ASH Clinical News ACN_4.5_FULL_ISSUE_DIGITAL - Page 24

BOSULIF ® ( bosutinib ) tablets for oral use
Initial U . S . Approval : 2012 Brief Summary of Prescribing Information
INDICATIONS AND USAGE BOSULIF ® ( bosutinib ) is indicated for the treatment of adult patients with newly diagnosed chronic phase ( CP ) Philadelphia chromosome – positive chronic myelogenous leukemia ( Ph + CML ). This indication is approved under accelerated approval based on molecular and cytogenetic response rates . Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow-up trial . BOSULIF is also indicated for the treatment of adult patients with CP , accelerated phase ( AP ), or blast phase ( BP ) Ph + CML with resistance or intolerance to prior therapy .
CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF . Reactions have included anaphylaxis . In the BOSULIF single-agent cancer studies , anaphylactic shock occurred in less than 0.2 % of treated patients .
WARNINGS AND PRECAUTIONS Gastrointestinal Toxicity : Diarrhea , nausea , vomiting , and abdominal pain occur with BOSULIF treatment . Monitor and manage patients using standards of care , including antidiarrheals , antiemetics , and fluid replacement . In the randomized clinical trial in patients with newly diagnosed Ph + CML , the median time to onset for diarrhea ( all grades ) was 3 days and the median duration per event was 3 days . Among 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy , the median time to onset for diarrhea ( all grades ) was 2 days and the median duration per event was 2 days . Among the patients who experienced diarrhea , the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 ( range 1-268 ). To manage gastrointestinal toxicity , withhold , dose reduce , or discontinue BOSULIF as necessary .
Myelosuppression : Thrombocytopenia , anemia , and neutropenia occur with BOSULIF treatment . Perform complete blood counts weekly for the first month of therapy and then monthly thereafter , or as clinically indicated . To manage myelosuppression , withhold , dose reduce , or discontinue BOSULIF as necessary .
Hepatic Toxicity : BOSULIF may cause elevations in serum transaminases ( alanine aminotransferase [ ALT ], aspartate aminotransferase [ AST ]). One case consistent with drug-induced liver injury ( defined as concurrent elevations in ALT or AST ≥3 x the upper limit of normal ( ULN ) with total bilirubin > 2 x ULN and alkaline phosphatase < 2 x ULN ) occurred without alternative causes in a breast cancer ( a disease for which BOSULIF is not indicated ) trial of BOSULIF in combination with letrozole . The patient recovered fully following discontinuation of BOSULIF . This case represented 1 out of 1611 patients in BOSULIF clinical trials . In the 268 patients from the safety population in the randomized clinical trial in patients with newly diagnosed CML in the BOSULIF treatment group , the incidence of ALT elevation was 31 % and AST elevation was 23 %. Of patients who experienced transaminase elevations of any grade , 79 % experienced their first event within the first 3 months . The median time to onset of increased ALT and AST was 32 and 43 days , respectively , and the median duration was 20 and 15 days , respectively . Among the 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy , the incidence of ALT elevation was 18 % and AST elevation was 15 %. Twenty percent of the patients experienced an increase in either ALT or AST . Most cases of transaminase elevations in this study occurred early in treatment ; of patients who experienced transaminase elevations of any grade , more than 80 % experienced their first event within the first 3 months . The median time to onset of increased ALT and AST was 35 and 33 days , respectively , and the median duration for each was 21 days . Perform hepatic enzyme tests monthly for the first 3 months of BOSULIF treatment and as clinically indicated . In patients with transaminase elevations , monitor liver enzymes more frequently . Withhold , dose reduce , or discontinue BOSULIF as necessary .
Fluid Retention : Fluid retention occurs with BOSULIF and may manifest as pericardial effusion , pleural effusion , pulmonary edema , and / or peripheral edema . In the randomized clinical trial of 268 patients with newly diagnosed CML in the BOSULIF treatment group , 1 patient ( 0.4 %) experienced severe fluid retention of Grade 3 pericardial effusion . Among 546 patients in a single-arm study in patients with Ph + CML who were resistant or intolerant to prior therapy , Grade 3 or 4 fluid retention was reported in 26 patients ( 5 %). Some patients experienced more than one fluid retention event . Specifically , 21 patients experienced Grade 3 or 4 pleural effusions , 7 patients experienced Grade 3 or Grade 4 pericardial effusions , and 6 patients experienced Grade 3 edema . Monitor and manage patients using standards of care . Interrupt , dose reduce , or discontinue BOSULIF as necessary .
Renal Toxicity : An on-treatment decline in estimated glomerular filtration rate ( eGFR ) has occurred in patients treated with BOSULIF . The following table identifies the shift from baseline to lowest observed eGFR during BOSULIF therapy for patients in the pooled leukemia studies regardless of line of therapy . The median duration of therapy with BOSULIF was approximately 14 months ( range , 0.03 to 123 ) for patients in these studies .
Shift from Baseline to Lowest Observed eGFR Group During Treatment Safety Population in Clinical Studies ( N = 1272 )*
Baseline
Follow-Up
Renal Function Status
N
Normal n (%)
Mild n (%)
Mild to Moderate n (%)
Moderate to Severe n (%)
Severe n (%)
Kidney Failure n (%)
Normal
468
102 ( 21.8 )
298 ( 63.7 )
46 ( 9.8 )
16 ( 3.4 )
2 ( 0.4 )
2 ( 0.4 )
Mild
639
11 ( 1.7 )
266 ( 41.6 )
250 ( 39.1 )
83 ( 13.0 )
21 ( 3.3 )
3 ( 0.5 )
Mild to Moderate
128
0
8 ( 6.3 )
45 ( 35.2 )
57 ( 44.5 )
18 ( 14.1 )
0
Moderate to Severe
32
0
1 ( 3.1 )
1 ( 3.1 )
9 ( 28.1 )
17 ( 53.1 )
3 ( 9.4 )
Severe
1
0
0
0
0
0
1 ( 100 )
Total
1268
113 ( 8.9 )
573 ( 45.2 )
342 ( 27.0 )
165 ( 13.0 )
58 ( 4.6 )
9 ( 0.7 )
Notes : Grading is based on Modification in Diet in Renal Disease method ( MDRD ). Kidney Disease : Improving Global Outcomes ( KDIGO ) Classification by eGFR : Normal : greater than or equal to 90 , Mild : 60 to less than 90 , Mild to Moderate : 45 to less than 60 , Moderate to Severe : 30 to less than 45 , Severe : 15 to less than 30 , Kidney Failure : less than 15 mL / min / 1.73 m 2 .
* Among the 1272 patients , eGFR was missing in 9 patients at baseline or on-therapy . There were no patients with kidney failure at baseline .
Monitor renal function at baseline and during therapy with BOSULIF , with particular attention to those patients who have preexisting renal impairment or risk factors for renal dysfunction . Consider dose adjustment in patients with baseline and treatment-emergent renal impairment .
Embryofetal Toxicity : Based on findings from animal studies and its mechanism of action , BOSULIF can cause fetal harm when administered to a pregnant woman . In animal reproduction studies conducted in rats and rabbits , oral administration of bosutinib caused adverse developmental outcomes . Administration of bosutinib to rats prior to fertilization until gestation day ( GD ) 7 caused increased embryonic resorptions at maternal exposures ( AUC ) approximately 0.5 and 0.4 times the human exposure at the recommended doses of 400 and 500 mg / day , respectively , and decreased implantations and reduced number of viable embryos at maternal exposures approximately 1.8 and 1.3 times the human exposure at the recommended doses of 400 or 500 mg / day , respectively . Administration of bosutinib to pregnant rabbits during organogenesis caused fetal anomalies ( fused sternebrae , and 2 fetuses had various visceral observations ), and an approximate 6 % decrease in fetal body weight at maternal exposures ( AUC ) approximately 2.3 and 1.7 times the human exposure at the recommended doses of 400 and 500 mg / day , respectively . Advise pregnant women of the potential risk to a fetus . Advise females of reproductive potential to use effective contraception during treatment and for at least 1 month after the last dose .
ADVERSE REACTIONS Clinical Trials Experience : Because clinical trials are conducted under widely varying conditions , adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice . Serious adverse reactions reported include anaphylactic shock , myelosuppression , gastrointestinal toxicity ( diarrhea ), fluid retention , hepatotoxicity , and rash .
Adverse Reactions in Patients with Newly Diagnosed CP CML : The clinical trial randomized and treated 533 patients with newly diagnosed CP CML to receive BOSULIF 400 mg daily or imatinib 400 mg daily as single agents ( Newly Diagnosed CP CML Study ). The safety population ( received at least 1 dose of BOSULIF ) included 268 patients with newly diagnosed CP CML that had a median duration of BOSULIF treatment of 14.1 months ( range : 0.3 to 24.7 months ) and a median dose intensity of 391.8 mg / day . Adverse reactions reported for ≥20 % of BOSULIF patients with newly diagnosed CML ( N = 268 ) were diarrhea ( 70 %), nausea ( 35 %), thrombocytopenia ( 35 %), rash ( 34 %), increased ALT ( 31 %), abdominal pain ( 25 %), and increased AST ( 23 %).
Adverse reactions with ≥10 % incidence in patients with newly diagnosed CML who received BOSULIF 400 mg ( N = 268 ) vs imatinib 400 mg ( N = 265 ) ( BOSULIF all grades [%]/ Grade 3-4 [%] vs imatinib ) were diarrhea ( 70 / 8 vs 34 /< 1 ); nausea ( 35 / 0 vs 38 / 0 ); thrombocytopenia a ( 35 / 14 vs 20 / 6 ); rash b ( 34 / 1 vs 21 / 2 ); ALT increased ( 31 / 19 vs 6 / 2 ); abdominal pain c ( 25 / 2 vs 15 /< 1 ); AST increased ( 23 / 10 vs 6 / 2 ); anemia d ( 19 / 3 vs 19 / 5 ); headache ( 19 / 1 vs 13 / 1 ); fatigue e ( 19 /< 1 vs 19 / 0 ); vomiting ( 18 / 1 vs 16 / 0 ); lipase increased f ( 13 / 10 vs 8 / 5 ); pyrexia ( 13 /< 1 vs 8 / 0 ); respiratory tract infection g ( 12 /< 1 vs 12 /< 1 ); neutropenia h ( 11 / 7 vs 21 / 12 ); arthralgia ( 11 /< 1 vs 13 / 0 ); asthenia ( 11 / 0 vs 6 / 0 ); appetite decreased ( 10 /< 1 vs 6 / 0 ).
In the randomized study in patients with newly diagnosed CP CML , one patient in the group treated with BOSULIF experienced a Grade 3 QTc prolongation (> 500 msec ). Patients with uncontrolled or significant cardiovascular disease including QT interval prolongation were excluded by protocol .
Clinically Relevant or Grade 3 / 4 Laboratory Test Abnormalities ( n /%) in Patients with Newly Diagnosed CML Administered BOSULIF 400 mg ( N = 268 ) vs Imatinib 400 mg ( N = 265 ), Safety Population : Hematology parameters were platelet count ( low ) less than 50 x 10 9 / L ( 38 / 14.2 vs 17 / 6.4 ); absolute neutrophil count less than 1 x 10 9 / L ( 24 / 9.0 vs 49 / 18.5 ); hemoglobin ( low ) less than 80 g / L ( 19 / 7.1 vs 15 / 5.7 ); white blood cell count ( low ) less than 2 x 10 9 / L ( 15 / 5.6 vs 20 / 7.5 ). Biochemistry parameters were serum glutamic-pyruvic transaminase ( SGPT )/ ALT greater than 5.0 x ULN ( 62 / 23.1 vs 7 / 2.6 ); serum glutamic-oxaloacetic transaminase ( SGOT )/ AST greater than 5.0 x ULN ( 32 / 11.9 vs 8 / 3.0 ); lipase greater than 2 x ULN ( 35 / 13.1 vs 16 / 6.0 ); phosphorus ( low ) less than 0.6 mmol / L ( 12 / 4.5 vs 45 / 17.0 ); total bilirubin greater than 3.0 x ULN ( 3 / 1.1 vs 2 / 0.8 ); amylase greater than 2 x ULN ( 6 / 2.2 vs 4 / 1.5 ); creatinine greater than 3.0 x baseline ; greater than 3.0 x ULN ( 0 vs 2 / 0.8 ).
Adverse Reactions in Patients with Imatinib-Resistant or -Intolerant Ph + CP , AP , and BP CML : The single-arm clinical trial enrolled patients with Ph + CP , AP , or BP CML and with resistance or intolerance to prior therapy . The safety population ( received at least 1 dose of BOSULIF ) included 546 CML patients : 284 patients with CP CML previously treated with imatinib only who had a median duration of BOSULIF treatment of 26 months and a median dose intensity of 442 mg / day ; 119 patients with CP CML previously treated with both imatinib and at least 1 additional TKI who had a median duration of BOSULIF treatment of 9 months and a median dose intensity of 442 mg / day ; and 143 patients with advanced phase ( AdvP ) CML , including 79 patients with AP CML and 64 patients with BP CML . In the patients with AP CML and BP CML , the median duration of BOSULIF treatment was 10 months and 3 months , respectively . The median dose intensity was 425 mg / day and 456 mg / day in the AP CML and BP CML cohorts , respectively . Adverse reactions of any toxicity grade reported for greater than or equal to 20 % of patients in the safety population of the single-arm trial in patients with CP CML ( N = 546 ) who were resistant or intolerant to prior therapy were diarrhea ( 85 %), nausea ( 47 %), abdominal pain ( 42 %), rash ( 42 %), thrombocytopenia ( 40 %), vomiting ( 37 %), anemia ( 27 %), fatigue ( 26 %), pyrexia ( 23 %), cough ( 22 %), headache ( 21 %), ALT increased ( 20 %), and edema ( 20 %).
Adverse reactions ( all grades [%]/ Grade 3 / 4 [%]) with ≥10 % incidence in patients with CP CML who were resistant or intolerant to prior therapy in the single-arm trial ( N = 403 ) based on a minimum of 48 months of follow-up were diarrhea ( 85 / 9 ), nausea ( 47 / 1 ), abdominal pain c ( 42 / 2 ), rash b ( 42 / 9 ), thrombocytopenia a ( 40 / 26 ), vomiting ( 37 / 3 ), anemia d ( 27 / 11 ), fatigue e ( 26 / 2 ), pyrexia ( 23 /< 1 ), cough ( 22 / 0 ), headache ( 21 /< 1 ), ALT increased ( 20 / 8 ), neutropenia h ( 18 / 12 ), arthralgia ( 17 /< 1 ), AST increased ( 16 / 3 ), edema i ( 20 / 1 ), respiratory tract infection g ( 15 /< 1 ), decreased appetite ( 14 /< 1 ), back pain ( 13 /< 1 ), nasopharyngitis ( 13 / 0 ), asthenia ( 13 / 2 ), pleural effusion ( 12 / 4 ), dyspnea ( 12 / 2 ), pruritus ( 12 /< 1 ), dizziness ( 11 / 0 ), leukopenia j ( 10 / 4 ), blood creatinine increased ( 10 /< 1 ), influenza ( 10 /< 1 ), chest pain k ( 7 / 1 ).
Adverse reactions ( all grades [%]/ Grade 3 / 4 [%]) with ≥10 % incidence in patients with AdvP CML who were resistant or intolerant to prior therapy in the single-arm trial ( N = 143 ) based on a minimum of 48 months of follow-up were diarrhea ( 76 / 4 ), nausea ( 48 / 2 ), abdominal pain c ( 31 / 6 ), rash b ( 38 / 5 ), thrombocytopenia a ( 45 / 39 ), vomiting ( 43 / 3 ), anemia d ( 38 / 27 ), fatigue e ( 21 / 5 ), pyrexia ( 37 / 2 ), cough ( 22 / 0 ), headache ( 17 / 4 ), ALT increased ( 10 / 5 ), neutropenia h ( 22 / 20 ), arthralgia ( 14 / 0 ), AST increased ( 11 / 3 ), edema i ( 17 / 2 ), respiratory tract infection g ( 10 / 0 ), decreased appetite ( 13 / 0 ), back pain ( 8 / 1 ), nasopharyngitis ( 6 / 0 ), asthenia ( 10 /< 1 ), pleural effusion ( 9 / 4 ), dyspnea ( 20 / 6 ), pruritus ( 7 / 0 ), dizziness ( 13 /< 1 ), leukopenia j ( 15 / 12 ), blood creatinine increased ( 6 /< 1 ), influenza ( 3 / 0 ), chest pain k ( 12 / 1 ).
BOSULIF ® (bosutinib) tablets for oral use Initial U.S. Approval: 2012 Brief Summary of Prescribing Information INDICATIONS AND USAGE BOSULIF® (bosutinib) is indicated for the treatment of adult patients with newly diagnosed chronic phase (CP) Philadelphia chromosome–positive chronic myelogenous leukemia (Ph+ CML). This indication is approved under accelerated approval based on molecular and cytogenetic response rates. Continued approval for this indication may be contingent upon verification and confirmation of clinical benefit in an ongoing long-term follow-up trial. BOSULIF is also indicated for the treatment of adult patients with CP, accelerated phase (AP), or blast phase (BP) Ph+ CML with resistance or intolerance to prior therapy. CONTRAINDICATIONS BOSULIF is contraindicated in patients with a history of hypersensitivity to BOSULIF. Reactions have included anaphylaxis. In the BOSULIF single-agent cancer studies, anaphylactic shock occurred in less than 0.2% of treated patients. WARNINGS AND PRECAUTIONS Gastrointestinal Toxicity: Diarrhea, nausea, vomiting, and abdominal pain occur with BOSULIF treatment. Monitor and manage patients using standards of care, including antidiarrheals, antiemetics, and fluid replacement. In the randomized clinical trial in patients with newly diagnosed Ph+ CML, the median time to onset for diarrhea (all grades) was 3 days and the median duration per event was 3 days. Among 546 patients in a single-arm study in patients with CML who were resistant or intolerant to prior therapy, the median time to onset for diarrhea (all grades) was 2 days and the median duration per event was 2 days. Among the patients who experienced diarrhea, the median number of episodes of diarrhea per patient during treatment with BOSULIF was 3 (range 1-268). To manage gastrointestinal toxicity, withhold, dose reduce, or discontinue BOSULIF as necessary. Myelosuppression: Thrombocytopenia, anemia, and neutropenia occur with BOSULIF treatment. Perform complete blood counts weekly for the first month of therapy and then monthly thereafter, or as clinically indicated. To manage myelosuppression, withhold, dose reduce, or discontinue BOSULIF as necessary. Hepatic Toxicity: BOSULIF may cause elevations in serum transaminases (alanine aminotransferase [ALT], aspartate aminotransferase [AST]). One case consistent with drug-induced liver injury (defined as concurrent elevations in ALT or AST ≥3 x the upper limit of normal (ULN) with total bilirubin >2 x ULN and alkaline phosphatase <2 x ULN) occurred without alternative causes in a breast cancer (a disease for which BOSULIF is not indicated) trial of BOSULIF in combination with letrozole. The patient recovered fully following discontinuation of BOSULIF. This case represented 1 out of 1611 patients in BOSULIF clinical G&2FR#cFVG2g&FR6fWGVFFR&F֗VB6Ɩ6G&FVG2vFWvǒFv6VB4FR$5TĔbG&VFVBw&WFR6FV6RbBVWfFv03RB5BVWfFv2#2RbFVG2vWW&V6VBG&6֖6RVWfF2bw&FRsRWW&V6VBFV"f'7BWfVBvFFRf'7B2F2FRVFFRF6WBb7&V6VB@B5Bv23"BC2F2&W7V7FfVǒBFRVFGW&Fv2#BRF2&W7V7FfVǒrFRSCbFVG26vR&7GVGFVG2vF4vvW&R&W67FB"FW&@F&"FW&FR6FV6RbBVWfFv2RB5BVWfFv2RRGvVGW&6VB`FRFVG2WW&V6VB7&V6RVFW"B"5B7B66W2bG&6֖6RVWfF2F07GVG67W'&VBV&ǒG&VFVCbFVG2vWW&V6VBG&6֖6RVWfF2bw&FR&RFRWW&V6VBFV"f'7BWfVBvFFRf'7B2F2FRVFFRF6WB`7&V6VBBB5Bv23RB32F2&W7V7FfVǒBFRVFGW&Ff"V6v2#F2W&f&WF2V秖RFW7G2Fǒf"FRf'7B2F2b$5TĔbG&VFVBB26Ɩ6ǐF6FVBFVG2vFG&6֖6RVWfF2F"ƗfW"V秖W2&Rg&WVVFǒvFBF6R&VGV6R"F66FVR$5TĔb2V6W76'fVB&WFVFfVB&WFVF67W'2vF$5TĔbBfW7B2W&6&FVfgW6WW&VfgW6V'VFVB"W&W&VFVFR&F֗VB6Ɩ6G&b#cFVG0vFWvǒFv6VB4FR$5TĔbG&VFVBw&WFVBBRWW&V6VB6WfW&RfV@&WFVFbw&FR2W&6&FVfgW6rSCbFVG26vR&7GVGFVG2vF4vvW&R&W67FB"FW&BF&"FW&w&FR2"BfVB&WFVFv2&W'FV@#bFVG2RR6RFVG2WW&V6VB&RFRfVB&WFVFWfVB7V6f6ǒ#FVG2WW&V6VBw&FR2"BWW&VfgW62rFVG2WW&V6VBw&FR2"w&FRBW&6&FVfgW62BbFVG2WW&V6VBw&FR2VFVF"BvRFVG2W6r7FF&G2`6&RFW''WBF6R&VGV6R"F66FVR$5TĔb2V6W76'&VF6GG&VFVBFV6ƖRW7FFVBvW'V"fG&F&FRTte"267W'&VBFVG2G&VFVBvF$5TĔbFRfvrF&RFVFfW2FR6gBg&&6VƖRFvW7B'6W'fV@Tte"GW&r$5TĔbFW&f"FVG2FRVBWVV֖7GVFW2&Vv&FW72bƖRbFW&FRVFGW&FbFW&vF$5TĔbv2&FVǒBF2&vR2F#2f FVG2FW6R7GVFW26gBg&&6VƖRFvW7B'6W'fVBTte"w&WGW&rG&VFV@6fWGVF6Ɩ67GVFW2#s"&6VƖP&VgV7F7FGW0&֖@֖BFFW&FPFW&FRF6WfW&P6WfW&PFFCcc3#3 #cfrW֖@FFW&FP&֖@F6WfW&PFW&FPRRRR"#を#c2rCbをb2Br#cbCb#S322b2CR3R"SrCBR22#2㒒Ss2CR"3C"#rcR26WfW&PR"B#22BrS2SBbFWfW&PR"B2R2BrFW3w&Fr2&6VBFf6FFWB&VF6V6RWFBE$BFWF6V6S&frv&WF6W2Dt676f6F'Tte#&âw&VFW"F"WVF֖CcFW72F֖BFFW&FSCRFW72FcFW&FRF6WfW&S3FW72FCR6WfW&SRFW72F3FWfW&SW72FR֖s2"ࢤrFR#s"FVG2Tte"v2֗76rFVG2B&6VƖR"FW&FW&RvW&RFVG2vFFWfW&RB&6VƖRF"&VgV7FB&6VƖRBGW&rFW&vF$5TĔbvF'F7V"GFVFFF6PFVG2vfR&VW7Fr&V&VB"&6f7F'2f"&VG6gV7F66FW"F6PFW7FVBFVG2vF&6VƖRBG&VFVBVW&vVB&V&VBV''fWFF6G&6VBfFw2g&7GVFW2BG2V66b7F$5TĔb66W6RfWF&vVF֖7FW&VBF&VvBv&W&GV7F7GVFW26GV7FVB&G2B&&&G2&F֖7G&Fb&7WF"6W6VBGfW'6RFWfVVFWF6W2F֖7G&Fb&7WF"F&G2&"FfW'FƗFVFvW7FFFtBr6W6VB7&V6VBV''2&W6'F0BFW&W7W&W2T2&FVǒRBBFW2FRVW7W&RBFR&V6VFV@F6W2bCBSrF&W7V7FfVǒBFV7&V6VBFF2B&VGV6VBV&W"bf&PV''2BFW&W7W&W2&FVǒB2FW2FRVW7W&RBFR&V6VFV@F6W2bC"SrF&W7V7FfVǒF֖7G&Fb&7WF"F&VvB&&&G2GW&p&vvVW626W6VBfWFƖW2gW6VB7FW&V'&RB"fWGW6W2Bf&W2f66W&'6W'fF2B&FRbRFV7&V6RfWF&GvVvBBFW&W7W&W2T2&FVǒ"2@rFW2FRVW7W&RBFR&V6VFVBF6W2bCBSrF&W7V7FfVǒGf6P&VvBvVbFRFVF&6FfWGW2Gf6RfVW2b&W&GV7FfRFVFFW6RVffV7FfP6G&6WFGW&rG&VFVBBf"BV7BFgFW"FR7BF6REdU%4R$T5D06Ɩ6G&2WW&V6S&V6W6R6Ɩ6G&2&R6GV7FVBVFW"vFVǒf'r6FF2GfW'6R&V7F&FW2'6W'fVBFR6Ɩ6G&2bG'Vr6B&RF&V7Fǒ6&VBF&FW2FR6Ɩ6G&2bFW"G'VrBB&VfV7BFR&FW2'6W'fVB&7F6R6W&W2GfW'6P&V7F2&W'FVB6VFR7F266זV7W&W76v7G&FW7FF6GF'&VfVB&WFVFWFF6GB&6GfW'6R&V7F2FVG2vFWvǒFv6VB54âFR6Ɩ6G&&F֗VBBG&VFV@S32FVG2vFWvǒFv6VB54F&V6VfR$5TĔbCrFǒ"F"CrFǐ26vRvVG2WvǒFv6VB547GVGFR6fWGVF&V6VfVBBV7B