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210795Orig1s000 CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210795Orig1s000 MULTI-DISCIPLINE REVIEW Summary Review Office Director Cross Discipline Team Leader Review Clinical Review Non-Clinical Review Statistical Review Clinical Pharmacology Review E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ʹ E ϮϭϬϳϵϱ Eͬ> DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ƉƉůŝĐĂƚŝŽŶ dLJƉĞ E͕ ϱϬϱ;ďͿ;ϭͿ ƉƉůŝĐĂƚŝŽŶ EƵŵďĞƌ;ƐͿ ϮϭϬϳϵϱ WƌŝŽƌŝƚLJ Žƌ ^ƚĂŶĚĂƌĚ WƌŝŽƌŝƚLJ ^Ƶďŵŝƚ ĂƚĞ;ƐͿ ϭϭͬϮϮͬϮϬϭϳ ZĞĐĞŝǀĞĚ ĂƚĞ;ƐͿ ϭϭͬϮϮͬϮϬϭϳ Wh& 'ŽĂů ĂƚĞ ϬϳͬϮϮͬϮϬϭϴ ŝǀŝƐŝŽŶͬKĨĨŝĐĞ /WͬKW ƐƚĂďůŝƐŚĞĚ EĂŵĞ dĂĨĞŶŽƋƵŝŶĞ ;WƌŽƉŽƐĞĚͿ dƌĂĚĞ EĂŵĞ <Z/Ed&> WŚĂƌŵĂĐŽůŽŐŝĐ ůĂƐƐ ŶƚŝŵĂůĂƌŝĂů ƉƉůŝĐĂŶƚ 'ůĂdžŽ^ŵŝƚŚ<ůŝŶĞ /ŶƚĞůůĞĐƚƵĂů WƌŽƉĞƌƚLJ ĞǀĞůŽƉŵĞŶƚ >ƚĚ͘ ŶŐůĂŶĚ &ŽƌŵƵůĂƚŝŽŶ;ƐͿ KƌĂů dĂďůĞƚ ŽƐŝŶŐ ZĞŐŝŵĞŶ dǁŽ ϭϱϬ ŵŐ ƚĂďůĞƚƐ͕ ƐŝŶŐůĞͲĚŽƐĞ ƉƉůŝĐĂŶƚ WƌŽƉŽƐĞĚ ZĂĚŝĐĂů ĐƵƌĞ ;ƉƌĞǀĞŶƚŝŽŶ ŽĨ ƌĞůĂƉƐĞͿ ŽĨ W͘ ǀŝǀĂdž ŵĂůĂƌŝĂ ŝŶ ƉĂƚŝĞŶƚƐ ϭϲ /ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ LJĞĂƌƐ ŽĨ ĂŐĞ ĂŶĚ ŽůĚĞƌ ZĞĐŽŵŵĞŶĚĂƚŝŽŶ ŽŶ ƉƉƌŽǀĂů ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶ ZĞĐŽŵŵĞŶĚĞĚ ZĂĚŝĐĂů ĐƵƌĞ ;ƉƌĞǀĞŶƚŝŽŶ ŽĨ ƌĞůĂƉƐĞͿ ŽĨ W͘ ǀŝǀĂdž ŵĂůĂƌŝĂ ŝŶ ƉĂƚŝĞŶƚƐ ϭϲ /ŶĚŝĐĂƚŝŽŶ;ƐͿͬWŽƉƵůĂƚŝŽŶ;ƐͿ LJĞĂƌƐ ŽĨ ĂŐĞ ĂŶĚ ŽůĚĞƌ ϭ Reference ID: 4294788 E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ʹ E ϮϭϬϳϵϱ dĂďůĞ ŽĨ ŽŶƚĞŶƚƐ ZĞǀŝĞǁĞƌƐ ŽĨ DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭ ĚĚŝƚŝŽŶĂů ZĞǀŝĞǁĞƌƐ ŽĨ ƉƉůŝĐĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϳ 'ůŽƐƐĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϴ ϭ džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ KĨĨŝĐĞ >ĞǀĞů ŽŶĐƵƌƌĞŶĐĞ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ WƌŽĚƵĐƚ /ŶƚƌŽĚƵĐƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ ŽŶĐůƵƐŝŽŶƐ ŽŶ ƚŚĞ ^ƵďƐƚĂŶƚŝĂů ǀŝĚĞŶĐĞ ŽĨ ĨĨĞĐƚŝǀĞŶĞƐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϮϬ ĞŶĞĨŝƚͲZŝƐŬ ƐƐĞƐƐŵĞŶƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϭ Ϯ dŚĞƌĂƉĞƵƚŝĐ ŽŶƚĞdžƚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϰ ŶĂůLJƐŝƐ ŽĨ ŽŶĚŝƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϰ ŶĂůLJƐŝƐ ŽĨ ƵƌƌĞŶƚ dƌĞĂƚŵĞŶƚ KƉƚŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϱ ϯ ZĞŐƵůĂƚŽƌLJ ĂĐŬŐƌŽƵŶĚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϲ h͘^͘ ZĞŐƵůĂƚŽƌLJ ĐƚŝŽŶƐ ĂŶĚ DĂƌŬĞƚŝŶŐ ,ŝƐƚŽƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϲ ^ƵŵŵĂƌLJ ŽĨ WƌĞƐƵďŵŝƐƐŝŽŶͬ^ƵďŵŝƐƐŝŽŶ ZĞŐƵůĂƚŽƌLJ ĐƚŝǀŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϲ ϰ ^ŝŐŶŝĨŝĐĂŶƚ /ƐƐƵĞƐ ĨƌŽŵ KƚŚĞƌ ZĞǀŝĞǁ ŝƐĐŝƉůŝŶĞƐ WĞƌƚŝŶĞŶƚ ƚŽ ůŝŶŝĐĂů ŽŶĐůƵƐŝŽŶƐ ŽŶ ĨĨŝĐĂĐLJ ĂŶĚ ^ĂĨĞƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ KĨĨŝĐĞ ŽĨ ^ĐŝĞŶƚŝĨŝĐ /ŶǀĞƐƚŝŐĂƚŝŽŶƐ ;K^/Ϳ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ WƌŽĚƵĐƚ YƵĂůŝƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ Ϯϳ ĞǀŝĐĞƐ ĂŶĚ ŽŵƉĂŶŝŽŶ ŝĂŐŶŽƐƚŝĐ /ƐƐƵĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϬ ϱ EŽŶĐůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJͬdŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϬ džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϬ ZĞĨĞƌĞŶĐĞĚ EƐ͕ >Ɛ͕ D&Ɛ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϯ WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϯ DͬW<͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϯϲ dŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϬ 'ĞŶĞƌĂů dŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϬ 'ĞŶĞƚŝĐ dŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϰ ĂƌĐŝŶŽŐĞŶŝĐŝƚLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϲ ZĞƉƌŽĚƵĐƚŝǀĞ ĂŶĚ ĞǀĞůŽƉŵĞŶƚĂů dŽdžŝĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϰϲ KƚŚĞƌ dŽdžŝĐŽůŽŐLJ ^ƚƵĚŝĞƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϮ Ϯ Reference ID: 4294788 E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ʹ E ϮϭϬϳϵϱ ϲ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϰ džĞĐƵƚŝǀĞ ^ƵŵŵĂƌLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϰ ^ƵŵŵĂƌLJ ŽĨ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ƐƐĞƐƐŵĞŶƚ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϱ WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ ůŝŶŝĐĂů WŚĂƌŵĂĐŽŬŝŶĞƚŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϱ 'ĞŶĞƌĂů ŽƐŝŶŐ ĂŶĚ dŚĞƌĂƉĞƵƚŝĐ /ŶĚŝǀŝĚƵĂůŝnjĂƚŝŽŶ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϱ ŽŵƉƌĞŚĞŶƐŝǀĞ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ ZĞǀŝĞǁ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϲ 'ĞŶĞƌĂů WŚĂƌŵĂĐŽůŽŐLJ ĂŶĚ WŚĂƌŵĂĐŽŬŝŶĞƚŝĐ ŚĂƌĂĐƚĞƌŝƐƚŝĐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϲ ůŝŶŝĐĂů WŚĂƌŵĂĐŽůŽŐLJ YƵĞƐƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϱϴ ϳ ^ƚĂƚŝƐƚŝĐĂů ĂŶĚ ůŝŶŝĐĂů ǀĂůƵĂƚŝŽŶ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϳ ^ŽƵƌĐĞƐ ŽĨ ůŝŶŝĐĂů ĂƚĂ ĂŶĚ ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϳ dĂďůĞ ŽĨ ůŝŶŝĐĂů dƌŝĂůƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϳ ZĞǀŝĞǁ ^ƚƌĂƚĞŐLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϵ ZĞǀŝĞǁ ŽĨ ZĞůĞǀĂŶƚ /ŶĚŝǀŝĚƵĂů dƌŝĂůƐ hƐĞĚ ƚŽ ^ƵƉƉŽƌƚ ĨĨŝĐĂĐLJ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϵ ^ƚƵĚLJ d&ϭϭϮϱϴϮ WĂƌƚ ϭ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϲϵ ^ƚƵĚLJ d&ϭϭϮϱϴϮ WĂƌƚ Ϯ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϴϬ ^ƚƵĚLJ d&ϭϭϲϱϲϰ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϵϭ /ŶƚĞŐƌĂƚĞĚ ZĞǀŝĞǁ ŽĨ ĨĨĞĐƚŝǀĞŶĞƐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϭ ^ƵŵŵĂƌLJ ĂŶĚ ŽŶĐůƵƐŝŽŶƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϭ ^ƵŵŵĂƌLJ ĂŶĚ ŽŶĐůƵƐŝŽŶƐ ʹ ^ƚĂƚŝƐƚŝĐƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϭ ^ƵŵŵĂƌLJ ĂŶĚ ŽŶĐůƵƐŝŽŶƐ Ͳ ůŝŶŝĐĂů ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϭ ƐƐĞƐƐŵĞŶƚ ŽĨ ĨĨŝĐĂĐLJ ĐƌŽƐƐ dƌŝĂůƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϮ ͺ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϱ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϲ ĐƚŝǀŝƚLJ ŝŶ ǀŝǀŽ ;ŶŝŵĂů ^ƚƵĚŝĞƐͿ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϳ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϳ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϴ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϴ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϴ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϬϵ ϵ ZĞǀŝĞǁ ŽĨ ^ĂĨĞƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϬ ϯ Reference ID: 4294788 E DƵůƚŝͲŝƐĐŝƉůŝŶĂƌLJ ZĞǀŝĞǁ ĂŶĚ ǀĂůƵĂƚŝŽŶ ʹ E ϮϭϬϳϵϱ ^ĂĨĞƚLJ ZĞǀŝĞǁ ƉƉƌŽĂĐŚ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϬ ZĞǀŝĞǁ ŽĨ ƚŚĞ ^ĂĨĞƚLJ ĂƚĂďĂƐĞ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϭ ĚĞƋƵĂĐLJ ŽĨ ƉƉůŝĐĂŶƚ͛Ɛ ůŝŶŝĐĂů ^ĂĨĞƚLJ ƐƐĞƐƐŵĞŶƚƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϰ ^ĂĨĞƚLJ ZĞƐƵůƚƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϭϱ ŶĂůLJƐŝƐ ŽĨ ^ƵďŵŝƐƐŝŽŶͲ^ƉĞĐŝĨŝĐ ^ĂĨĞƚLJ /ƐƐƵĞƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϯϬ ^ĂĨĞƚLJ ŶĂůLJƐĞƐ ďLJ ĞŵŽŐƌĂƉŚŝĐ ^ƵďŐƌŽƵƉƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϲϭ ^ƉĞĐŝĨŝĐ ^ĂĨĞƚLJ ^ƚƵĚŝĞƐͬůŝŶŝĐĂů dƌŝĂůƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϲϮ ĚĚŝƚŝŽŶĂů ^ĂĨĞƚLJ džƉůŽƌĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϴϵ ^ĂĨĞƚLJ ŝŶ ƚŚĞ WŽƐƚŵĂƌŬĞƚ ^ĞƚƚŝŶŐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϵϬ /ŶƚĞŐƌĂƚĞĚ ƐƐĞƐƐŵĞŶƚ ŽĨ ^ĂĨĞƚLJ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϵϬ ϭϬ ĚǀŝƐŽƌLJ ŽŵŵŝƚƚĞĞ DĞĞƚŝŶŐ ĂŶĚ KƚŚĞƌ džƚĞƌŶĂů ŽŶƐƵůƚĂƚŝŽŶƐ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϵϰ ϭϭ WĞĚŝĂƚƌ ŝĐƐ ͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘͘ ϭϵϱ ϭϮ >ĂďĞůŝŶŐ
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