ASH Clinical News July 2017 V2 - Page 6

Calendar

7th InterAmerican Oncology Conference
October 5 – 6 , 2017 Buenos Aires , Argentina The InterAmerican Oncology Conference focuses on translational advances in the treatment of cancer , as well as provides updates on targeted therapies , immunotherapies , and emerging treatments in early development .
American Association of Blood Banks Annual Meeting
October 7 – 10 , 2017 San Diego , CA The AABB Annual Meeting brings together transfusion specialists , laboratory supervisors , cellular therapy and blood banking professionals , medical technologists , donor recruiters , physicians , and nurses to advance transfusion and cellular therapies worldwide .
CAP17 : The Pathologists ’ Meeting
October 8 – 11 , 2017 National Harbor , MD The College of American Pathologists ’ 2017 meeting brings together pathology and laboratory medicine experts from around the world .
Clinical Application of CAR T Cells
November 16 – 17 , 2017 New York , NY Memorial Sloan Kettering faculty and national and international experts will discuss clinical and translational aspects of Chimeric antigen receptors , both for hematologic malignancies and solid tumors .
Mark your calendar for the 2017 ASH Annual Meeting taking place December 9-12 , 2017 , in Atlanta , Georgia .
adverse reaction was 38 % in the GAZYVA treated arm and 32 % in the rituximab treated arm , with the incidence of serious adverse events being 1 % and < 1 %, respectively ( Table 4 ). Cases of late-onset neutropenia ( occurring 28 days after completion of treatment or later ) were 16 % in the GAZYVA treated arm and 12 % in the rituximab treated arm .
Non-Hodgkin Lymphoma The incidence of neutropenia was higher in the GAZYVA plus bendamustine arm ( 38 %) compared to the arm treated with bendamustine alone ( 32 %). Cases of prolonged neutropenia ( 3 %) and late onset neutropenia ( 7 %) were also reported in the GAZYVA plus bendamustine arm .
Infection : Chronic Lymphocytic Leukemia The incidence of infections was similar between GAZYVA and rituximab treated arms . Thirty-eight percent of patients in the GAZYVA treated arm and 37 % in the rituximab treated arm experienced an infection , with Grade 3 – 4 rates being 11 % and 13 %, respectively . Fatal events were reported in 1 % of patients in both arms .
Non-Hodgkin Lymphoma The incidence of infection was 66 % in the GAZYVA plus bendamustine arm and 56 % in the bendamustine arm , with Grade 3-4 events reported in 16 % and 14 %, respectively . Fatal events were reported in 3 % of patients in the GAZYVA plus bendamustine arm and 4 % in the bendamustine arm .
Thrombocytopenia : Chronic Lymphocytic Leukemia The overall incidence of thrombocytopenia reported as an adverse reaction was higher in the GAZYVA treated arm ( 14 %) compared to the rituximab treated arm ( 7 %), with the incidence of Grade 3 – 4 events being 10 % and 3 %, respectively ( Table 4 ). The difference in incidences between the treatment arms is driven by events occurring during the first cycle . The incidence of thrombocytopenia ( all grades ) in the first cycle were 11 % in the GAZYVA and 3 % in the rituximab treated arms , with Grade 3 – 4 rates being 8 % and 2 %, respectively . Four percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia ( occurring within 24 hours after the GAZYVA infusion ).
The overall incidence of hemorrhagic events and the number of fatal hemorrhagic events were similar between the treatment arms , with 3 in the rituximab and 4 in the GAZYVA treated arms . However , all fatal hemorrhagic events in patients treated with GAZYVA occurred in Cycle 1 .
Non-Hodgkin Lymphoma The incidence of thrombocytopenia was lower in the GAZYVA plus bendamustine arm ( 15 %) compared to the arm treated with bendamustine alone ( 24 %). The incidence of hemorrhagic events in GAZYVA plus bendamustine treated patients compared to bendamustine alone was 11 % and 10 %, respectively . Grade 3-4 hemorrhagic events were similar in both treatment arms ( 5 % in the GAZYVA plus bendamustine arm and 3 % in the bendamustine arm ).
Tumor Lysis Syndrome : The incidence of Grade 3 or 4 tumor lysis syndrome in patients with CLL was 2 % in the GAZYVA treated arm , and in patients with iNHL was 0.5 % in the GAZYVA plus bendamustine treated arm .
Musculoskeletal Disorders : Chronic Lymphocytic Leukemia Adverse events related to musculoskeletal disorders ( all events from the System Organ Class ), including pain , have been reported in the GAZYVA treated arm with higher incidence than in the rituximab treated arm ( 18 % vs . 15 %).
Non-Hodgkin Lymphoma Adverse events related to musculoskeletal disorders ( all events from the System Organ Class ), including pain , have been reported in the GAZYVA plus bendamustine treated arm with higher incidence than in the bendamustine alone arm ( 41 % vs . 29 %).
Liver Enzyme Elevations : Hepatic enzyme elevations have occurred in CLL patients who received GAZYVA in clinical trials and had normal baseline hepatic enzyme levels ( AST , ALT , and ALP ). The events occurred most frequently within 24-48 hours of the first infusion . In some patients , elevations in liver enzymes were observed concurrently with infusion reactions or tumor lysis syndrome . In the pivotal CLL study , there was no clinically meaningful difference in overall hepatotoxicity adverse events between all arms ( 4 % of patients in the GAZYVA treated arm ). Medications commonly used to prevent infusion reactions ( e . g ., acetaminophen ) may also be implicated in these events . Monitor liver function tests during treatment , especially during the first cycle . Consider treatment interruption or discontinuation for hepatotoxicity .
Gastro-Intestinal Perforation : Cases of gastrointestinal perforation have been reported in patients receiving GAZYVA , mainly in NHL .
6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA . Of the GAZYVA treated patients with CLL , 7 % ( 18 / 271 ) tested positive for anti-GAZYVA antibodies at one or more time points . In the pivotal iNHL trial , two out of 194 ( 1 %) patients in the GAZYVA plus bendamustine arm tested positive for anti-GAZYVA antibodies at baseline and experienced infusion reactions . No patients with iNHL developed anti-GAZYVA antibodies during or following GAZYVA treatment . Neutralizing activity of anti-GAZYVA antibodies has not been assessed .
Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used . Additionally , the observed incidence of a positive result in a test method may be influenced by several factors , including sample handling , timing of sample collection , drug interference , concomitant medication , and the underlying disease . Therefore , comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading . Clinical significance of anti-GAZYVA antibodies is not known .
6.3 Additional Clinical Trial Experience Worsening of Pre-existing Cardiac Conditions : Fatal cardiac events have been reported in patients treated with GAZYVA .
7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA .
8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary
GAZYVA is likely to cause fetal B-cell depletion based on findings from animal studies and the drug ’ s mechanism of action [ see Clinical Pharmacology ( 12.1 )]. There are no data with GAZYVA use in pregnant women to inform a drug-associated risk . Monoclonal antibodies are transferred across the placenta . In animal reproduction studies , weekly intravenous administration of obinutuzumab to pregnant cynomolgus monkeys from day 20 of pregnancy until parturition which includes the period of organogenesis at doses with exposures up to 2.4 times the exposure at the clinical dose of 1000 mg monthly produced opportunistic infections and immune complex mediated hypersensitivity reactions . No embryo-toxic or teratogenic effects were observed in the monkeys [ see Data ]. Consider the potential risk to the fetus when prescribing GAZYVA to a pregnant woman .
The background risk of major birth defects and miscarriage for the indicated population is unknown ; however , the estimated background risk in the U . S . general population of major birth defects is 2 % to 4 % and of miscarriage is 15 % to 20 % of clinically recognized pregnancies .
Clinical Considerations Fetal / Neonatal Adverse Reactions GAZYVA is likely to cause fetal B-cell depletion [ see Data ]. Avoid administering live vaccines to neonates and infants exposed to GAZYVA in utero until B-cell recovery occurs [ see Warnings and Precautions ( 5.8 )] and Clinical Pharmacology ( 12.2 )].
Data Animal Data In a pre- and post-natal development study , pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg / kg obinutuzumab from day 20 of pregnancy until parturition , which includes the period of organogenesis . The high dose results in an exposure ( AUC ) that is 2.4 times the exposure in patients with CLL at the recommended label dose . There were no embryo-toxic or teratogenic effects in animals . Secondary opportunistic infections , immune complex mediated hypersensitivity reactions , or a combination of both were observed in exposed dams . When first measured on day 28 postpartum , obinutuzumab was detected in offspring at levels in the range of maternal serum levels on the same day , and B-cells were completely depleted . The B-cell counts returned to normal levels , and immunologic function was restored within 6 months after birth .
Obinutuzumab was measured in the milk of lactating cynomolgus monkeys on day 28 postpartum after weekly intravenous administration from day 20 of pregnancy until parturition . Concentrations in milk were approximately 0.04 % and 0.13 % of concentrations in maternal serum in the 25 and 50 mg / kg groups , respectively .
8.2 Lactation Risk Summary
There is no information regarding the presence of GAZYVA in human milk , the effects on the breastfed infant , or the effects on milk production . However , low levels of obinutuzumab were present in the milk of lactating cynomolgus monkeys [ see Use in Specific Populations ( 8.1 )]. Human IgG is known to be present in human milk . Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts . The developmental and health benefits of breastfeeding should be considered along with the mother ’ s clinical need for GAZYVA and any potential adverse effects on the breastfed infant from GAZYVA or from the underlying maternal condition .
8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients have not been established .
8.5 Geriatric Use Chronic Lymphocytic Leukemia
Of 336 patients with previously untreated CLL who received GAZYVA in combination with chlorambucil , 81 % were 65 years and older , while 46 % were 75 and older . Of the patients 75 years and older , 46 % experienced serious adverse events and 7 % experienced adverse events leading to death . Of the patients younger than 75 , 33 % experienced a serious adverse event and 2 % an adverse event leading to death . No significant differences in efficacy were observed between younger and older patients [ see Clinical Studies ( 14.1 )].
Non-Hodgkin Lymphoma Of 194 patients with iNHL treated with GAZYVA plus bendamustine , 44 % were 65 and over , while 14 % were 75 and over . In patients 65 and over , 52 % of patients experienced serious adverse events and 26 % experienced adverse events leading to treatment withdrawal while in patients under 65 , 28 % and 12 % experienced serious adverse events and adverse events leading to treatment withdrawal , respectively . No clinically meaningful differences in efficacy were observed between these patients and younger patients .
10 OVERDOSAGE There has been no experience with overdose in human clinical trials . Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials . For patients who experience overdose , treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy .
17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following :
• Signs and symptoms of infusion reactions including dizziness , nausea , chills , fever , vomiting , diarrhea , breathing problems , or chest pain [ see Warnings and Precautions ( 5.3 ) and Adverse Reactions ( 6.1 )].
• Symptoms of tumor lysis syndrome such as nausea , vomiting , diarrhea , and lethargy [ see Warnings and Precautions ( 5.4 ) and Adverse Reactions ( 6.1 )].
• Signs of infections including fever and cough [ see Warnings and Precautions ( 5.5 ) and Adverse Reactions ( 6.1 )].
• Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [ see Warnings and Precautions ( 5.1 )].
• New or changes in neurological symptoms such as confusion , dizziness or loss of balance , difficulty talking or walking , or vision problems [ see Warnings and Precautions ( 5.2 )].
Advise patients of the need for :
• Periodic monitoring of blood counts [ see Warnings and Precautions ( 5.6 and 5.7 ) and Adverse Reactions ( 6.1 )].
• Avoid vaccinations with live viral vaccines [ see Warnings and Precautions ( 5.8 )].
• Patients with a history of hepatitis B infection ( based on the blood test ) should be monitored and sometimes treated for their hepatitis [ see Warnings and Precautions ( 5.1 )].
Advise pregnant women of potential fetal B-cell depletion [ see Use in Specific Populations ( 8.1 )].
GAZYVA ® ( obinutuzumab )
Manufactured by : Genentech , Inc . A Member of the Roche Group South San Francisco , CA 94080-4990
U . S . License No . 1048
Initial US Approval : 2013
Code Revision Date : February 2016
GAZYVA is a registered trademark of Genentech , Inc .
GAZ / 010816 / 0009 02 / 16 © 2016 Genentech , Inc .

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Calendar 7th InterAmerican Oncology Conference October 5 – 6, 2017 Buenos Aires, Argentina The InterAmerican Oncology Conference focuses on translational advances in the treatment of cancer, as well as provides updates on targeted therapies, immunotherapies, and emerging treatments in early development. adverse reaction was 38% in the GAZYVA treated arm and 32% in the rituximab treated arm, with the incidence of serious adverse events being 1% and < 1%, respectively (Table 4). Cases of late-onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the rituximab treated arm. Non-Hodgkin Lymphoma The incidence of neutropenia was higher in the GAZYVA plus bendamustine arm (38%) compared to the arm treated with bendamustine alone (32%). Ca ͕́ɽɽ̔є͕)ɽܔݕɔͼɕѕѡieY)́ѥɴ)%ѥ) ɽ1ѥ1խ)Qѥ́݅́ͥȁݕ)ieYɥ᥵ɕѕɵ̸Q䵕)ɍЁѥ́ѡieYɕѕɴ(ܔѡɥ᥵ɕѕɴɥ)ѥݥѠɅϊLЁɅѕ́Ĕ̔)ɕѥٕ丁хٕ́ݕɔɕѕĔ)ѥ́Ѡɵ̸)9!1)Qѥ݅̀ؔѡ)ieÝѥɴؔѡ)ѥɴݥѠɅ̴Ёٕ́ɕѕ)ؔДɕѥٕ丁хٕ́ݕɔ)ɕѕ̔ѥ́ѡieY)ѥɴДѡѥɴ)Qɽѽ) ɽ1ѥ1խ)QٕɅѡɽѽɕѕ)ٕ͔́ɕѥ݅́ȁѡieY)ɕѕɴДɕѼѡɥ᥵ɕѕ)ɴܔݥѠѡɅϊLЁٕ)̔ɕѥٕ䀡QФQ)ɕ́ݕѡɕѵЁɵ)́ɥٕ䁕ٕ́ɥɥѡЁ危)QѡɽѽɅ̤ѡ)Ё危ݕɔĔѡieY̔ѡ)ɥ᥵ɕѕɵ̰ݥѠɅϊLЁɅѕ́(Ȕɕѥٕ丁ȁɍЁѥ)ѡieYɕѕɴɥє)ѡɽѽɥݥѡЁ́ѕ)ѡieYͥ)QٕɅɡٕ́)ѡյȁхɡٕ́ݕɔͥ)ݕѡɕѵЁɵ̰ݥѠ́ѡɥ᥵)ЁѡieYɕѕɵ̸!ݕٕȰх)ɡٕ́ѥ́ɕѕݥѠieY)ɕ 危ĸ)9!1)Qѡɽѽ݅́ݕȁѡ)ieÝѥɴԔɕѼ)ѡɴɕѕݥѠѥД)Qɡٕ́ieY)́ѥɕѕѥ́ɕѼ)ѥ݅̀Ĕɕѥٕ)Ʌ̴Ёɡٕ́ݕɔͥȁ)ѠɕѵЁɵ̀ԔѡieY)ѥɴ̔ѡѥɴ)Qյȁ1ͥ́M幑ɽQɅ)ȀЁյȁͥ́幑ɽѥ́ݥѠ 10݅(ȔѡieYɕѕɴѥ́ݥѠ)9!0݅̀ԔѡieÝѥ)ɕѕɴ)5͍ձͭхͽɑ) ɽ1ѥ1խ)ٕ͔ٕ́ɕѕѼ͍ձͭхͽɑ(ٕ́ɽѡMѕ=ɝ ̤Ց)ٔɕѕѡieYɕѕɴ)ݥѠȁѡѡɥ᥵ɕѕ)ɴ̸Ԕ)9!1)ٕ͔ٕ́ɕѕѼ͍ձͭхͽɑ(ٕ́ɽѡMѕ=ɝ ̤Ց)ٔɕѕѡieY)ѥɕѕɴݥѠȁѡ)ѡѥɴĔ̸䔤)1ٕȁ嵔مѥ!ѥ嵔مѥ)ٔɕ 10ѥ́ݡɕٕ)ieYɥ́ɵ͕)ѥ嵔ٕ̀MP1P1@Q)ٕ́ɕЁɕՕѱݥѡд)ѡЁͥ%ͽѥ̰مѥ)ٕȁ嵕́ݕɔ͕ٕɕѱݥѠ)ͥɕѥ́ȁյȁͥ́幑ɽ%ѡ)ٽх 10Ց䰁ѡɔ݅́䁵հ)ɕٕɅѽѽ᥍䁅ٕ͔ٕ)ݕɵ̀Дѥ́ѡieY)ɕѕɴ5ѥ͕́Ѽ)ɕٕЁͥɕѥ̀х)䁅ͼѕѡ̸͔ٕ5ѽȁٕ)չѥѕ́ɥɕѵа䁑ɥ)ѡЁ危 ͥȁɕѵЁѕѥ)͍ѥՅѥȁѽѽ᥍)ɥͽѥ )Յ5ѥ)=ѽȀ܃L)M )Q Յ5ѥɥ́ѽѡȁɅ͙ͥ)̰Ʌѽ٥ͽ̰ձȁѡɅ䁅)ɽ̰ͥѕ̰)ȁɕեѕ̰̰͕ͥ́Ѽم)Ʌ͙ͥձȁѡɅ́ݽɱݥ)ɼ%ѕѥAəɅѥ ͕́ɼ)ѕѥəɅѥٔɕѕѥ)ɕ٥ieY䁥9!0(ظȁ%չ)Mմ́ͅɽѥ́ݥѠɕ٥ͱ)չɕѕ 10ݕɔѕѕɥѕȁɕѵ)ȁѥ́ѼieY=ѡieYɕѕ)ѥ́ݥѠ 10ܔĤѕѕͥѥٔ)ѤieYѥ́Ёȁɔѥ̸)%ѡٽх9!0ɥݼЁЀĔѥ)ѡieÝѥɴѕѕ)ͥѥٔȁѤieYѥ́Ё͕)ɥͥɕѥ̸9ѥ́ݥѠ)9!0ٕѤieYѥ́ɥ)ݥieYɕѵи9Ʌ饹ѥ٥䁽)ѤieYѥ́́Ё͕͕)%չ䁑фɔ䁑Ё)ѡ͕ͥѥ٥䁅䁽ѡѕЁѡ)͕ѥ䰁ѡ͕ٕ)ͥѥٔɕձЁѕЁѡ䁉Օ)͕ٕɅѽ̰Ցͅѥ)ͅѥ՜ѕəɕх)ѥѡչɱ她͕͔Qɕɔ)ɥͽѡѥ́Ѽ)ieYݥѠѡѥ́Ѽѡ)ɽՍ́䁉ͱ ͥ)ѤieYѥ́́Ёݸ(ظ́ѥ Qɥɥ)]͕Aɔѥ ɑ ѥх)ɑٕ́ٔɕѕѥ́ɕѕ)ݥѠieY(܁IU%9QI Q%=9L)9ɵ՜ѕɅѥՑ́ٔ)ՍѕݥѠieY(UM%8MA %% A=AU1Q%=9L(āAɕ)IͬMյ)ieÝѼ͔хѥ)͕́ɽՑ́ѡ՟e)ʹѥm͕ Aɵ(ȸĥtQɔɔфݥѠieY͔)ɕЁݽѼɴ՜ͽѕɥͬ)5ѥ́ɔɅ͙ɕɽ́ѡ)ф%ɕɽՍѥՑ̰ݕ)Ʌٕ́ɅѥյѼ) ɕЁ幽́́ɽ)ɕչѥɥѥݡՑ́ѡɥ)ɝͥ́Ё͕́ݥѠɕ́Ѽ(ȸЁѥ́ѡɔЁѡ͔)ѡɽՍչѥѥ́)չѕ͕ͥѥ٥ɕѥ̸)9張ѽ᥌ȁѕɅѽ́ݕɔ)͕ٕѡ́m͕хt ͥȁѡ)ѕѥɥͬѼѡ́ݡɕ͍ɥieY)ѼɕЁݽ)QɽչɥͬȁѠ́)͍ɥȁѡѕձѥ́չݸ)ݕٕȰѡѥѕɽչɥͬѡTL)ɅձѥȁѠ́̀ȔѼ(Д͍ɥ̀ԔѼ)ɕ镐ɕ̸) ͥɅѥ)х9хٕ͔Iѥ)ieÝѼ͔хѥ)m͕хtٽѕɥٔم́Ѽ)ѕ͕́́ѼieYѕɼ)չѥɕٕ䁽́m͕]ɹ́)Aɕѥ̀Ըt Aɵ䀠ȸȥt)ф)ф)%ɔехٕЁՑ䰁ɕ)幽́́ɕٕݕ䁥Ʌٕ)͕́ԁȀյɽ(ɕչѥɥѥݡՑ́ѡ)ɥɝ̸ͥQ͔ɕձ́)ɔU ѡЁ̀ȸЁѥ́ѡɔ)ѥ́ݥѠ 10Ёѡɕ͔)Qɔݕɔ張ѽ᥌ȁѕɅѽ́)̸M䁽չѥѥ̰չ)ѕ͕ͥѥ٥ɕѥ̰ȁ)ѥѠݕɔ͕ٕ͕)̸]Ёɕմ)յ݅́ѕѕɥЁٕ́)ѡɅѕɹ͕մٕ́ѡͅ)́ݕɔѕ䁑ѕQ)չ́ɕɹѼɵٕ̰չ)չѥ݅́ɕѽɕݥѡ؁ѡ́ѕȁѠ)=յ݅́ɕѡхѥ)幽́́մ)ѕȁݕ䁥Ʌٕ́Ʌѥɽ(ɕչѥɥѥ Ʌѥ)ݕɔɽ᥵ѕД̔)Ʌѥ́ѕɹ͕մѡԁ(ɽ̰ɕѥٕ) @QAѡϊd5ѥ)=ѽȀLİ)9ѥ!ɉȰ5)Q ɥAѡϊd܁ѥ)ɥ́ѽѡȁѡ䁅Ʌѽ䁵)́ɽɽչѡݽɱ)5ɬȁȁȁѡ(܁M Յ5ѥ)хȀȰ(ܰѱфɝ) ѥ HP )9ٕȀ؃Lܰ)9܁eɬ9d)5ɥM-ѕɥձ䁅ѥ)ѕɹѥ́ݥ͍́Ʌͱ)ѥ́ ɥѥɕѽ̰Ѡ)ѽ́ͽյ̸(ȁ1хѥ)IͬMյ)Qɔ́ɵѥɕɑѡɕ͕)ieYյѡ́ѡ)ɕљаȁѡ́ɽՍѥ)!ݕٕȰ܁ٕ́յݕɔɕ͕)ѡхѥ幽́́m͕)U͔MAձѥ̀ĥt!յ%)ݸѼɕ͕ЁյAՉ͡ф)՝ЁѡЁѥ́ɕЁЁѕ)ѡхЁɍձѥ́Չхѥ)չ̸QٕхѠ́)ɕљ͡ձͥɕݥѠѡ)ѡˊéȁieYѕѥ)ٕ͔́ѡɕљЁɽieY)ȁɽѡչɱ她ѕɹѥ(ЁAɥU͔)Qͅ䁅ѥٕ́ieY)ɥѥ́ٔЁх͡(ԁɥɥU͔) ɽ1ѥ1խ)=؁ѥ́ݥѠɕ٥ͱչɕѕ 10ݡ)ɕٕieYѥݥѠɅՍ(Ĕݕɔԁ啅́Ȱݡؔݕɔ(ԁȸ=ѡѥ̀ԁ啅́Ȱ(ؔɥ͕ɥٕ͔ٕ́́ܔ)ɥٕ͔ٕ́ѼѠ=)ѡѥ́չȁѡ԰̔ɥ)͕ɥٕ͔ٕ́ЁȔٕ͔ٕ)ѼѠ9ͥЁɕ́)ݕɔ͕ٕݕչȁȁѥ)m͕ MՑ̀иĥt)9!1)=Ёѥ́ݥѠ9!0ɕѕݥѠieY)́ѥДݕɔԁٕȰݡ(Дݕɔԁٕȸ%ѥ̀ԁٕȰȔ)ѥ́ɥ͕ɥٕ͔ٕ́)ؔɥٕ͔ٕ́Ѽ)ɕѵЁݥѡɅ݅ݡѥ́չȀ԰(Ȕɥ͕ɥٕ͔ٕ́)ٕ͔ٕ́ѼɕѵЁݥѡɅ݅)ɕѥٕ丁9䁵հɕ́)ݕɔ͕ٕݕѡ͔ѥ́)չȁѥ̸) )ѡ)))ɽٕ)M! )9̹ɜ)EU% -1d%9Q!)1QMP9]L(=YI=M)Qɔ́ɥݥѠٕɑ͔)յɥ̸͕́Ʌɽ)ѼՑȁͥٔ)ѕɕɥ̸ȁѥ́ݡ)ɥٕɑ͔ɕѵЁ͡ձͥЁ)єѕѥȁɕՍѥieY)ѥٔѡɅ(܁AQ%9P =U9M1%9%9=I5Q%=8)٥͔ѥ́Ѽ͕єѕѥ)ȁ䁽ѡݥ+Ḿѽ́ͥɕѥ)Ց饹̰͕̰ٕȰ)ٽѥɡɕѡɽ̰)Ёm͕]ɹ́Aɕѥ(Ը̤ٕ͔Iѥ̀ظĥt+Mѽ́յȁͥ́幑ɽՍ)͕ٽѥɡѡɝm͕)]ɹ́Aɕѥ̀ԸФٕ͔)Iѥ̀ظĥt+Ḿѥ́Ցٕȁ՝)m͕]ɹ́Aɕѥ̀ԸԤٕ͔)Iѥ̀ظĥt+Mѽ́ѥѥ́Ցݽ͕)ѥՔȁ啱܁͍Ʌѥͭȁ)m͕]ɹ́Aɕѥ̀Ըĥt+9܁ȁ́ɽѽ)Ս́ͥ饹́ȁ́)ձхȁ݅ȁ٥ͥɽ)m͕]ɹ́Aɕѥ̀Ըȥt)٥͔ѥ́ѡ+Aɥѽɥչ́m͕)]ɹ ́Aɕѥ̀Ը؁Ըܤ)ٕ͔Iѥ̀ظĥt+ٽمѥ́ݥѠٔ٥Ʌم́m͕)]ɹ́Aɕѥ̀Ըt+Aѥ́ݥѠѽ䁽ѥѥ́ѥ(͕ѡѕФ͡ձѽɕ)ͽѥ́ɕѕȁѡȁѥѥ́m͕)]ɹ́Aɕѥ̀Ըĥt)٥͔ɕЁݽѕѥх)ѥm͕U͔MAձѥ̀ĥt)ieY յ%ѥULɽم)5ՙɕ)ѕ%)5ȁѡIɽ)MѠMɅ͍ ( I٥ͥє)Յ)TL1͔9)ieÝɕѕɕ)Ʌɬѕ%)hؼ(ȼ+ ؁ѕ%)9M%1d I=]M)Q!AI%9P%MMU