n t S u b j e c t . 5OJ QJ \mH sH tH F /F . V* C o m m e n t S u b j e c t C h a r 5\@ @ V* 0 R e v i s i o n 0 CJ _HmH sH tH & /& jFW b i b l i s t B O "B 9$ d e s c 2 2 ^ ` CJ aJ @ &@ 1@
F o o t n o t e R e f e r e n c e H* : / A: ,& 0 F o o t e r C h a r CJ OJ QJ PK ! [Content_Types].xmlj0Eжr(Iw},-j4 wP-t#bΙ{UTU^hd}㨫)*1P' ^W0)T9<l#$yi} ;~@(Hu* Dנz/0ǰ $ X3aZ,D0j~3߶b~i>3\`?/[G\!-Rk.sԻ..a濭? PK ! ֧ 6 _rels/.relsj0 }Q%v/C/} (h"O
= C?hv=Ʌ%[xp{۵_Pѣ<1H0ORBdJE4b$q_ 6LR7`0̞O,En7Lib/Se е PK ! ky theme/theme/themeManager.xml M
@}w7c(Ebˮ CAǠҟ7՛K
Y,
e.|,H ,lxɴIsQ}#Ր ֵ+!,^$j=GW)E+&
8 PK ! P theme/theme/theme1.xmlYOo6w toc'vuر-Mn iP@I}úama[إ4:l ЯGRX^6؊>$ !)O^rC$y@ /yH*)UDb`}"qۋJחX^)I`nEp)liV[]1M<OP6r=zgbIguSe bORD۫qu gZo~ٺlAplxpT0+[}`j zA V2Fi@qv֬5\|ʜ̭NleXd sjcs7f
W+Ն7` g ȘJj|h(KD-
dXiJ؇(x$( :;˹! I_TS 1?E ??ZBΪmU/ ?~xY'y5g&/ɋ>GMGeD3Vq%'#q$8K )fw 9:ĵ
x}rxwr:\TZaG*y8IjbRc|XŻǿI
u3KGnD 1NIBs
RuK>V.E L+M2#'fi ~V vl{u8z H
* :( W ☕
~JTe\O*tHGHY }KNP*ݾ˦ TѼ9/#A7qZ $*c?qUnwN%Oi4 =3ڗP
1Pm \\9Mؓ2aD];Yt\[x]}Wr|]g-
eW
)6-rC Sj
id DЇAΜIqbJ#x꺃 6k#ASh&ʌt(Q% p%m&]caS l=X\P1Mh9MVdDAaVB[݈fJíP|8 քAV^f
Hn- "d>znNJ ة>b&2vKyϼD:,AGm\nziÙ .uχYC6OMf3or$5N HT[XF64T,ќM0E)`#5XY`פ ;%1U٥m;R>QD DcpU'&LE/pm%]8firS4d 7y\`JnίI R 3U~7+#m qBiDi*L69mY&iHE=(K&N!V.KeLDĕ{D vEꦚdeNƟe(MN9ߜR6&3(a/DUz<{ˊYȳV)9Z[4^n5!J?Q3eBoCM m<.vp IYfZY_p[=al-Y}Nc͙ŋ4vfavl'SA8|*u{-ߟ0%M07% < ҍ PK !
ѐ ' theme/theme/_rels/themeManager.xml.relsM
0wooӺ&݈Э5
6?$Q
,.aic21h:qm@RN;d`o7gK(M&$R(.1r'JЊT8V"AȻHu}|$b{ P8g/ ]QAsم(#L[ PK- ! [Content_Types].xmlPK- ! ֧ 6 + _rels/.relsPK- ! ky theme/theme/themeManager.xmlPK- ! P theme/theme/theme1.xmlPK- !
ѐ ' theme/theme/_rels/themeManager.xml.relsPK ]
< [ I L ;B L [ ; v + - k 1& * @/ 2 ;9 > C F CK N VP R S yT 8U V Y Z u[ R\ I^ ` b d g n x i~ C V e x ݩ dz *
e ' 4 g K w
A " i# # d$ [ g o w y | I} ! # & * 0 6 9 ; ? D H K N P S X a f h i m r v z } % & & & ' z' ' ) ) 1* T* * * + , r6 G @ A B C E F G I J L M O Q R T U V W Y Z [ \ ] ^ _ ` b c d e g j k l n o p q s t u w x y { | ~ . 0 J ` b & *' ,' I5 a5 i5 : : : : : : ; H; J; d; ; ; ? ? ? )A TA VA AB WB YB L L L L L L 5N KN MN MP xP zP R S S %S ;S =S p p p s s s S \z hz z 5| ~ f \ # - ' z 7 A r { H R R R S S S S " + W a ] _ ` b c e f h i k m w
: ; > H Y \ % @ n C " 0" " # a. r. 0 0 2 2 8 8 : : $H H H H &I _I L 0L lS nS W W Y Y g 6g g h i i k k Gn Ln o o s t 5v @v \z gz "| &| <} @} R V # ߇ / 1 { ~ n p S T + . 1 6 ] _ ` b c e f h i k : ; Y \ 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 ' ' i n S S S S S S S S Qz Sz [ ] i k m z { { : Y \ ' ' i n S S S S S S S S Qz Sz ] i k m z { { : Y \ & " hT y iR Q/z ]< =
d O ;, Q9M%J 'P :J)|>0 }3R ~ ' 58b m-7v@ \&:䚱 V:g 9\A?( [.D4 ),GX7 `Nf H BO.L 8)VѨ #d%[xZ 8!\k C[\|>0 WF>^λڑ a(F ' '9;bl\ `bn Hg I tgf5# RclԼ WmU o Z{ttа #w 8 Khz fd dk|* ^`OJ QJ o( - h h^h`OJ QJ o( h H h 8^8`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^ `OJ QJ o( h H h ^ `OJ QJ ^J o( h H o h x^x`OJ QJ o( h H h H^H`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ o( h H % h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`CJ OJ QJ aJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H
^`o( h H .
^`h H .
pL^p`Lh H .
@ ^@ `h H .
^`h H .
L^`Lh H .
^`h H .
^`h H .
PL^P`Lh H . h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( ^`CJ OJ QJ o( ^`CJ OJ QJ o( o p p^p`CJ OJ QJ o( @ @ ^@ `CJ OJ QJ o( ^`CJ OJ QJ o( ^`CJ OJ QJ o( ^`CJ OJ QJ o( ^`CJ OJ QJ o( P P^P`CJ OJ QJ o( ^`OJ QJ o( - ^`OJ QJ o( o p p^p`OJ QJ o( @ @ ^@ `OJ QJ o( ^`OJ QJ o( o ^`OJ QJ o( ^`OJ QJ o( ^`OJ QJ o( o P P^P`OJ QJ o( h h^h`OJ QJ ^J o( h H o h 8^8`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^ `OJ QJ o( h H h ^ `OJ QJ ^J o( h H o h x^x`OJ QJ o( h H h H^H`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h h^h`OJ QJ o( h H h 8^8`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^ `OJ QJ o( h H h ^ `OJ QJ ^J o( h H o h x^x`OJ QJ o( h H h H^H`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h h^h`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h ^`OJ QJ o( h H % h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h h^h`OJ QJ o( h H h 8^8`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^ `OJ QJ o( h H h ^ `OJ QJ ^J o( h H o h x^x`OJ QJ o( h H h H^H`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H
^`o( h H .
^`h H .
pL^p`Lh H .
@ ^@ `h H .
^`h H .
L^`Lh H .
^`h H .
^`h H .
PL^P`Lh H . h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h h^h`OJ QJ o( h H h 8^8`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^ `OJ QJ o( h H h ^ `OJ QJ ^J o( h H o h x^x`OJ QJ o( h H h H^H`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( 8^8`OJ QJ ^J o( o ^`OJ QJ o( ^ `OJ QJ o( ^ `OJ QJ ^J o( o x^x`OJ QJ o( H^H`OJ QJ o( ^`OJ QJ ^J o( o ^`OJ QJ o( h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h^h`OJ QJ o( h H ^`OJ QJ ^J o( h H o p^p`OJ QJ o( h H @ ^@ `OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^`OJ QJ o( h H ^`OJ QJ ^J o( h H o P^P`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h p^p`OJ QJ o( h H h @ ^@ `OJ QJ o( h H h ^`OJ QJ ^J o( h H o h ^`OJ QJ o( h H h ^`OJ QJ o( h H h ^`OJ QJ ^J o( h H o h P^P`OJ QJ o( h H h h^h`OJ QJ o( h H 8^8`OJ QJ ^J o( h H o ^`OJ QJ o( h H ^ `OJ QJ o( h H ^ `OJ QJ ^J o( h H o x^x`OJ QJ o( h H H^H`OJ QJ o( h H ^`OJ QJ ^J o( h H o ^`OJ QJ o( h H * \&: WF>^ [.D Q/z V: 9\A Wm Z{t BO ),G dk| Q9M% o ; Rcl `b 8)V p ' Hg C[\ Rcl o `b #d%[ }3 ' 5 a tg '9;b O m-7 h 8!\ :J) 8)V y =
`N ]< Khz #w & & p VF 9 YB ̎%b܌?6P@"z־ Lv83Ƅ#B]pA.<2X }nOEfg& DNL @'>\02ۖ^yd {1 " % +{ )sRz 'gk)_ x h -E
d C[Pw9 %\L7 J l~ )2% %
% |0=YxT b5W-D ( Z \L7 w9tb W-D u G 6OZL =YxT
% _.V) cbXb5 k)_J S
b)2% tbS
b Yyfc Yk %et mt yeu ;u:= w " " := w 'g sRzcbX $ h +{C[P l~|0 &h j P \ 6 : a &+ 5 ZU ] +l [ p # p l< J jS b wN #m ! P |i o
!!
~
` L ~ + C ) L0 c k u &> Q u
x 7 & nT % o2 TO "X" $ 9$ WB$ `$ r% % Q% ,& :& D& r& ' ' W' `h' $( =) |K) Rf)
* V* 2* b+ [l+ B- u- (O. v. ^z/ 0 d0 2 3 &3 b3 <4 4 p 5 5 V6 7 7 c7 y8 19 E9 : TC: r: n+; <; =\; /< ~g< o< = 9= fY= > D> z> 9? M? (V? S@ @ [@ 2s@ )t@ A ?$A :A B B 7B OB {B !C %C dWC IE 2PE ZZE 4F uF G G 1G ?G drH zH 3J b 5}b kc eWd ud &e
f !f g ,h 5h \h kh lh D@i Qi 7`i 1j ;j Ej nSj <[j k l -tl o x
o o o )8o ;1p =Tp N^p =_p >q #_q [x }~ => }
%' q a ., 6^ S ) f k r (9 9 R p u% L5 ] } m X t h " P ] qv ;Z \ f * g ( > s M u} { ^d b nj 7 ]] K. j $0 ?n 5= ?? J u 2 0f t lI }J J [ ~? m + > ' 0 > k m 0 Mk yi & G, 6 LH OT #` g X kr Gk Z ; ' w % e4 G r] p ) \ j N G % L N^ F /| .d l
M 8Q f2 EU Z QM k 75 % . , Y >2 4 K |q z; f b_ ;d 5 C Q 4 R 5 H /_ u M K 9 Q c P <4 |G X u M @\ 0 1 7 8 @ A C D kS kT kV kX kY x x x x x x x x x / / [ @ : x @ B @ L @ P @ b @ f j @ L@ \@ d@ t@ @ @ @ @ @ @ @ (@ 8@ @@ & @ U n k n o w n F G G * T i m e s N e w R o m a n 5 S y m b o l 3. * A r i a l ; A d v P S 9 B 2 B 5. * a T a h o m a ?= * C o u r i e r N e w ; W i n g d i n g s A B C a m b r i a M a t h " 1 h ' ' 2 * * 0 2Q HX ? +l 2 ! x x q C : \ D o c u m e n t s a n d S e t t i n g s \ v h a p b h g o o d m f \ A p p l i c a t i o n D a t a \ M i c r o s o f t \ T e m p l a t e s \ A b b r e v R e v i e w T e m p l a t e - 2 0 1 1 1 0 . d o t x N a t i o n a l P B M M o n o g r a p h T e m p l a t e F G F G &
! " # $ % Oh +'0 0 < H
h t
FG < 02/10/05 Added legal statement
03/07/07 Added disclaimer ( Abbrev Review Template - 2011 10.dotx FG 8 Microsoft Office Word @ # @ RgG@ * * ՜. +,D ՜. +,T h p
VHA PBM SHG National PBM Monograph Template Title 8 @ _PID_HLINKS A \ h t t p : / / w w w . p b m . /
! " # $ % & ' ( ) * + , - . / 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 { | } ~ R o o t E n t r y F N D a t a
| 1 T a b l e > m W o r d D o c u m e n t
' S u m m a r y I n f o r m a t i o n ( D o c u m e n t S u m m a r y I n f o r m a t i o n 8 M s o D a t a S t o r e 210ϧ1 X B 2 H U W Z A Q P F G V A = = 2 211 I t e m
P r o p e r t i e s U C o m p O b j
y K 0 B Q S F W F 1 A = = 2 210ϧ1
F' Microsoft Office Word 97-2003 Document
MSWordDoc Word.Document.8 9q
I t e m
W P r o p e r t i e s 1 R E O U O A X P 3 D E F A = = 2 210ϧ1 I t e m
P r o p e r t i e s
This value indicates the number of saves or revisions. The application is responsible for updating this value after each revision.
DocumentLibraryFormDocumentLibraryFormDocumentLibraryForm
Oh +'0 0 < H
h t
FG < 02/10/05 Added legal statement
03/07/07 Added disclaimer ( Abbrev Review Template - 2011 10.dotx FG 8 Microsoft Office Word @ # @ RgG@ *