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Adverse reactions occurring in ≥1 % of patients undergoing hip or knee replacement surgery in
the 1 Phase II study and the 3 Phase III studies are listed in Table 4 .
Table 4 :
Adverse Reactions Occurring in ≥1 % of Patients in Either Group
Undergoing Hip or Knee Replacement Surgery
ELIQUIS ( apixaban ), n (%) 2.5 mg po bid
Enoxaparin , n (%) 40 mg sc qd or
30 mg sc q12h
N = 5924
N = 5904
Nausea
153 ( 2.6 )
159 ( 2.7 )
Anemia ( including postoperative and hemorrhagic
153 ( 2.6 )
178 ( 3.0 )
anemia , and respective laboratory parameters )
Contusion
83 ( 1.4 )
115 ( 1.9 )
Hemorrhage ( including hematoma , and vaginal
67 ( 1.1 )
81 ( 1.4 )
and urethral hemorrhage )
Postprocedural hemorrhage ( including
54 ( 0.9 )
60 ( 1.0 )
postprocedural hematoma , wound hemorrhage , vessel puncture site hematoma and catheter site hemorrhage )
Transaminases increased ( including alanine
50 ( 0.8 )
71 ( 1.2 )
aminotransferase increased and alanine aminotransferase abnormal )
Aspartate aminotransferase increased
47 ( 0.8 )
69 ( 1.2 )
Gamma-glutamyltransferase increased
38 ( 0.6 )
65 ( 1.1 )
Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1 % to < 1 %:
Blood and lymphatic system disorders : thrombocytopenia ( including platelet count decreases ) Vascular disorders : hypotension ( including procedural hypotension ) Respiratory , thoracic , and mediastinal disorders : epistaxis
Gastrointestinal disorders : gastrointestinal hemorrhage ( including hematemesis and melena ), hematochezia
Hepatobiliary disorders : liver function test abnormal , blood alkaline phosphatase increased , blood bilirubin increased
Renal and urinary disorders : hematuria ( including respective laboratory parameters )
Injury , poisoning , and procedural complications : wound secretion , incision-site hemorrhage ( including incision-site hematoma ), operative hemorrhage
Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of < 0.1 %:
Gingival bleeding , hemoptysis , hypersensitivity , muscle hemorrhage , ocular hemorrhage ( including conjunctival hemorrhage ), rectal hemorrhage
Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT or PE
The safety of ELIQUIS has been evaluated in the AMPLIFY and AMPLIFY-EXT studies , including 2676 patients exposed to ELIQUIS 10 mg twice daily , 3359 patients exposed to ELIQUIS 5 mg twice daily , and 840 patients exposed to ELIQUIS 2.5 mg twice daily .
Common adverse reactions ( ≥1 %) were gingival bleeding , epistaxis , contusion , hematuria , rectal hemorrhage , hematoma , menorrhagia , and hemoptysis .
AMPLIFY Study
The mean duration of exposure to ELIQUIS was 154 days and to enoxaparin / warfarin was 152 days in the AMPLIFY study . Adverse reactions related to bleeding occurred in 417 ( 15.6 %) ELIQUIS-treated patients compared to 661 ( 24.6 %) enoxaparin / warfarin-treated patients . The discontinuation rate due to bleeding events was 0.7 % in the ELIQUIS-treated patients compared to 1.7 % in enoxaparin / warfarin-treated patients in the AMPLIFY study .
In the AMPLIFY study , ELIQUIS was statistically superior to enoxaparin / warfarin in the primary safety endpoint of major bleeding ( relative risk 0.31 , 95 % CI [ 0.17 , 0.55 ], P-value < 0.0001 ).
Bleeding results from the AMPLIFY study are summarized in Table 5 . Table 5 :
Bleeding Results in the AMPLIFY Study
ELIQUIS N = 2676 n (%)
Enoxaparin / Warfarin N = 2689 n (%)
Relative Risk ( 95 % CI )
Major
15 ( 0.6 )
49 ( 1.8 )
0.31 ( 0.17 , 0.55 ) p < 0.0001
CRNM *
103 ( 3.9 )
215 ( 8.0 )
Major + CRNM
115 ( 4.3 )
261 ( 9.7 )
Minor
313 ( 11.7 )
505 ( 18.8 )
All
402 ( 15.0 )
676 ( 25.1 )
* CRNM = clinically relevant nonmajor bleeding .
Events associated with each endpoint were counted once per subject , but subjects may have
contributed events to multiple endpoints .
Adverse reactions occurring in ≥1 % of patients in the AMPLIFY study are listed in Table 6 .
Table 6 : Adverse Reactions Occurring in ≥1 % of Patients Treated for DVT and PE in the AMPLIFY Study
ELIQUIS N = 2676 n (%)
Enoxaparin / Warfarin N = 2689 n (%)
Epistaxis
77 ( 2.9 )
146 ( 5.4 )
Contusion
49 ( 1.8 )
97 ( 3.6 )
Hematuria
46 ( 1.7 )
102 ( 3.8 )
Menorrhagia
38 ( 1.4 )
30 ( 1.1 )
Hematoma
35 ( 1.3 )
76 ( 2.8 )
Hemoptysis
32 ( 1.2 )
31 ( 1.2 )
Rectal hemorrhage
26 ( 1.0 )
39 ( 1.5 )
Gingival bleeding
26 ( 1.0 )
50 ( 1.9 )
AMPLIFY-EXT Study
The mean duration of exposure to ELIQUIS was approximately 330 days and to placebo was 312 days in the AMPLIFY-EXT study . Adverse reactions related to bleeding occurred in 219 ( 13.3 %) ELIQUIS-treated patients compared to 72 ( 8.7 %) placebo-treated patients . The discontinuation rate due to bleeding events was approximately 1 % in the ELIQUIS-treated patients compared to 0.4 % in those patients in the placebo group in the AMPLIFY-EXT study .
Bleeding results from the AMPLIFY-EXT study are summarized in Table 7 .
Table 7 :
Bleeding Results in the AMPLIFY-EXT Study
ELIQUIS ( apixaban ) 2.5 mg bid N = 840 n (%)
ELIQUIS 5 mg bid N = 811 n (%)
Placebo
N = 826 n (%)
Major 2 ( 0.2 ) 1 ( 0.1 ) 4 ( 0.5 ) CRNM * 25 ( 3.0 ) 34 ( 4.2 ) 19 ( 2.3 ) Major + CRNM 27 ( 3.2 ) 35 ( 4.3 ) 22 ( 2.7 ) Minor 75 ( 8.9 ) 98 ( 12.1 ) 58 ( 7.0 ) All 94 ( 11.2 ) 121 ( 14.9 ) 74 ( 9.0 )
* CRNM = clinically relevant nonmajor bleeding . Events associated with each endpoint were counted once per subject , but subjects may have contributed events to multiple endpoints .
Adverse reactions occurring in ≥1 % of patients in the AMPLIFY-EXT study are listed in Table 8 .
Table 8 :
Adverse Reactions Occurring in ≥1 % of Patients Undergoing Extended
Treatment for DVT and PE in the AMPLIFY-EXT Study
ELIQUIS 2.5 mg bid N = 840 n (%)
ELIQUIS 5 mg bid N = 811 n (%)
Placebo
N = 826 n (%)
Epistaxis
13 ( 1.5 )
29 ( 3.6 )
9 ( 1.1 )
Hematuria
12 ( 1.4 )
17 ( 2.1 )
9 ( 1.1 )
Hematoma
13 ( 1.5 )
16 ( 2.0 )
10 ( 1.2 )
Contusion
18 ( 2.1 )
18 ( 2.2 )
18 ( 2.2 )
Gingival bleeding
12 ( 1.4 )
9 ( 1.1 )
3 ( 0.4 )
Other Adverse Reactions
Less common adverse reactions in ELIQUIS-treated patients in the AMPLIFY or AMPLIFY-EXT studies occurring at a frequency of ≥0.1 % to < 1 %:
Blood and lymphatic system disorders : hemorrhagic anemia
Gastrointestinal disorders : hematochezia , hemorrhoidal hemorrhage , gastrointestinal hemorrhage , hematemesis , melena , anal hemorrhage
Injury , poisoning , and procedural complications : wound hemorrhage , postprocedural hemorrhage , traumatic hematoma , periorbital hematoma
Musculoskeletal and connective tissue disorders : muscle hemorrhage
Reproductive system and breast disorders : vaginal hemorrhage , metrorrhagia , menometrorrhagia , genital hemorrhage
Vascular disorders : hemorrhage Skin and subcutaneous tissue disorders : ecchymosis , skin hemorrhage , petechiae Eye disorders : conjunctival hemorrhage , retinal hemorrhage , eye hemorrhage
Investigations : blood urine present , occult blood positive , occult blood , red blood cells urine positive
General disorders and administration-site conditions : injection-site hematoma , vessel puncture-site hematoma
DRUG INTERACTIONS
Apixaban is a substrate of both CYP3A4 and P-gp . Inhibitors of CYP3A4 and P-gp increase exposure to apixaban and increase the risk of bleeding . Inducers of CYP3A4 and P-gp decrease exposure to apixaban and increase the risk of stroke and other thromboembolic events .
Strong Dual Inhibitors of CYP3A4 and P-gp
For patients receiving ELIQUIS 5 mg or 10 mg twice daily , the dose of ELIQUIS should be decreased by 50 % when it is coadministered with drugs that are strong dual inhibitors of CYP3A4 and P-gp ( e . g ., ketoconazole , itraconazole , ritonavir , or clarithromycin ) [ see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
For patients receiving ELIQUIS at a dose of 2.5 mg twice daily , avoid coadministration with strong dual inhibitors of CYP3A4 and P-gp [ see Dosage and Administration ( 2.5 ) and Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Strong Dual Inducers of CYP3A4 and P-gp
Avoid concomitant use of ELIQUIS with strong dual inducers of CYP3A4 and P-gp ( e . g ., rifampin , carbamazepine , phenytoin , St . John ’ s wort ) because such drugs will decrease exposure to apixaban [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Anticoagulants and Antiplatelet Agents
Coadministration of antiplatelet agents , fibrinolytics , heparin , aspirin , and chronic NSAID use increases the risk of bleeding .
APPRAISE-2 , a placebo-controlled clinical trial of apixaban in high-risk , post-acute coronary syndrome patients treated with aspirin or the combination of aspirin and clopidogrel , was terminated early due to a higher rate of bleeding with apixaban compared to placebo . The rate of ISTH major bleeding was 2.8 % per year with apixaban versus 0.6 % per year with placebo in patients receiving single antiplatelet therapy and was 5.9 % per year with apixaban versus 2.5 % per year with placebo in those receiving dual antiplatelet therapy .
In ARISTOTLE , concomitant use of aspirin increased the bleeding risk on ELIQUIS from 1.8 % per year to 3.4 % per year and concomitant use of aspirin and warfarin increased the bleeding risk from 2.7 % per year to 4.6 % per year . In this clinical trial , there was limited ( 2.3 %) use of dual antiplatelet therapy with ELIQUIS .
USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B
There are no adequate and well-controlled studies of ELIQUIS in pregnant women . Treatment is likely to increase the risk of hemorrhage during pregnancy and delivery . ELIQUIS should be used during pregnancy only if the potential benefit outweighs the potential risk to the mother and fetus .
Treatment of pregnant rats , rabbits , and mice after implantation until the end of gestation resulted in fetal exposure to apixaban , but was not associated with increased risk for fetal malformations or toxicity . No maternal or fetal deaths were attributed to bleeding . Increased incidence of maternal bleeding was observed in mice , rats , and rabbits at maternal exposures that were 19 , 4 , and 1 times , respectively , the human exposure of unbound drug , based on area under plasma-concentration time curve ( AUC ) comparisons at the maximum recommended human dose ( MRHD ) of 10 mg ( 5 mg twice daily ).
Labor and Delivery
Safety and effectiveness of ELIQUIS during labor and delivery have not been studied in clinical trials . Consider the risks of bleeding and of stroke in using ELIQUIS in this setting [ see Warnings and Precautions ].
Treatment of pregnant rats from implantation ( gestation Day 7 ) to weaning ( lactation Day 21 ) with apixaban at a dose of 1000 mg / kg ( about 5 times the human exposure based on unbound apixaban ) did not result in death of offspring or death of mother rats during labor in association with uterine bleeding . However , increased incidence of maternal bleeding , primarily during gestation , occurred at apixaban doses of ≥25 mg / kg , a dose corresponding to ≥1.3 times the human exposure .
Nursing Mothers
It is unknown whether apixaban or its metabolites are excreted in human milk . Rats excrete apixaban in milk ( 12 % of the maternal dose ).
Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS ( apixaban ) therapy , taking into account the importance of the drug to the mother .
Pediatric Use Safety and effectiveness in pediatric patients have not been established . Geriatric Use
Of the total subjects in the ARISTOTLE and AVERROES clinical studies , > 69 % were 65 and older , and > 31 % were 75 and older . In the ADVANCE-1 , ADVANCE-2 , and ADVANCE-3 clinical studies , 50 % of subjects were 65 and older , while 16 % were 75 and older . In the AMPLIFY and AMPLIFY-EXT clinical studies , > 32 % of subjects were 65 and older and > 13 % were 75 and older . No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups .
Renal Impairment
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation
The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics [ see Dosage and Administration ( 2.1 ) in full Prescribing Information ]:
• age ≥80 years
• body weight ≤60 kg
• serum creatinine ≥1.5 mg / dL Patients with End-Stage Renal Disease on Dialysis
Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease ( ESRD ) on dialysis . In patients with ESRD maintained on intermittent hemodialysis , administration of ELIQUIS at the usually recommended dose [ see Dosage and Administration ( 2.1 ) in full Prescribing Information ] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ARISTOTLE .
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery , and Treatment of DVT and PE and Reduction in the Risk of Recurrence of DVT and PE
No dose adjustment is recommended for patients with renal impairment , including those with ESRD on dialysis [ see Dosage and Administration ( 2.1 ) in full Prescribing Information ].
Clinical efficacy and safety studies with ELIQUIS did not enroll patients with ESRD on dialysis or patients with a CrCl < 15 mL / min ; therefore , dosing recommendations are based on pharmacokinetic and pharmacodynamic ( anti-FXa activity ) data in subjects with ESRD maintained on dialysis [ see Clinical Pharmacology ( 12.3 ) in full Prescribing Information ].
Hepatic Impairment
No dose adjustment is required in patients with mild hepatic impairment ( Child-Pugh class A ). Because patients with moderate hepatic impairment ( Child-Pugh class B ) may have intrinsic coagulation abnormalities and there is limited clinical experience with ELIQUIS in these patients , dosing recommendations cannot be provided [ see Clinical Pharmacology ( 12.2 ) in full Prescribing Information ]. ELIQUIS is not recommended in patients with severe hepatic impairment ( Child-Pugh class C )[ see Clinical Pharmacology ( 12.2 ) in full Prescribing Information ].
OVERDOSAGE
There is no antidote to ELIQUIS . Overdose of ELIQUIS increases the risk of bleeding [ see Warnings and Precautions ].
In controlled clinical trials , orally administered apixaban in healthy subjects at doses up to 50 mg daily for 3 to 7 days ( 25 mg twice daily for 7 days or 50 mg once daily for 3 days ) had no clinically relevant adverse effects .
In healthy subjects , administration of activated charcoal 2 and 6 hours after ingestion of a 20-mg dose of apixaban reduced mean apixaban AUC by 50 % and 27 %, respectively . Thus , administration of activated charcoal may be useful in the management of apixaban overdose or accidental ingestion .
PATIENT COUNSELING INFORMATION Advise patients to read the FDA-approved patient labeling ( Medication Guide ). Advise patients of the following :
• Not to discontinue ELIQUIS without talking to their physician first .
• That it might take longer than usual for bleeding to stop , and they may bruise or bleed more easily when treated with ELIQUIS . Advise patients about how to recognize bleeding or symptoms of hypovolemia and of the urgent need to report any unusual bleeding to their physician .
• To tell their physicians and dentists they are taking ELIQUIS , and / or any other product known to affect bleeding ( including nonprescription products , such as aspirin or NSAIDs ), before any surgery or medical or dental procedure is scheduled and before any new drug is taken .
• If the patient is having neuraxial anesthesia or spinal puncture , inform the patient to watch for signs and symptoms of spinal or epidural hematomas [ see Warnings and Precautions ]. If any of these symptoms occur , advise the patient to seek emergent medical attention .
• To tell their physicians if they are pregnant or plan to become pregnant or are breastfeeding or intend to breastfeed during treatment with ELIQUIS [ see Use in Specific Populations ].
• How to take ELIQUIS if they cannot swallow , or require a nasogastric tube [ see Dosage and Administration ( 2.6 ) in full Prescribing Information ].
• What to do if a dose is missed [ see Dosage and Administration ( 2.2 ) in full Prescribing Information ].
Marketed by : Bristol-Myers Squibb Company Princeton , New Jersey 08543 USA and Pfizer Inc New York , New York 10017 USA
1356615A2 / 1356514A1 Rev July 2016 432US1603587-13-01
Adverse reactions occurring in ≥1% of patients undergoing hip or knee replacement surgery in the 1 Phase II study and the 3 Phase III studies are listed in Table 4. Table 4: Table 7: Bleeding Results in the AMPLIFY-EXT Study ELIQUIS (apixaban) 2.5 mg bid N=840 n (%) Adverse Reactions Occurring in ≥1% of Patients in Either Group Undergoing Hip or Knee Replacement Surgery ELIQUIS (apixaban), Enoxaparin, n (%) n (%) 2.5 mg po bid 40 mg sc qd or 30 mg sc q12h N=5924 N=5904 Nursing Mothers ELIQUIS 5 mg bid N=811 n (%) Placebo N=826 n (%) 2 (0.2) 1 (0.1) 4 (0.5) CRNM* 25 (3.0) 34 (4.2) 19 (2.3) Major + CRNM 27 (3.2) 35 (4.3) 22 (2.7) Geriatric Use Of the total subjects in the ARISTOTLE and AVERROES clinical studies, >69% were 65 and older, and >31% were 75 and older. In the ADVANCE-1, ADVANCE-2, and ADVANCE-3 clinical studies, 50% of subjects were 65 and older, while 16% were 75 and older. In the AMPLIFY and AMPLIFY-EXT clinical studies, >32% of subjects were 65 and older and >13% were 75 and older. No clinically significant differences in safety or effectiveness were observed when comparing subjects in different age groups. 153 (2.6) 159 (2.7) Minor 75 (8.9) 98 (12.1) 58 (7.0) Anemia (including postoperative and hemorrhagic anemia, and respective laboratory parameters) 153 (2.6) 178 (3.0) All 94 (11.2) 121 (14.9) 74 (9.0) Contusion 83 (1.4) 115 (1.9) Hemorrhage (including hematoma, and vaginal and urethral hemorrhage) 67 (1.1) 81 (1.4) * CRNM = clinically relevant nonmajor bleeding. Events associated with each endpoint were counted once per subject, but subjects may have contributed events to multiple endpoints. Postprocedural hemorrhage (including postprocedural hematoma, wound hemorrhage, vessel puncture site hematoma and catheter site hemorrhage) 54 (0.9) 60 (1.0) Adverse reactions occurring in ≥1% of patients in the AMPLIFY-EXT study are listed in Table 8. Transaminases increased (including alanine aminotransferase increased and alanine aminotransferase abnormal) 50 (0.8) Aspartate aminotransferase increased 47 (0.8) 69 (1.2) Gamma-glutamyltransferase increased 38 (0.6) 65 (1.1) Table 8: Adverse Reactions Occurring in ≥1% of Patients Undergoing Extended Treatment for DVT and PE in the AMPLIFY-EXT Study ELIQUIS 2.5 mg bid N=840 n (%) ELIQUIS 5 mg bid N=811 n (%) Placebo Epistaxis 13 (1.5) 29 (3.6) 9 (1.1) Hematuria 12 (1.4) 17 (2.1) 9 (1.1) Hematoma 13 (1.5) 16 (2.0) 10 (1.2) Contusion 18 (2.1) 18 (2.2) 18 (2.2) Gingival bleeding 12 (1.4) 9 (1.1) 3 (0.4) 71 (1.2) Blood and lymphatic system disorders: thrombocytopenia (including platelet count decreases) Vascular disorders: hypotension (including procedural hypotension) Respiratory, thoracic, and mediastinal disorders: epistaxis Gastrointestinal disorders: gastrointestinal hemorrhage (including hematemesis and melena), hematochezia Women should be instructed either to discontinue breastfeeding or to discontinue ELIQUIS (apixaban) therapy, taking into account the importance of the drug to the mother. Major Nausea Less common adverse reactions in apixaban-treated patients undergoing hip or knee replacement surgery occurring at a frequency of ≥0.1% to <1%: It is unknown whether apixaban or its metabolites are excreted in human milk. Rats excrete apixaban in milk (12% of the maternal dose). N=826 n (%) Pediatric Use Safety and effectiveness in pediatric patients have not been established. Renal Impairment Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular Atrial Fibrillation The recommended dose is 2.5 mg twice daily in patients with at least two of the following characteristics [see Dosage and Administration (2.1) in full Prescribing Information]: • age ≥80 years • body weight ≤60 kg • serum creatinine ≥1.5 mg/dL Patients with End-Stage Renal Disease on Dialysis Other Adverse Reactions Clinical efficacy and safety studies with ELIQUIS did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of ELIQUIS at the usually recommended dose [see Dosage and Administration (2.1) in full Prescribing Information] will result in concentrations of apixaban and pharmacodynamic activity similar to those observed in the ARISTOTLE study [see Clinical Pharmacology (1 "2gV&W67&&rf&FB2BvvWFW"FW6R66VG&F0vVBF6֖"7G&R&VGV7FB&VVFr&6FVG2vFU5$BFǗ622v06VV$5DDRࠤW726GfW'6R&V7F2TĕT2G&VFVBFVG2FRĔe"ĔeU@7GVFW267W'&rBg&WVV7b(SRFS&2bFVWfVF&&62fvr"VR&W6VVB7W&vW'@G&VFVBbEeBBRB&VGV7FFR&6b&V7W'&V6RbEeBBP&BBǖF277FVF6&FW'3V'&v2V֖F6RFW7FVB2&V6VFVBf"FVG2vF&V&VB6VFrF6RvFU5$BFǗ626VRF6vRBF֖7G&F"gV&W67&&rf&FࠤWF&Ɩ'F6&FW'3ƗfW"gV7FFW7B&&&BƶƖR7F6R7&V6VB&B&Ɨ'V&7&V6V@v7G&FW7FF6&FW'3VF6WV'&FV'&vRv7G&FW7FV'&vRVFVW62VVV'&vP&VBW&'F6&FW'3VGW&6VFr&W7V7FfR&&F'&WFW'2W'6rB&6VGW&6Ɩ6F3vVBV'&vR7G&6VGW&V'&vRG&VF2VFW&&&FVF6Ɩ6Vff67B6fWG7GVFW2vFTĕT2FBBV&FVG2vFU5$BFǗ60"FVG2vF7$6R֖FW&Vf&RF6r&V6VFF2&R&6VB&6WF2B&6G֖2Fe7FfGFF7V&V7G2vFU5$@FVBFǗ626VR6Ɩ6&6w"2gV&W67&&rf&FࠤW67V6VWFB6V7FfRF77VRF6&FW'3W66RV'&vPWF2&V@W'6rB&6VGW&6Ɩ6F3vVB6V7&WF666FRV'&vP6VFr666FRVFW&FfRV'&vP6B7V&7WFVW2F77VRF6&FW'3V66626V'&vRWFV6PF6RFW7FVB2&WV&VBFVG2vF֖BWF2&VB6BVv670&V6W6RFVG2vFFW&FRWF2&VB6BVv672"fPG&626wVF&&ƗFW2BFW&R2Ɩ֗FVB6Ɩ6WW&V6RvFTĕT2FW6PFVG2F6r&V6VFF26B&R&fFVB6VR6Ɩ6&6w""gV&W67&&rf&FTĕT22B&V6VFVBFVG2vF6WfW&RWF0&VB6BVv67226VR6Ɩ6&6w""gV&W67&&rf&FࠥG&VFVBbEeBBRB&VGV7FFR&6b&V7W'&V6RbEeB"PWRF6&FW'36V7FfV'&vR&WFV'&vRWRV'&vPdU$D4tPFR6fWGbTĕT22&VVWfVFVBFRĔeBĔeUB7GVFW26VFp#csbFVG2W6VBFTĕT2rGv6RFǒ33SFVG2W6VBFTĕT2RpGv6RFǒBCFVG2W6VBFTĕT2"RrGv6RFǒࠤfW7FvF3&BW&R&W6VB67VB&B6FfR67VB&B&VB&B6V2W&P6FfPFW&R2FFFRFTĕT2fW&F6RbTĕT27&V6W2FR&6b&VVFr6VRv&w0B&V6WF5ࠤvVW&F6&FW'2BF֖7G&F6FR6FF3V7F6FRVFfW76VV7GW&R6FRVF6G&VB6Ɩ6G&2&ǒF֖7FW&VB&VF7V&V7G2BF6W2WFSrFǒf"2FrF2#RrGv6RFǒf"rF2"Sr6RFǒf"2F2@6Ɩ6ǒ&VWfBGfW'6RVffV7G2ࠤW726GfW'6R&V7F2&G&VFVBFVG2VFW&vr"VP&W6VVB7W&vW'67W'&rBg&WVV7bSvvf&VVFrVG62W'6V6FfGW66RV'&vR7V"V'&vP6VFr6V7FfV'&vR&V7FV'&vP#R#^( РCN( Р3.( Р6GfW'6R&V7F2(SRvW&Rvvf&VVFrW7F26GW6VGW&&V7FV'&vRVFV'&vBVG62Ĕe7GVGFRVGW&FbW7W&RFTĕT2v2SBF2BFV&v&f&v0S"F2FRĔe7GVGGfW'6R&V7F2&VFVBF&VVFr67W'&VBCrRbRTĕT2G&VFVBFVG26&VBFcc#BbRV&v&f&G&VFVBFVG2FRF66FVF&FRGVRF&VVFrWfVG2v2rRFRTĕT2G&VFVBFVG06&VBFrRV&v&f&G&VFVBFVG2FRĔe7GVGखFRĔe7GVGTĕT2v27FF7F6ǒ7WW&"FV&v&f&FR&'6fWGVGBb"&VVFr&VFfR&63RR4rSUfVR&VVFr&W7VG2g&FRĔe7GVG&R7V&VBF&RRࠥF&RS&VVFr&W7VG2FRĔe7GVGV&v&f&#cR&VFfR&6RR4 RbCゐ3rSR5$Ҡ22㒐#RRB2#cr֖ 32rSRゐC"Rcsb#RF6&FW'3fvV'&vRWG&'&vf67V"F6&FW'3V'&vPE%TrDU$5D0&27V'7G&FRb&F54BBw憖&F'2b54BBw7&V6PW7W&RF&B7&V6RFR&6b&VVFrGV6W'2b54BBwFV7&V6PW7W&RF&B7&V6RFR&6b7G&RBFW"F&&V&Ɩ2WfVG2ࠤVF7V&V7G2F֖7G&Fb7FfFVB6&6"BbW'2gFW"vW7F`#rF6Rb&&VGV6VBV&T2'SRB#rR&W7V7FfVǒFW2F֖7G&Fb7FfFVB6&6&RW6VgVFRvVVBb&fW&F6R"66FVFvW7Fࠥ7G&rGV憖&F'2b54BBwDTB4T4TĔrd$Dࠤf"FVG2&V6VfrTĕT2Rr"rGv6RFǒFRF6RbTĕT26VB&PFV7&V6VB'SRvVB26F֖7FW&VBvFG'Vw2FB&R7G&rGV憖&F'2`54BBwRrWF6RG&6R&Ff""6&F&ז66VRF6vR@F֖7G&F"RB6Ɩ6&6w"2gV&W67&&rf&FࠤGf6RFVG2F&VBFRdD&fVBFVB&VƖrVF6FwVFRࠤf"FVG2&V6VfrTĕT2BF6Rb"RrGv6RFǒfB6F֖7G&FvF7G&rGV憖&F