Aspirin in the prevention of cardiovascular disease in type 2 diabetes Hovens, M.M.C.

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Citation

Hovens, M. M. C. (2010, June 3). Aspirin in the prevention of cardiovascular disease in type 2 diabetes. Retrieved from https://hdl.handle.net/1887/15583

Version: Corrected Publisher’s Version

License: Licence agreement concerning inclusion of doctoral thesis in the Institutional Repository of the University of Leiden

Downloaded from: https://hdl.handle.net/1887/15583

Note: To cite this publication please use the final published version (if applicable).

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>ĂďŽƌĂƚŽƌǇͲĚĞĮŶĞĚ

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝƐ

ĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŚŝŐŚĞƌ

ƌŝƐŬŽĨƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽͲ ǀĂƐĐƵůĂƌĞǀĞŶƚƐ͗

ĂƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁĂŶĚ

ŵĞƚĂͲĂŶĂůǇƐŝƐ

:^ŶŽĞƉ DD,ŽǀĞŶƐ

::ŝŬĞŶďŽŽŵ :'ǀĂŶĚĞƌŽŵ Ds,ƵŝƐŵĂŶ

ƌĐŚ/ŶƚDĞĚϮϬϬϳ͖ϭϲϳ;ϭϱͿ͗ϭϱϵϯͲϭϱϵϵ

ϳ

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ϭϭϴ

ďƐƚƌĂĐƚ

ĂĐŬŐƌŽƵŶĚ͗ dŚĞ ƌŝƐŬ ŽĨ ƌĞĐƵƌƌĞŶĐĞƐ ĂŵŽŶŐ ƉĂƟĞŶƚƐ ƵƐŝŶŐ ĂƐƉŝƌŝŶ ĨŽƌ ƐĞĐŽŶĚĂƌǇ

ƉƌĞǀĞŶƟŽŶ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ ƌĞŵĂŝŶƐ ŚŝŐŚ͘ WĞƌƐŝƐƚĞŶƚ ƉůĂƚĞůĞƚ ƌĞĂĐƟǀŝƚǇ

ĚĞƐƉŝƚĞĂƐƉŝƌŝŶƚŚĞƌĂƉǇ͕ĂůĂďŽƌĂƚŽƌǇƉŚĞŶŽŵĞŶŽŶĐĂůůĞĚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͕ŵŝŐŚƚ

ĞǆƉůĂŝŶƚŚŝƐŝŶƉĂƌƚ͕ďƵƚŝƚƐĂĐƚƵĂůĐŽŶƚƌŝďƵƟŽŶƚŽƚŚĞƌŝƐŬƌĞŵĂŝŶƐƵŶĐůĞĂƌ͘

KďũĞĐƟǀĞ͗dŽƐǇƐƚĞŵĂƟĐĂůůǇƌĞǀŝĞǁĂůůĂǀĂŝůĂďůĞĞǀŝĚĞŶĐĞŽŶƚŚĞƋƵĞƐƟŽŶǁŚĞƚŚĞƌ

ůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝƐƌĞůĂƚĞĚƚŽĂŚŝŐŚĞƌƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌƌĞĐƵƌƌĞŶƚ

ĞǀĞŶƚƐ͘

DĞƚŚŽĚƐ͗ hƐŝŶŐ Ă ƉƌĞĚĞĮŶĞĚ ƐĞĂƌĐŚ ƐƚƌĂƚĞŐǇ͕ ǁĞ ƐĞĂƌĐŚĞĚ ĞůĞĐƚƌŽŶŝĐ ĚĂƚĂďĂƐĞƐ͘

dŽďĞŝŶĐůƵĚĞĚŝŶŽƵƌĂŶĂůǇƐŝƐ͕ĂƌƟĐůĞƐŚĂĚƚŽƌĞƉŽƌƚŽŶƉĂƟĞŶƚƐƵƐŝŶŐĂƐƉŝƌŝŶĨŽƌ

ƐĞĐŽŶĚĂƌǇĐĂƌĚŝŽǀĂƐĐƵůĂƌƉƌĞǀĞŶƟŽŶ͕ƚŽĐŽŶƚĂŝŶĂĐůĞĂƌĚĞƐĐƌŝƉƟŽŶŽĨĂŵĞƚŚŽĚƚŽ

ĞƐƚĂďůŝƐŚƚŚĞĞīĞĐƚƐŽĨĂƐƉŝƌŝŶŽŶƉůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇ͕ĂŶĚƚŽƌĞƉŽƌƚƌĞĐƵƌƌĞŶĐĞƌĂƚĞƐŽĨ

ĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘KĚĚƐƌĂƟŽƐŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞŽĨĞůŝŐŝďůĞƐƚƵĚŝĞƐǁĞƌĞ

ƉŽŽůĞĚŝŶĂƌĂŶĚŽŵͲĞīĞĐƚƐŵŽĚĞů͘

ZĞƐƵůƚƐ͗tĞŝŶĐůƵĚĞĚĮŌĞĞŶĨƵůůͲƚĞǆƚĂƌƟĐůĞƐĂŶĚŽŶĞŵĞĞƟŶŐĂďƐƚƌĂĐƚ͘dŚŝƌƚĞĞŶŽĨ

ƚŚĞƐĞ ƐƚƵĚŝĞƐ ƌĞǀĞĂůĞĚ ĂŶ ĂĚǀĞƌƐĞ ƌĞůĂƟŽŶ ďĞƚǁĞĞŶ ůĂďŽƌĂƚŽƌǇ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ

ĂŶĚŽĐĐƵƌƌĞŶĐĞŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘dŚĞƉŽŽůĞĚŽĚĚƐƌĂƟŽŽĨĂůůĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ŽƵƚĐŽŵĞƐǁĂƐϯ͘ϴ;ϵϱй/Ϯ͘ϯͲϲ͘ϭͿĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘

ŽŶĐůƵƐŝŽŶƐ͗ dŚŝƐ ƐǇƐƚĞŵĂƟĐ ƌĞǀŝĞǁ ĂŶĚ ŵĞƚĂͲĂŶĂůǇƐŝƐ ƐŚŽǁƐ ƚŚĂƚ ƉĂƟĞŶƚƐ

ďŝŽĐŚĞŵŝĐĂůůǇůĂďĞůĞĚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶƚĂƌĞůŝŬĞůǇƚŽďĞĂůƐŽ͞ĐůŝŶŝĐĂůůǇƌĞƐŝƐƚĂŶƚ͟ĂƐ

ƚŚĞǇĞǆŚŝďŝƚƐŝŐŶŝĮĐĂŶƚůǇŚŝŐŚĞƌƌŝƐŬƐŽĨƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͕ĐŽŵƉĂƌĞĚ

ǁŝƚŚƉĂƟĞŶƚƐǁŚŝĐŚĂƌĞůĂďĞůĞĚƐĞŶƐŝƟǀĞ͘

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ϭϭϵ

/ŶƚƌŽĚƵĐƟŽŶ

ĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐĂƌĞƚŚĞŵŽƐƚĐŽŵŵŽŶĐĂƵƐĞŽĨŵŽƌƚĂůŝƚǇĂŶĚŵŽƌďŝĚŝƚǇŝŶ

ǁĞƐƚĞƌŶĐŽƵŶƚƌŝĞƐŝŶƚŚĞƚǁĞŶƚǇͲĮƌƐƚĐĞŶƚƵƌǇ͘/ŶƚŚĞhŶŝƚĞĚ^ƚĂƚĞƐ͕ƚŚĞŵŽƌƚĂůŝƚǇŽĨ

ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐǁĂƐŶĞĂƌůǇϰϬйŽĨƚŽƚĂůŵŽƌƚĂůŝƚǇŝŶϮϬϬϯ;ϭͿ͘ƐĂŐŐƌĞŐĂƟŽŶ

ŽĨƉůĂƚĞůĞƚƐŚŝŐŚůǇĐŽŶƚƌŝďƵƚĞƐƚŽƚŚĞĚĞǀĞůŽƉŵĞŶƚŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͕ŝŶŚŝďŝƟŽŶ

ŽĨƚŚŝƐƉƌŽĐĞƐƐĐŽƵůĚƉůĂǇĂŶŝŵƉŽƌƚĂŶƚƌŽůĞŝŶƉƌĞǀĞŶƟŽŶŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ

;ϮͿ͘

EŽǁĂĚĂǇƐ͕ ĂƐƉŝƌŝŶ ;ĂĐĞƚǇůƐĂůŝĐǇůŝĐ ĂĐŝĚͿ ĨŽƌŵƐ ƚŚĞ ĐŽƌŶĞƌƐƚŽŶĞ ŝŶ ƚŚĞ ƐĞĐŽŶĚĂƌǇ

ƉƌĞǀĞŶƟŽŶ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ͘ dŚĞ ĞīĞĐƚ ŽĨ ůŽǁͲĚŽƐĞ ĂƐƉŝƌŝŶ ŝƐ ŵŽƐƚ ůŝŬĞůǇ

ďĂƐĞĚŽŶƚŚĞƉĞƌŵĂŶĞŶƚŝŶĂĐƟǀĂƟŽŶŽĨĐǇĐůŽŽǆǇŐĞŶĂƐĞͲϭ;KyͲϭͿƚŚƌŽƵŐŚďůŽĐŬĂĚĞ

ŽĨ ƚŚĞ KyͲĐŚĂŶŶĞů ďǇ ƚŚĞ ĂĐĞƚǇůĂƟŽŶ ŽĨ ƐĞƌŝŶĞ ƌĞƐŝĚƵĞ ϱϮϵ͕ ǁŚŝĐŚ ƌĞƐƵůƚƐ ŝŶ ĂŶ

ŝƌƌĞǀĞƌƐŝďůĞ ŝŶŚŝďŝƟŽŶ ŽĨ ƚŚĞ ƉƌŽĚƵĐƟŽŶ ŽĨ ƚŚƌŽŵďŽǆĂŶĞ Ϯ ďǇ ƉůĂƚĞůĞƚƐ ;ϯͿ͘ Ɛ

ƚŚƌŽŵďŽǆĂŶĞ Ϯ ŝƐ Ă ƉŽƚĞŶƚ ƉůĂƚĞůĞƚ ĂĐƟǀĂƚŽƌ ƚŚĂƚ ĂůƐŽ ĐĂƵƐĞƐ ǀĂƐŽĐŽŶƐƚƌŝĐƟŽŶ

ĂŶĚƐŵŽŽƚŚŵƵƐĐůĞƉƌŽůŝĨĞƌĂƟŽŶ͕ĂĚĞĐƌĞĂƐĞŝŶƚŚƌŽŵďŽǆĂŶĞϮůĞĂĚƐƚŽƌĞĚƵĐĞĚ

ĂŐŐƌĞŐĂƟŽŶŽĨƉůĂƚĞůĞƚƐ;ϯ͕ϰͿ͘

dŚĞ ĐůŝŶŝĐĂů ĞīĞĐƟǀĞŶĞƐƐŽĨ ĂƐƉŝƌŝŶ ŝŶ ƚŚĞ ƐĞĐŽŶĚĂƌǇƉƌĞǀĞŶƟŽŶ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ĞǀĞŶƚƐ ŚĂƐ ďĞĞŶ ǁĞůů ĞƐƚĂďůŝƐŚĞĚ͘ dŚĞ ŶƟƚŚƌŽŵďŽƟĐ dƌŝĂůŝƐƚƐ͛ ŽůůĂďŽƌĂƟŽŶ ŚĂƐ

ĚŽĐƵŵĞŶƚĞĚ Ă ϮϮй ƌĞĚƵĐƟŽŶ ŽĨ ĚĞĂƚŚ ĂŶĚ ƐĞƌŝŽƵƐ ŝƐĐŚĞŵŝĐ ǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ ďǇ

ĂŶƟƉůĂƚĞůĞƚƚŚĞƌĂƉǇĐŽŵƉĂƌĞĚǁŝƚŚƉůĂĐĞďŽ͕ŝŶƚŚĞŝƌŵŽƐƚƌĞĐĞŶƚŵĞƚĂͲĂŶĂůǇƐŝƐŽĨ

ϮϴϳƌĂŶĚŽŵŝǌĞĚƚƌŝĂůƐ͕ŝŶĐŽƌƉŽƌĂƟŶŐŵŽƌĞƚŚĂŶϮϬϬ͕ϬϬϬƉĂƟĞŶƚƐ;ϱͿ͘

,ŽǁĞǀĞƌ͕ŶŽƚĂůůƉĂƟĞŶƚƐƉƌŽĮƚƚŽƚŚĞƐĂŵĞĞǆƚĞŶƚ͕ǁŚŝĐŚĐŽƵůĚďĞĞǆƉůĂŝŶĞĚďǇ

Ă ǀĂƌŝĞƚǇ ŽĨ ƉŚĂƌŵĂĐŽĚǇŶĂŵŝĐ͕ ƉŚĂƌŵĂĐŽŬŝŶĞƟĐ ĂŶĚ ďŝŽĐŚĞŵŝĐĂů ĨĞĂƚƵƌĞƐ ;ϲͿ͘

ĚĚƌĞƐƐĞĚ ďŝŽĐŚĞŵŝĐĂůůǇ ĂƐ ƉĞƌƐŝƐƚĞŶƚ ƉůĂƚĞůĞƚ ƌĞĂĐƟǀŝƚǇ Ğǆ ǀŝǀŽ͕ ĚĞƐƉŝƚĞ ƚŚĞ ƵƐĞ

ŽĨ ĂƐƉŝƌŝŶ͕ ƚŚŝƐ ƉŚĞŶŽŵĞŶŽŶ ŝƐ ĐĂůůĞĚ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ͘ ĂƐĞĚ ŽŶ ƚŚĞ ĨĂŝůƵƌĞ ŽĨ

ĂƐƉŝƌŝŶƚŽŝŶŚŝďŝƚƉůĂƚĞůĞƚƚŚƌŽŵďŽǆĂŶĞϮƉƌŽĚƵĐƟŽŶŽƌƚŽŝŶŚŝďŝƚƚĞƐƚƐŽĨƉůĂƚĞůĞƚ

ĨƵŶĐƟŽŶ͕ĂǀĂƌŝĞƚǇŽĨůĂďŽƌĂƚŽƌǇƚĞƐƚƐƚŽĚĞĮŶĞĂŶĚƋƵĂŶƟĨǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŚĂƐ

ďĞĞŶ ƉƌŽƉŽƐĞĚ͘ zĞƚ͕Ă ƵŶŝĨŽƌŵ ĂŶĚ ĂŐƌĞĞĚ ĚĞĮŶŝƟŽŶ ŽĨ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ ĂŶĚ ŝƚƐ

ŵĞĂƐƵƌĞŵĞŶƚŝƐůĂĐŬŝŶŐ;ϳͲϵͿ͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŚĂƐƌĞĐĞŝǀĞĚŵƵĐŚĂƩĞŶƟŽŶ͕ŝŶďŽƚŚ

ŵĞĚŝĐĂůũŽƵƌŶĂůƐ;ϴ͕ϭϬ͕ϭϭͿĂŶĚůĂǇŵĞĚŝĂ;ϭϮͿ͘

ƌĞĐĞŶƚ ŵĞƚĂͲĂŶĂůǇƐŝƐ ŽĨ ƐƚƵĚŝĞƐ ĂĚĚƌĞƐƐŝŶŐ ƉƌĞǀĂůĞŶĐĞ ŽĨ ƉĞƌƐŝƐƚĞŶƚ ƉůĂƚĞůĞƚ

ƌĞĂĐƟǀŝƚǇ ĚĞƐƉŝƚĞ ƵƐĞ ŽĨ ĂƐƉŝƌŝŶ ŝŶ Ă ƐĞĐŽŶĚĂƌǇ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ƉƌĞǀĞŶƟŽŶ ƐĞƫŶŐ͕

(5)

ϭϮϬ

ƌĞƉŽƌƚĞĚĂŵĞĂŶƉƌĞǀĂůĞŶĐĞŽĨůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŽĨĂƉƉƌŽǆŝŵĂƚĞůǇϮϱй

;ϭϯͿ͘,ŽǁĞǀĞƌ͕ƚŚĞŵĂŝŶƋƵĞƐƟŽŶǁŚĞƚŚĞƌƉĂƟĞŶƚƐǁŚŽĂƌĞďŝŽĐŚĞŵŝĐĂůůǇůĂďĞůĞĚ

ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶƚ ĞǆŚŝďŝƚ ĂůƐŽ ͞ĐůŝŶŝĐĂů ƌĞƐŝƐƚĂŶĐĞ͟ ƚŽ ĂƐƉŝƌŝŶ͕ ŝ͘Ğ͘ Ă ŚŝŐŚĞƌ ƌŝƐŬ ŽĨ

ƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͕ƌĞŵĂŝŶƐůĂƌŐĞůǇƵŶĂŶƐǁĞƌĞĚŚŝƚŚĞƌƚŽ͘/ŶŽƌĚĞƌƚŽ

ƚƌǇƚŽƋƵĂŶƟĨǇĞǀŝĚĞŶĐĞĂĚĚƌĞƐƐŝŶŐƚŚŝƐƚŽƉŝĐ͕ǁĞĐŽŶĚƵĐƚĞĚĂƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁĂŶĚ

ŵĞƚĂͲĂŶĂůǇƐŝƐŽĨĂůůƌĞƉŽƌƚƐŽŶĐůŝŶŝĐĂůĐŽŶƐĞƋƵĞŶĐĞƐŽĨůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ

ĂŵŽŶŐƉĂƟĞŶƚƐƵƐŝŶŐĂƐƉŝƌŝŶĨŽƌƐĞĐŽŶĚĂƌǇƉƌĞǀĞŶƟŽŶŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘dŽ

ƚŚŝƐĂŝŵ͕ǁĞĚĞĮŶĞĚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂƐĞǆǀŝǀŽŶŽŶͲƌĞƐƉŽŶƐŝǀĞŶĞƐƐĂĐĐŽƌĚŝŶŐƚŽ

ĂŶǇƚĞƐƚƌĞŇĞĐƟŶŐƉůĂƚĞůĞƚƚŚƌŽŵďŽǆĂŶĞϮƐǇŶƚŚĞƐŝƐŽƌƉůĂƚĞůĞƚĨƵŶĐƟŽŶ͘

DĞƚŚŽĚƐ

^ĞůĞĐƟŽŶ͕ƋƵĂůŝƚǇĂƐƐĞƐƐŵĞŶƚĂŶĚĚĂƚĂĞǆƚƌĂĐƟŽŶ

tĞƵƐĞĚĞůĞĐƚƌŽŶŝĐĚĂƚĂďĂƐĞƐƚŽŝĚĞŶƟĨǇƌĞůĞǀĂŶƚƌĞƉŽƌƚƐ͘dŚĞĨŽůůŽǁŝŶŐĚĂƚĂďĂƐĞƐ

ǁĞƌĞƐĞĂƌĐŚĞĚ͗D>/E;ĨƌŽŵ:ĂŶƵĂƌǇϭϵϲϲƵŶƟůKĐƚŽďĞƌϮϬϬϲͿ͕D^;ĨƌŽŵ

:ĂŶƵĂƌǇϭϵϳϰƵŶƟůKĐƚŽďĞƌϮϬϬϲͿ͕ƚŚĞŽĐŚƌĂŶĞĞŶƚƌĂůZĞŐŝƐƚĞƌŽĨŽŶƚƌŽůůĞĚƚƌŝĂůƐ

;EdZ>Ϳ ;ĨƌŽŵ ϭϴϬϬ ƵŶƟů KĐƚŽďĞƌ ϮϬϬϲͿ ĂŶĚ tĞď ŽĨ ^ĐŝĞŶĐĞ ;ĨƌŽŵ ϭϵϰϱ ƵŶƟů

KĐƚŽďĞƌϮϬϬϲͿ͕ƵƐŝŶŐƉƌĞĚĞĮŶĞĚƐĞĂƌĐŚƚĞƌŵƐ;ƉƉĞŶĚŝǆϭͿ͘tĞƵƐĞĚŶŽůĂŶŐƵĂŐĞ

ƌĞƐƚƌŝĐƟŽŶƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ǁĞƚƌŝĞĚƚŽŝĚĞŶƟĨǇĂĚĚŝƟŽŶĂůƐƚƵĚŝĞƐďǇƐĞĂƌĐŚŝŶŐƚŚĞ

ƌĞĨĞƌĞŶĐĞůŝƐƚƐŽĨƌĞůĞǀĂŶƚƐƚƵĚŝĞƐĂŶĚƌĞĂĚŝŶŐƌĞǀŝĞǁƐ͕ĞĚŝƚŽƌŝĂůƐĂŶĚůĞƩĞƌƐŽŶƚŚŝƐ

ƚŽƉŝĐ͘ƵƚŚŽƌƐŽĨĂƉƉƌŽƉƌŝĂƚĞŝĚĞŶƟĮĞĚƐƚƵĚŝĞƐǁĞƌĞĐŽŶƚĂĐƚĞĚƚŽŽďƚĂŝŶĂĚĚŝƟŽŶĂů

ĚĂƚĂŶŽƚƌĞƉŽƌƚĞĚŝŶƚŚĞŽƌŝŐŝŶĂůƌĞƉŽƌƚ͘ŽƚŚĨƵůůͲƚĞǆƚĂƌƟĐůĞƐĂŶĚŵĞĞƟŶŐĂďƐƚƌĂĐƚƐ

ǁĞƌĞŝŶĐůƵĚĞĚ͘

dŽ ďĞ ŝŶĐůƵĚĞĚ ŝŶ ƚŚĞ ĂŶĂůǇƐŝƐ͕ ƐĞůĞĐƚĞĚ ƐƚƵĚŝĞƐ ŚĂĚ ƚŽ ŵĞĞƚ Ăůů ŽĨ ƚŚĞ ĨŽůůŽǁŝŶŐ

ŝŶĐůƵƐŝŽŶ ĐƌŝƚĞƌŝĂ͗ ϭͿ ŝŶĐůƵĚĞĚ ƉĂƟĞŶƚƐ ƐŚŽƵůĚ ŚĂǀĞ ĞƐƚĂďůŝƐŚĞĚ ĐŽƌŽŶĂƌǇ ĂƌƚĞƌǇ͕

ĐĞƌĞďƌŽǀĂƐĐƵůĂƌ Žƌ ƉĞƌŝƉŚĞƌĂů ĂƌƚĞƌǇ ĚŝƐĞĂƐĞ͖ ϮͿ ƉĂƟĞŶƚƐ ƐŚŽƵůĚ ďĞ ƚƌĞĂƚĞĚ ǁŝƚŚ

ĂƐƉŝƌŝŶ ĨŽƌ ƐĞĐŽŶĚĂƌǇ ƉƌĞǀĞŶƟŽŶ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞǀĞŶƚƐ͖ ϯͿ ƚŚĞ ƐƚƵĚǇ ƐŚŽƵůĚ

ĐŽŶƚĂŝŶĂĐůĞĂƌĚĞƐĐƌŝƉƟŽŶŽĨƚŚĞŵĞƚŚŽĚƵƐĞĚƚŽ ĞƐƚĂďůŝƐŚ ƚŚĞĞīĞĐƚƐŽĨ ĂƐƉŝƌŝŶ

ŽŶƉůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇƚŽĐŽŵƉĂƌĞĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶƚĂŶĚŶŽŶͲƌĞƐŝƐƚĂŶƚƉĂƟĞŶƚƐ͖ĂŶĚϰͿ

ƚŚĞƐƚƵĚǇƐŚŽƵůĚƌĞƉŽƌƚĚĂƚĂŽŶƌĞĐƵƌƌĞŶĐĞƌĂƚĞƐŽĨĨĂƚĂůĂŶĚŶŽŶͲĨĂƚĂůŵǇŽĐĂƌĚŝĂů

ŝŶĨĂƌĐƟŽŶ͕ĨĂƚĂůĂŶĚŶŽŶͲĨĂƚĂůƐƚƌŽŬĞŽƌŽƚŚĞƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĞŶĚƉŽŝŶƚƐĂƐƉƌĞĚĞĮŶĞĚ

ďǇŝŶǀĞƐƟŐĂƚŽƌƐ͘

(6)

ϭϮϭ dŚĞƋƵĂůŝƚǇŽĨƚŚĞŝĚĞŶƟĮĞĚƐƚƵĚŝĞƐǁĂƐĂƐƐĞƐƐĞĚďĂƐĞĚůĂƌŐĞůǇŽŶƋƵĂůŝƚǇĐƌŝƚĞƌŝĂ

ĐŽŶĐĞƌŶŝŶŐ ŵŝŶŝŵŝƐĂƟŽŶ ŽĨ ďŝĂƐ͘ /Ŷ ĚĞƚĂŝů͕ ǁĞ ĞǀĂůƵĂƚĞĚ ŝŶĨŽƌŵĂƟŽŶ ƌĞŐĂƌĚŝŶŐ

ĐŽŶƚƌŽůĨŽƌĐŽŶĨŽƵŶĚĞƌƐ͕ŵĞĂƐƵƌĞŵĞŶƚŽĨĞǆƉŽƐƵƌĞ͕ĐŽŵƉůĞƚĞŶĞƐƐŽĨĨŽůůŽǁͲƵƉĂŶĚ

ďůŝŶĚŝŶŐ͘&ŽƌĐĂƐĞͲĐŽŶƚƌŽůƐƚƵĚŝĞƐ͕ǁĞĂůƐŽĂƐƐĞƐƐĞĚŵĂƚĐŚŝŶŐĂŶĚĐĂƐĞĚĞĮŶŝƟŽŶ͘EŽ

ĨŽƌŵĂůƐĐŽƌŝŶŐƐǇƐƚĞŵǁĂƐƵƐĞĚ͘ZĞǀŝĞǁĞƌƐǁĞƌĞŶŽƚďůŝŶĚĞĚƚŽũŽƵƌŶĂů͕ĂƵƚŚŽƌŽƌ

ŝŶƐƟƚƵƟŽŶŽĨƉƵďůŝĐĂƟŽŶ͘

tĞƵƐĞĚĂƉƌĞƐƉĞĐŝĮĞĚĚĂƚĂĐŽůůĞĐƟŽŶĨŽƌŵƚŽĞǆƚƌĂĐƚŝŶĨŽƌŵĂƟŽŶĨŽƌĞĂĐŚƌĞƉŽƌƚ

ƌĞŐĂƌĚŝŶŐ ǇĞĂƌ ŽĨ ƉƵďůŝĐĂƟŽŶ͕ ĚƵƌĂƟŽŶ ĂŶĚ ƐĞƫŶŐ ŽĨ ƐƚƵĚǇ͕ ƐƚƵĚǇ ĚĞƐŝŐŶ͕ ƚŽƚĂů

ƐĂŵƉůĞƐŝǌĞĂŶĚƐƚƵĚǇƉŽƉƵůĂƟŽŶ;ďĂƐĞůŝŶĞĐŚĂƌĂĐƚĞƌŝƐƟĐƐͿ͘ŽŶĐĞƌŶŝŶŐŽƵƌƌĞƐĞĂƌĐŚ

ƋƵĞƐƟŽŶ͕ ƚŚĞ ĨŽůůŽǁŝŶŐ ǀĂƌŝĂďůĞƐ ǁĞƌĞ ĐŽůůĞĐƚĞĚ ĨƌŽŵ ƐĞůĞĐƚĞĚ ƐƚƵĚŝĞƐ͗ ĚŽƐĂŐĞ ŽĨ

ĂƐƉŝƌŝŶ͕ĚĞĮŶŝƟŽŶŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͕ƉƌĞǀĂůĞŶĐĞŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͕ĚĞĮŶŝƟŽŶŽĨ

ĐůŝŶŝĐĂůŽƵƚĐŽŵĞƐĂŶĚŽĐĐƵƌƌĞŶĐĞƌĂƚĞƐŽĨĐůŝŶŝĐĂůŽƵƚĐŽŵĞƐ͘

^ĞůĞĐƟŽŶ͕ ƋƵĂůŝƚǇ ĂƐƐĞƐƐŵĞŶƚ ĂŶĚ ĚĂƚĂ ĞǆƚƌĂĐƟŽŶ ŽĨ ƐƚƵĚŝĞƐ ƚŽ ďĞ ŝŶĐůƵĚĞĚ ŝŶ

ƚŚŝƐ ƌĞǀŝĞǁ ǁĞƌĞ Ăůů ŝŶĚĞƉĞŶĚĞŶƚůǇ ĚŽŶĞ ďǇ ƚǁŽ ƌĞǀŝĞǁĞƌƐ ;:^ ĂŶĚ DD,Ϳ͘

ŝƐĂŐƌĞĞŵĞŶƚƐǁĞƌĞƌĞƐŽůǀĞĚďǇĐŽŶƐĞŶƐƵƐĂŶĚĚŝƐĐƵƐƐŝŽŶǁŝƚŚĂƚŚŝƌĚƉĂƌƚǇ;Ds,Ϳ͘

<ĂƉƉĂƐƚĂƟƐƟĐƐĨŽƌĂŐƌĞĞŵĞŶƚďĞƚǁĞĞŶƌĞǀŝĞǁĞƌƐǁĞƌĞƉĞƌĨŽƌŵĞĚŵĂŶƵĂůůǇĨŽƌĞĂĐŚ

ƉƌŽĐĞƐƐŝŶƐƚƵĚǇƐĞůĞĐƟŽŶ͘dŚĞŽǀĞƌĂůůŬĂƉƉĂǁĂƐĐĂůĐƵůĂƚĞĚĂƐĂǁĞŝŐŚƚĞĚŵĞĂŶŽĨ

ƚŚŽƐĞĚŝīĞƌĞŶƚǀĂůƵĞƐ͘

^ƚĂƟƐƟĐĂůĂŶĂůǇƐĞƐ

dŽ ƌĞůĂƚĞ ůĂďŽƌĂƚŽƌǇ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ ƚŽ ĐůŝŶŝĐĂů ŽƵƚĐŽŵĞƐ͕ ǁĞ ĐĂůĐƵůĂƚĞĚ ŽĚĚƐ

ƌĂƟŽƐǁŝƚŚĐŽƌƌĞƐƉŽŶĚŝŶŐϵϱйĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂůƐ;/ͿĨŽƌĞĂĐŚƐƚƵĚǇƚŚĂƚƌĞƉŽƌƚĞĚ

ƚŚĞƉƌŽƉŽƌƟŽŶƐŽĨƌĞƐŝƐƚĂŶƚĂŶĚŶŽŶͲƌĞƐŝƐƚĂŶƚƉĂƟĞŶƚƐǁŝƚŚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘

WͲǀĂůƵĞƐ ĂƌĞ ĐĂůĐƵůĂƚĞĚ ǁŝƚŚ ƚŚĞ ʖ^ϮͲƚĞƐƚ Žƌ &ŝƐŚĞƌ͛Ɛ ĞǆĂĐƚ ƚĞƐƚ ǁŚĞƌĞ ĂƉƉƌŽƉƌŝĂƚĞ͘

KĚĚƐ ƌĂƟŽƐ ĨƌŽŵ ĐŽŚŽƌƚ ƐƚƵĚŝĞƐ ǁĞƌĞ ƉŽŽůĞĚ ƵƐŝŶŐ Ă ƌĂŶĚŽŵͲĞīĞĐƚƐ ŵŽĚĞů ;ϭϰͿ͘

dŚŝƐ ƌĂƚŚĞƌ ĐŽŶƐĞƌǀĂƟǀĞ ŵĞƚŚŽĚ ĨŽƌ ŵĞƚĂͲĂŶĂůǇƐŝƐ ĂĐĐŽƵŶƚƐ ĨŽƌ ƚŚĞ ƉŽƐƐŝďŝůŝƚǇ ŽĨ

ƐƚĂƟƐƟĐĂůŝŶƚĞƌͲƐƚƵĚǇŚĞƚĞƌŽŐĞŶĞŝƚǇ͘dŽƚĞƐƚĨŽƌƐƚĂƟƐƟĐĂůŝŶƚĞƌͲƐƚƵĚǇŚĞƚĞƌŽŐĞŶĞŝƚǇ͕

ƚŚĞ ʖ^ϮͲǀĂůƵĞ ǁĂƐ ĐĂůĐƵůĂƚĞĚ ĨŽƌ ƚŚĞ ŚǇƉŽƚŚĞƐŝƐ ŽĨ ŚŽŵŽŐĞŶĞŝƚǇ͘ YƵĂŶƟĮĐĂƟŽŶ ŽĨ

ƚŚĞĞīĞĐƚŽĨŚĞƚĞƌŽŐĞŶĞŝƚǇǁĂƐĂƐƐĞƐƐĞĚďǇŵĞĂŶƐŽĨ/^Ϯ͕ǁŚŝĐŚĚĞŵŽŶƐƚƌĂƚĞƐƚŚĞ

ƉĞƌĐĞŶƚĂŐĞŽĨƚŽƚĂůǀĂƌŝĂƟŽŶĂĐƌŽƐƐƐƚƵĚŝĞƐĚƵĞƚŽŚĞƚĞƌŽŐĞŶĞŝƚǇ͘

tĞƉŽŽůĞĚĂůůĐŽŚŽƌƚƐƚƵĚŝĞƐƌĞƉŽƌƟŶŐĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞƐ͕ĂƐǁĞůůĂƐƐĞǀĞƌĂů

ƐƵďŐƌŽƵƉƐ ŽĨ ĐŽŚŽƌƚ ƐƚƵĚŝĞƐ͘ dŚĞƐĞ ƐƵďŐƌŽƵƉƐ ŝŶĐůƵĚĞĚ ƐƚƵĚŝĞƐ ƌĞƉŽƌƟŶŐ ĐůŝŶŝĐĂů

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ϭϮϮ

ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞŶĚƉŽŝŶƚƐ ĂƐ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĚĞĂƚŚ͕ ŵǇŽĐĂƌĚŝĂů ŝŶĨĂƌĐƟŽŶ͕ ƐƚƌŽŬĞ͕

ĂĐƵƚĞĐŽƌŽŶĂƌǇƐǇŶĚƌŽŵĞĂŶĚƌĞǀĂƐĐƵůĂƌŝǌĂƟŽŶ͖ƐƚƵĚŝĞƐƌĞƉŽƌƟŶŐŽŶ;ƌĞͿŽĐĐůƵƐŝŽŶ

ĂŌĞƌ ďǇƉĂƐƐ ŐƌĂŌŝŶŐ Žƌ ĂŶŐŝŽƉůĂƐƚǇ͖ ĂŶĚ ƐƚƵĚŝĞƐ ƉƌŽǀŝĚŝŶŐ ĚĂƚĂ ŽŶ ŽĐĐƵƌƌĞŶĐĞ ŽĨ

ŵǇŽŶĞĐƌŽƐŝƐ ƌĞƉƌĞƐĞŶƚĞĚ ďǇ ĐƌĞĂƟŶĞ ŬŝŶĂƐĞͲŵǇŽĐĂƌĚŝĂů ďĂŶĚ ;<ͲDͿ ĞůĞǀĂƟŽŶ

ĂŌĞƌ ƉĞƌĐƵƚĂŶĞŽƵƐ ĐŽƌŽŶĂƌǇ ŝŶƚĞƌǀĞŶƟŽŶ͘ tĞ ĂƐƐĞƐƐĞĚ ƉŽƚĞŶƟĂů ƉƵďůŝĐĂƟŽŶ ďŝĂƐ

ŐƌĂƉŚŝĐĂůůǇ͕ƵƐŝŶŐĨƵŶŶĞůƉůŽƚƐŽŶŽĚĚƐƌĂƟŽƐĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ;ϭϱͿ͘

ŶĂůǇƐĞƐǁĞƌĞƉĞƌĨŽƌŵĞĚƵƐŝŶŐŽĐŚƌĂŶĞZĞǀŝĞǁDĂŶĂŐĞƌϰ͘Ϯ͘ϴ;ŽĐŚƌĂŶĞ>ŝďƌĂƌǇ

^ŽŌǁĂƌĞ͕KǆĨŽƌĚ͕h͘<͘Ϳ͘&ŽƌĂůůĂŶĂůǇƐĞƐ͕ĂůĞǀĞůŽĨƐŝŐŶŝĮĐĂŶĐĞŽĨɲсϬ͘ϬϱǁĂƐƵƐĞĚ͘

:^͕DD,ĂŶĚDs,ŚĂĚĨƵůůĂĐĐĞƐƐƚŽĂůůƚŚĞĚĂƚĂŝŶƚŚĞƐƚƵĚǇĂŶĚƚĂŬĞƌĞƐƉŽŶƐŝďŝůŝƚǇ

ĨŽƌƚŚĞŝŶƚĞŐƌŝƚǇŽĨƚŚĞĚĂƚĂĂŶĚƚŚĞĂĐĐƵƌĂĐǇŽĨƚŚĞĚĂƚĂĂŶĂůǇƐŝƐ͘

ZĞƐƵůƚƐ

ŚĂƌĂĐƚĞƌŝƐƟĐƐŽĨŝŶĐůƵĚĞĚƐƚƵĚŝĞƐ

tĞŝŶĐůƵĚĞĚĮŌĞĞŶĨƵůůͲƚĞǆƚĂƌƟĐůĞƐ;ϭϲͲϯϬͿĂŶĚŽŶĞŵĞĞƟŶŐĂďƐƚƌĂĐƚ;ϯϭͿ;&ŝŐƵƌĞ

ϭͿ͘ KǀĞƌĂůů͕ ŬĂƉƉĂ ƐƚĂƟƐƟĐƐ ǁĞƌĞ Ϭ͘ϴϲ͕ ŝŶĚŝĐĂƟŶŐ ŐŽŽĚ ŝŶƚĞƌͲŽďƐĞƌǀĞƌ ĂŐƌĞĞŵĞŶƚ͘

ĞƚĂŝůƐŽĨŝŶĐůƵĚĞĚƐƚƵĚŝĞƐĂƌĞƐƵŵŵĂƌŝǌĞĚŝŶdĂďůĞϭ͘^ƚƵĚŝĞƐĂƌĞŐƌŽƵƉĞĚĂĐĐŽƌĚŝŶŐ

ƚŽƵƐĞĚĞŶĚƉŽŝŶƚƐ͘dĞŶƐƚƵĚŝĞƐƵƐĞĚĂĐŽŵƉŽƐŝƚĞĞŶĚƉŽŝŶƚŽĨĐůŝŶŝĐĂůĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ĞǀĞŶƚƐ ;ϭϲͲϮϰ͕ϯϭͿ͘ /Ŷ ĨŽƵƌ ƌĞƉŽƌƚƐ͕ ƚŚĞ ƐƚƵĚŝĞĚ ŽƵƚĐŽŵĞ ǁĂƐ ;ƌĞͿŽĐĐůƵƐŝŽŶ ĂŌĞƌ

ďǇƉĂƐƐŐƌĂŌŝŶŐŽƌĂŶŐŝŽƉůĂƐƚǇ;ϮϱͲϮϴͿ͘dǁŽƐƚƵĚŝĞƐĂƐƐĞƐƐĞĚŵǇŽŶĞĐƌŽƐŝƐ͕ĚĞĮŶĞĚďǇ

ĞůĞǀĂƚĞĚ<ͲDůĞǀĞůƐ͕ĂŌĞƌƉĞƌĐƵƚĂŶĞŽƵƐĐŽƌŽŶĂƌǇŝŶƚĞƌǀĞŶƟŽŶ;Ϯϵ͕ϯϬͿ͘

hƐĞĚĂƐƉŝƌŝŶĚŽƐĂŐĞǀĂƌŝĞĚĨƌŽŵϴϬŵŐƚŽϭϱϬϬŵŐĚĂŝůǇ;ϭϲ͕Ϯϵ͕ϯϭͿ͕ƚŚŽƵŐŚŶĞĂƌůǇ

Ăůů ƐƚƵĚŝĞƐ ƵƐĞĚ Ă ůŽǁ ƚŽ ŝŶƚĞƌŵĞĚŝĂƚĞ ĚŽƐĂŐĞ ďĞƚǁĞĞŶ ϴϬ ĂŶĚ ϯϮϱ ŵŐ ;ϭϳͲϯϭͿ͘

sĂƌŝŽƵƐŵĞƚŚŽĚƐǁĞƌĞƵƐĞĚƚŽĞƐƚĂďůŝƐŚƚŚĞĞīĞĐƚƐŽĨĂƐƉŝƌŝŶŽŶƉůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇ͘

ŽŶǀĞŶƟŽŶĂů ŽƉƟĐĂů ůŝŐŚƚ ƚƌĂŶƐŵŝƩĂŶĐĞ ĂŐŐƌĞŐŽŵĞƚƌǇ ǁĂƐ ƵƐĞĚ ŝŶ ĮǀĞ ƐƚƵĚŝĞƐ

;Ϯϭ͕Ϯϰ͕Ϯϱ͕Ϯϴ͕ϯϬͿ͘DƵůƟƉůĞĂŐŽŶŝƐƚƐǁĞƌĞƵƐĞĚƚŽŝŶĚƵĐĞĂŐŐƌĞŐĂƟŽŶ͘dŚƌĞĞƐƚƵĚŝĞƐ

ĚĞƚĞƌŵŝŶĞĚƚŚƌŽŵďŽǆĂŶĞϮŝŶƉůĂƐŵĂŽƌƵƌŝŶĞ;ϭϵ͕ϮϮ͕ϮϴͿ͕ǁŚŝĐŚŝƐĂƐƚĂďůĞŵĞƚĂďŽůŝƚĞ

ŽĨƚŚƌŽŵďŽǆĂŶĞϮ͘&ŝǀĞƐƚƵĚŝĞƐƵƐĞĚƚŚĞƉůĂƚĞůĞƚĨƵŶĐƟŽŶĂŶĂůǇǌĞƌ;W&ͿϭϬϬƐǇƐƚĞŵ

;ĂĚĞĞŚƌŝŶŐ͕ĞĞƌĮĞůĚ͕/ůůŝŶŽŝƐ͕h^Ϳ͕ǁŚŝĐŚŵĞĂƐƵƌĞƐŝŶǀŝƚƌŽƐŚĞĂƌͲƐƚƌĞƐƐͲŝŶĚƵĐĞĚ

ƉůĂƚĞůĞƚĂĐƟǀĂƟŽŶŝŶƚĞƌŵƐŽĨƉůĂƚĞůĞƚŽĐĐůƵƐŝŽŶŽĨĂŵĞŵďƌĂŶĞĐŽĂƚĞĚǁŝƚŚƉůĂƚĞůĞƚ

ĂŐŽŶŝƐƚƐ;ϭϴ͕ϮϬ͕Ϯϯ͕Ϯϲ͕ϮϳͿ͘/ŶƚŚƌĞĞƐƚƵĚŝĞƐƉůĂƚĞůĞƚĨƵŶĐƟŽŶǁĂƐĂƐƐĞƐƐĞĚǁŝƚŚƚŚĞ

(8)

ϭϮϯ hůƚĞŐƌĂͬsĞƌŝĨǇ EŽǁ ƌĂƉŝĚ ƉůĂƚĞůĞƚ ĨƵŶĐƟŽŶ ĂƐƐĂǇ ;ZW&͕ ĐĐƵŵĞƚƌŝĐƐ͕ ^ĂŶ ŝĞŐŽ͕

ĂůŝĨŽƌŶŝĂ͕h^Ϳ͕ǁŚŝĐŚŵĞĂƐƵƌĞƐĐŚĂŶŐĞƐŝŶůŝŐŚƚƚƌĂŶƐŵŝƩĂŶĐĞƌĞůĂƚĞĚƚŽƚŚĞƌĂƚĞŽĨ

ĂŐŐƌĞŐĂƟŽŶ͕ƵƐŝŶŐĂĚŝƐƉŽƐĂďůĞĐĂƌƚƌŝĚŐĞǁŝƚŚĮďƌŝŶŽŐĞŶͲĐŽĂƚĞĚďĞĂĚƐĂŶĚĂƉůĂƚĞůĞƚ

ĂĐƟǀĂƚŽƌ ;ϮϵͲϯϭͿ͘ dŚƌĞĞ ƐƚƵĚŝĞƐ ĞŵƉůŽǇĞĚ ŽƚŚĞƌ ƚĞĐŚŶŝƋƵĞƐ ;ϭϲ͕ϭϳ͕ϮϴͿ͘ &ŽůůŽǁͲƵƉ

ƌĂŶŐĞĚĨƌŽŵϲͲϴŚŽƵƌƐ;<ͲDĞůĞǀĂƟŽŶͿƚŽŵŽƌĞƚŚĂŶϳ͘ϱǇĞĂƌƐ;Ϯϳ͕ϮϵͿ͘

&ŝŐƵƌĞϭͲ&ůŽǁĐŚĂƌƚŽĨƚŚĞƉƌŽĐĞƐƐŽĨƐƚƵĚǇƐĞůĞĐƟŽŶ 1978 Potentially relevant studies identified

by search strategy for retrieval

232 Studies retrieved for evaluation of abstracts

157 Potentially appropriate studies to be included in the meta-analysis

104 Potentially appropriate studies to be included in the meta-analysis after deleting duplicate articles

16 Studies included in the meta-analysis (15 articles and 1 meeting abstract)

1746 Studies excluded by the title evaluation because they did not address aspirin resistance

75 Studies excluded by the abstract evaluation because they did not fulfill inclusion criteria

53 Studies excluded because of duplicate retrieval (from different databases) or the studies’

meeting abstracts were already included in our analysis

88 Studies excluded by thorough article evaluation because they did not fulfill inclusion criteria or were of insufficient quality. Most of them (n = 64) did provide data on prevalence of LAR, which was addressed in a previous meta-analysis,¹³ but did not contain sufficient data on clinical consequences of LAR

(9)

ϭϮϰ

dĂďůĞϭͲĞƚĂŝůƐŽĨŝŶĐůƵĚĞĚƐƚƵĚŝĞƐ

/ŶǀĞƐƟŐĂƚŽƌƐ ĞƐŝŐŶ WŽƉƵůĂƟŽŶ͕

Ŷ ƐƉŝƌŝŶĚŽƐĞ

;ŵŐͬĚͿ ƐƐĞƐƐŵĞŶƚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ KƵƚĐŽŵĞ 'ƌŽƚĞŵĞǇĞƌĞƚ

Ăů͕͘ϭϵϵϯ^ϭϲ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ ^ƚƌŽŬĞ

ϭϴϬ ϭϱϬϬŵŐ WůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇŝŶĚĞǆхϭ͘Ϯϱ͕

ƵƐŝŶŐĂƚĞĐŚŶŝƋƵĞƌĞŇĞĐƟŶŐ

ƉůĂƚĞůĞƚĂĐƟǀĂƟŽŶĨŽůůŽǁŝŶŐďůŽŽĚ

ƐĂŵƉůŝŶŐ^ϯϳ

sĚĞĂƚŚ͕D/͕ƐƚƌŽŬĞ

ƵĐŚĂŶĂŶĞƚĂů͕͘

ϮϬϬϬ^ϭϳ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ '

Ϯϴϵ ϯϮϱŵŐ sĂƌŝĂƟŽŶĐŽĞĸĐŝĞŶƚďůĞĞĚŝŶŐƟŵĞ

фϮϲйǁŝƚŚĂŶĚǁŝƚŚŽƵƚĂƐƉŝƌŝŶ ;ϭͿĞĂƚŚ͕D/͕ƐƚƌŽŬĞ͕

ŐƌĂŌŽĐĐůƵƐŝŽŶ

ŶĚĞƌƐĞŶĞƚĂů͕͘

ϮϬϬϮ^ϭϴ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ

ϳϭ ϭϲϬŵŐ W&ͲϭϬϬW/ͲdчϭϵϲƐ EŽŶͲĨĂƚĂůD/͕ƐƚƌŽŬĞ͕

ƌĞǀĂƐĐƵůĂƌŝǌĂƟŽŶ

ŝŬĞůďŽŽŵĞƚĂů͕͘

ϮϬϬϮ^ϭϵ EĞƐƚĞĚ

ĐĂƐĞͲĐŽŶƚƌŽů

ŽĨ,KW

ƐƚƵĚǇ^ϯϴ͖ϯϵ

sĚŝƐĞĂƐĞ ϰϴϴĐĂƐĞƐ

ϰϴϴĐŽŶƚƌŽůƐ

EŽƚƌĞƉŽƌƚĞĚ hƌŝŶĂƌǇdǆ_Ϯ͗ϰ^ƚŚƋƵĂƌƟůĞ;ŵŽƐƚ

ƉůĂƚĞůĞƚĂĐƟǀĂƟŽŶͿůĞĂƐƚƐĞŶƐŝƟǀĞ sĚĞĂƚŚ͕D/͕ƐƚƌŽŬĞ

'ƌƵŶĚŵĂŶŶĞƚ

Ăů͕͘ϮϬϬϯ^ϮϬ ĂƐĞͲĐŽŶƚƌŽů ^ƚƌŽŬĞ ϯϱĐĂƐĞƐ ϭϴĐŽŶƚƌŽůƐ

ϭϬϬŵŐ W&ͲϭϬϬW/ͲdчϭϲϱƐ ^ƚƌŽŬĞ͕ƚƌĂŶƐŝĞŶƚ

ŝƐĐŚĞŵŝĐĂƩĂĐŬ 'ƵŵĞƚĂů͕͘

ϮϬϬϯ^Ϯϭ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ sĚŝƐĞĂƐĞ

ϯϮϲ ϯϮϱŵŐ >dшϳϬй;ϭϬʅŵŽůͬ>WͿĂŶĚш

ϮϬй;Ϭ͘ϱŵŐͬŵ>Ϳ sĚĞĂƚŚ͕D/͕ƐƚƌŽŬĞ

ŽƩĞƌĞƚĂů͕͘

ϮϬϬϰ^ϮϮ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ

ϳϯ ϭϬϬŵŐ WůĂƐŵĂͲdǆ_ϮхůŽǁĞƐƚǀĂůƵĞĨŽƵŶĚ

ŝŶĂƐƉŝƌŝŶŶŽŶͲƵƐĞƌƐ sĚĞĂƚŚ͕D/͕ƐƚƌŽŬĞ͕

sͲƌĞůĂƚĞĚĂĚŵŝƐƐŝŽŶ

ŚĞŶŐĞƚĂů͕͘

ϮϬϬϱ^ϯϭ

;ĂďƐƚƌĂĐƚͿ

WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ

ϰϮϮ ϴϬͲϯϬϬŵŐ ZW&ZhшϱϱϬ ĞĂƚŚ͕D/͕ƐƚƌŽŬĞ͕

ĂĚŵŝƐƐŝŽŶĨŽƌƵŶƐƚĂďůĞ

ĂŶŐŝŶĂ WĂŵƵŬĐƵĞƚĂů͕͘

ϮϬϬϲ^Ϯϯ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ

ϭϬϱ ϭϬϬͲϯϬϬŵŐ W&ͲϭϬϬW/ͲdфϭϴϲƐ sĚĞĂƚŚ͕D/͕ƐƚƌŽŬĞ͕

ƵŶƐƚĂďůĞĂŶŐŝŶĂ

^ƚĞũƐŬĂůĞƚĂů͕͘

ϮϬϬϲ^Ϯϰ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ

ϭϬϯ ϭϬϬŵŐ >dшϱй;ƐƉŽŶƚĂŶĞŽƵƐͿŽƌшϱϯй

;ϯʅŵŽůͬ>ĐĂƟŽŶŝĐƉƌŽƉǇůŐĂůůĂƚĞͿ D/͕ƐƚƌŽŬĞ͕ƵŶƐƚĂďůĞ

ĂŶŐŝŶĂ DƵĞůůĞƌĞƚĂů͕͘

ϭϵϵϳ^Ϯϱ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ WͬWd

ϭϬϬ ϭϬϬŵŐ >d;ϭϬĂŶĚϱʅŵŽůͬ>WĂŶĚϱ

ĂŶĚϮʅŐͬŵ>ĐŽůůĂŐĞŶͿ͕ŽŶĂǀĞƌĂŐĞ

хϴϬйŽĨďĂƐĞůŝŶĞ

ZĞŽĐĐůƵƐŝŽŶ

ŝĞŐůĞƌĞƚĂů͕͘

ϮϬϬϮ^Ϯϲ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ Wͬ

WdϱϮ

ϭϬϬŵŐ W&ͲϭϬϬW/ͲdчϭϳϬƐ ZĞƐƚĞŶŽƐŝƐ͕ƌĞŽĐĐůƵƐŝŽŶ

zŝůŵĂǌĞƚĂů͕͘

ϮϬϬϱ^Ϯϳ ĂƐĞͲĐŽŶƚƌŽů ' ϭϰĐĂƐĞƐ ϭϰĐŽŶƚƌŽůƐ

ĂƐĞƐ͗ϭϴϵц

ϭϬϬŵŐ͕Ž͗

ϮϭϰцϵϬŵŐ

W&ͲϭϬϬW/ͲdчϭϵϯƐ 'ƌĂŌŽĐĐůƵƐŝŽŶ

WŽƐƚŽŶĞƚĂů͕͘

ϮϬϬϲ^Ϯϴ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ '

ϮϮϱ ϯϮϱŵŐ ϮŽĨϯ͗d';Ϭ͘ϱʅŵŽůͬ>ͿхϱϬй͕

>d;ϭĂŶĚϱʅŐͬŵ>ĐŽůůĂŐĞŶͿхϱϬй͕

WůĂƐŵĂͲdǆ_ϮхϮϱйŽĨďĂƐĞůŝŶĞ

'ƌĂŌŽĐĐůƵƐŝŽŶ

ŚĞŶĞƚĂů͕͘

ϮϬϬϰ^Ϯϵ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ W/

ϭϱϭ ϴϬͲϯϬϬŵŐ ZW&ZhшϱϱϬ DǇŽŶĞĐƌŽƐŝƐ;<ͲDх

ϭϲhͬ>Ϳ

>ĞǀĞƚĂů͕͘

ϮϬϬϲ^ϯϬ WƌŽƐƉĞĐƟǀĞ

ĐŽŚŽƌƚ W/

ϭϱϬ ϴϭͲϯϮϱŵŐ ϮŽĨϯ͗>dшϳϬй;ϭϬʅŵŽůͬ>WͿ͕

>dшϮϬй;Ϭ͘ϱŵŐͬŵ>Ϳ͕ZW&

ZhшϱϱϬ

DǇŽŶĞĐƌŽƐŝƐ;<ͲDх

ϱ͘ϬŶŐͬŵ>Ϳ

(10)

ϭϮϱ dĂďůĞϭĐŽŶƟŶƵĞĚͲĞƚĂŝůƐŽĨŝŶĐůƵĚĞĚƐƚƵĚŝĞƐ

&ŽůůŽǁͲƵƉ

ƟŵĞ ZĞƐŝƐƚĂŶĐĞ͕

Ŷ;йͿ ůŝŶŝĐĂůĐŽŶƐĞƋƵĞŶĐĞƐ͕ƌĞƐŝƐƚĂŶƚǀƐ͘

ŶŽŶͲƌĞƐŝƐƚĂŶƚƉĂƟĞŶƚƐ ŽŵŵĞŶƚƐ

ϮǇĞĂƌƐ ϲϬ;ϯϯйͿ ϮϰͬϲϬ;ϰϬйͿǀƐ͘ϱͬϭϭϰ;ϰйͿ

KZϭϰ͘ϱ͕ϵϱй/ϱ͘ϮͲϰϬͲϵ͕ƉфϬ͘ϬϬϬϭ sĞƌǇŚĞƚĞƌŽŐĞŶĞŽƵƐĚŝƐƚƌŝďƵƟŽŶŽĨǁŝƚŚĚƌĂǁĂůƐ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ͕ĂĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϮǇĞĂƌƐ ϭϱϴ;ϱϱйͿ ϭϱͬϭϱϴ;ϭϬйͿǀƐ͘ϵͬϭϯϭ;ϳйͿ

KZϭ͘ϰ͕ϵϱй/Ϭ͘ϲͲϯ͘ϰ͕ƉсϬ͘ϰϮϭ ůĞĞĚŝŶŐƟŵĞƉŽŽƌůǇĞƐƚĂďůŝƐŚĞĚĨŽƌƚŚŝƐŐŽĂů

>ŽǁĞǀĞŶƚƌĂƚĞƐ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ ϰǇĞĂƌƐ Ϯϱ;ϯϱйͿ ϵͬϮϱ;ϯϲйͿǀƐ͘ϭϭͬϰϲ;ϮϰйͿ

KZϭ͘ϴ͕ϵϱй/Ϭ͘ϲͲϱ͘Ϯ͕ƉсϬ͘ϮϴϬ ^ŵĂůůŐƌŽƵƉƐ͕ŶŽĞǆĐůƵƐŝŽŶĐƌŝƚĞƌŝĂ;ĐŽŶĨŽƵŶĚŝŶŐͿ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϱǇĞĂƌƐ EŽƚ

ƌĞƉŽƌƚĞĚ WƌŽƉŽƌƟŽŶƐŶŽƚƌĞƉŽƌƚĞĚ

ZĞƉŽƌƚĞĚKZƵƉƉĞƌǀƐ͘ůŽǁĞƌƋƵĂƌƟůĞс

ϭ͘ϴ͕ϵϱй/сϭ͘ϮͲϮ͘ϵ͕ƉсϬ͘ϬϬϵ

ŽŶĨŽƵŶĚĞƌƐĐĂƐĞƐͬĐŽŶƚƌŽůƐ͗ŝĂďĞƚĞƐ͕ďŽĚǇŵĂƐƐŝŶĚĞǆ͕

ƚĞŶƐŝŽŶ͕ƉĞƌŝƉŚĞƌĂůĂƌƚĞƌǇĚŝƐĞĂƐĞ

dǆ_ϮĐŽƵůĚďĞŝŶŇƵĞŶĐĞĚďǇƌĞĐĞŶƚĞǀĞŶƚƐ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ͕ĂĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ хϮǇĞĂƌƐ ϭϮ;ϮϯйͿ ĂƐĞƐǀƐ͘ĐŽŶƚƌŽůƐ͗ϭϮͬϯϱ;ϯϰйͿǀƐ͘Ϭͬϭϴ

;ϬйͿƌĞƐŝƐƚĂŶƚ

KZϲ͘ϴ͕ϵϱй/ϭ͘ϴͲϮϲ͘Ϯ͕ƉсϬ͘ϬϬϰ

^ŵĂůůƐĂŵƉůĞƐŝǌĞ

ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĐĂƵƐĞŽƌƌĞƐƵůƚŽĨĞǀĞŶƚƐ͍

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ͕ĂĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ ϲϳϵцϭϯϳ

ĚĂǇƐ ϭϳ;ϱйͿ ϰͬϭϳ;ϮϰйͿǀƐ͘ϯϬͬϯϬϵ;ϭϬйͿ

KZϮ͘ϵ͕ϵϱй/Ϭ͘ϵͲϵ͘ϯ͕ƉсϬ͘Ϭϴϴ &ĞǁƉĂƟĞŶƚƐƌĞƐŝƐƚĂŶƚ͕ĨĞǁĞǀĞŶƚƐ

&ŽůůŽǁͲƵƉƟŵĞŶŽƚƐƉĞĐŝĮĞĚĨŽƌĂƐƉŝƌŝŶƌĞƐƉŽŶƐĞ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ͕ĂĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ ϭǇĞĂƌ Ϯϭ;ϮϵйͿ ϲͬϮϭ;ϮϵйͿǀƐ͘ϯͬϱϮ;ϲйͿ

KZϲ͘ϱ͕ϵϱй/ϭ͘ϱͲϮϵ͘ϯ͕ƉсϬ͘Ϭϭϰ ^ŵĂůůŐƌŽƵƉƐ͕ŶŽĞǆĐůƵƐŝŽŶĐƌŝƚĞƌŝĂ;ĐŽŶĨŽƵŶĚŝŶŐͿ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ EŽƚƌĞƉŽƌƚĞĚ ϭϭϯ;ϮϳйͿ WƌŽƉŽƌƟŽŶƐŶŽƚƌĞƉŽƌƚĞĚ

ZĞƉŽƌƚĞĚŚĂǌĂƌĚƌĂƟŽϮ͘ϵ͕ϵϱй/ϭ͘ϱͲϱ͘ϳ͕

ƉсϬ͘ϬϬϮ

&ŽůůŽǁͲƵƉƟŵĞĂŶĚĂďƐŽůƵƚĞĞǀĞŶƚƌĂƚĞƐŶŽƚƌĞƉŽƌƚĞĚ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϭǇĞĂƌ ϮϬ;ϭϵйͿ ϵͬϮϬ;ϰϱйͿǀƐ͘ϭϬͬϴϱ;ϭϮйͿ

KZϲ͘ϭ͕ϵϱй/Ϯ͘ϬͲϭϴ͘ϱ͕ƉфϬ͘ϬϬϭ ^ƵďũĞĐƟǀĞĞŶĚƉŽŝŶƚ;ƵŶƐƚĂďůĞĂŶŐŝŶĂͿ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϰǇĞĂƌƐ ϱϳ;ϱϱйͿ ϱϬͬϱϳ;ϴϴйͿǀƐ͘Ϯϭͬϰϲ;ϰϲйͿ

KZϴ͘ϱ͕ϵϱй/ϯ͘ϮͲϮϮ͘ϳ͕ƉфϬ͘ϬϬϬϭ ^ƵďũĞĐƟǀĞĞŶĚƉŽŝŶƚ;ƵŶƐƚĂďůĞĂŶŐŝŶĂͿ

ĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϭ͘ϱǇĞĂƌƐ ϲϱ;ϲϱйͿ

;ĂŌĞƌϰ

ǁĞĞŬƐͿ

ϴͬϲϱ;ϭϮйͿǀƐ͘Ϭͬϯϱ;ϬйͿ

KZϭϬ͘ϱ͕ϵϱй/Ϭ͘ϲͲϭϴϳ͘ϱͿ͕ƉсϬ͘Ϭϰϴ ZĞĂƐŽŶƐĨŽƌĞǆĐůƵƐŝŽŶŶŽƚŵĞŶƟŽŶĞĚ

ůůƉĂƟĞŶƚǁĞƌĞƐĞŶƐŝƟǀĞǁŝƚŚͲĂŐŐƌĞŐŽŵĞƚƌǇ͕

ŵĂŬŝŶŐƌĞĐƵƌƌĞŶĐĞƌĂƚĞƐůĞƐƐƌĞůĂƚĞĚƚŽƌĞƐŝƐƚĂŶĐĞ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϭǇĞĂƌ ϱ;ϭϬйͿ Ϭͬϱ;ϬйͿǀƐ͘ϭϯͬϰϳ;ϮϴйͿ

KZϬ͘Ϯ͕ϵϱй/Ϭ͘ϬͲϰ͘ϱ͕ƉсϬ͘ϯϭϰ ^ŵĂůůƐĂŵƉůĞƐŝǌĞ͕ĨĞǁŶŽŶͲƌĞƐƉŽŶĚĞƌƐ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ

ĂƐĞƐ͗ϳ͘ϱц

ϯ͘ϵǇƌƐ͕Ž͗

ϲ͘ϮцϮ͘ϱǇƌƐ

ϴ;ϮϵйͿ ĂƐĞƐǀƐ͘ĐŽŶƚƌŽůƐ͗ϳͬϭϰ;ϱϬйͿǀƐ͘ϭͬϭϰ

;ϳйͿƌĞƐŝƐƚĂŶƚ

KZϭϯ͘Ϭ͕ϵϱй/ϭ͘ϯͲϭϮϴ͘ϭ͕ƉсϬ͘Ϭϯϯ

DŽƐƚĐĂƐĞƐŚĂĚĂĐƵƚĞĐŽƌŽŶĂƌǇƐǇŶĚƌŽŵĞĂƚ

ƉƌĞƐĞŶƚĂƟŽŶǀƐ͘ƐƚĂďůĞĂŶŐŝŶĂŝŶĐŽŶƚƌŽůƐƵďũĞĐƚƐ

ZĞƐŝƐƚĂŶĐĞĚĞƚĞƌŵŝŶĞĚŽŶĐĞ͕ĂĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ ϯϬĚĂǇƐ ϮϮ;ϭϬйͿ

;ŽŶĚĂǇϭͿ ϰͬϮϮ;ϭϴйͿǀƐ͘ϭϮͬϮϬϯ;ϲйͿ

KZϯ͘ϱ͕ϵϱй/ϭ͘ϬͲϭϮ͘ϭ͕ƉсϬ͘Ϭϱϳ sĞƌǇůŽǁĞǀĞŶƚƌĂƚĞƐ

ĚŚĞƌĞŶĐĞŶŽƚĂƐƐĞƐƐĞĚ ϲͲϴŚŽƵƌƐ

ĂŌĞƌW/ Ϯϵ;ϭϵйͿ ϭϱͬϮϵ;ϱϮйͿǀƐ͘ϯϬͬϭϮϮ;ϮϱйͿ

KZϯ͘ϯ͕ϵϱй/ϭ͘ϰͲϳ͘ϲ͕ƉсϬ͘ϬϬϰ ƐŝĂŶƉŽƉƵůĂƟŽŶ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ ϮϬͲϮϰŚŽƵƌƐ

ĂŌĞƌW/ ϭϵ;ϭϯйͿ ϳͬϭϴ;ϯϴ͘ϵйͿǀƐ͘ϮϯͬϭϮϲ;ϭϴ͘ϯйͿ

KZϮ͘ϵ͕ϵϱй/ϭ͘ϬͲϴ͘ϭ͕ƉсϬ͘Ϭϰϱ <ͲDǀĂůƵĞƐŶŽƚĂǀĂŝůĂďůĞĨŽƌϲƉĂƟĞŶƚƐ

ĚũƵĚŝĐĂƟŽŶĞŶĚƉŽŝŶƚƐƵŶďůŝŶĚĞĚ

(11)

ϭϮϲ

ďďƌĞǀŝĂƟŽŶƐ͗ ͗ ĂƌĂĐŚŝĚŽŶŝĐ ĂĐŝĚ͖ W͗ ĂĚĞŶŽƐŝŶĞ ĚŝƉŚŽƐƉŚĂƚĞ͖ Zh͗ ĂƐƉŝƌŝŶ ƌĞƐƉŽŶƐĞ ƵŶŝƚ͖ '͗

ĐŽƌŽŶĂƌǇĂƌƚĞƌǇďǇƉĂƐƐŐƌĂŌ͖͗ĐŽƌŽŶĂƌǇĂƌƚĞƌǇĚŝƐĞĂƐĞ͖W/Ͳd͗ĐŽůůĂŐĞŶĞƉŝŶĞƉŚƌŝŶĞĐůŽƐƵƌĞƟŵĞ͖/͗

ĐŽŶĮĚĞŶĐĞŝŶƚĞƌǀĂů͖<ͲD͗ĐƌĞĂƟŶĞŬŝŶĂƐĞͲŵǇŽĐĂƌĚŝĂůďĂŶĚ͕s͗ĐĂƌĚŝŽǀĂƐĐƵůĂƌ͖>d͗ůŝŐŚƚƚƌĂŶƐŵŝƐƐŝŽŶ

ĂŐŐƌĞŐŽŵĞƚƌǇ͖D/͗ŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶ͖KZ͗ŽĚĚƐƌĂƟŽ͖W͗ƉĞƌŝƉŚĞƌĂůĂƌƚĞƌǇĚŝƐĞĂƐĞ͖W/͗ƉĞƌĐƵƚĂŶĞŽƵƐ

ĐŽƌŽŶĂƌǇ ŝŶƚĞƌǀĞŶƟŽŶ͖ W&ͲϭϬϬ͗ ƉůĂƚĞůĞƚ ĨƵŶĐƟŽŶ ĂŶĂůǇǌĞƌͲϭϬϬ͖ Wd͗ ƉĞƌĐƵƚĂŶĞŽƵƐ ƚƌĂŶƐůƵŵŝŶĂů

ĂŶŐŝŽƉůĂƐƚǇ͕ZW&͗ƌĂƉŝĚƉůĂƚĞůĞƚĨƵŶĐƟŽŶĂƐƐĂǇ͖d'͗ƚŚƌŽŵďĞůĂƐƚŽŐƌĂƉŚǇ͖dǆϮ͗ƚŚƌŽŵďŽǆĂŶĞϮ͘

ZĞůĂƟŽŶďĞƚǁĞĞŶůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂŶĚĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞ WƌĞǀĂůĞŶĐĞ ŽĨ ůĂďŽƌĂƚŽƌǇ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ ƌĂŶŐĞĚ ĨƌŽŵ ϱ ƚŽ ϲϱй ;Ϯϭ͕ϮϱͿ͘ /Ŷ ƚŚĞ

ϭϮƐƚƵĚŝĞƐĞůŝŐŝďůĞĨŽƌƉŽŽůŝŶŐ;ϭϲͲϭϴ͕ϮϭͲϮϲ͕ϮϴͲϯϬͿ͕ƚŽƚĂůůǇŝŶĐůƵĚŝŶŐϭϴϭϯƉĂƟĞŶƚƐ͕

ƚŚĞ ŵĞĂŶ ƉƌĞǀĂůĞŶĐĞ ŽĨ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ ǁĂƐ Ϯϳй͘ dŚĞ ƚŽƚĂů ǀĂƌŝĂƟŽŶ ďĞƚǁĞĞŶ

ƚŚĞƐĞƐƚƵĚŝĞƐ͕ůŝŬĞůǇƌĞŇĞĐƟŶŐĂĨŽƌĞŵĞŶƟŽŶĞĚĚŝīĞƌĞŶĐĞƐ͕ǁĂƐϰϵй͕ƌĞƐƵůƟŶŐŝŶĂ

ƐŝŐŶŝĮĐĂŶƚƐƚĂƟƐƟĐĂůŚĞƚĞƌŽŐĞŶĞŝƚǇĂŵŽŶŐƐƚƵĚŝĞƐ;ƉсϬ͘ϬϯͿ͘

KĚĚƐ ƌĂƟŽƐ ŽĨ ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ŽƵƚĐŽŵĞ ǀĂƌŝĞĚ ĨƌŽŵ Ϭ͘Ϯ ;ϵϱй/ Ϭ͘ϬͲϰ͘ϱͿ ƚŽ ϭϰ͘ϱ

;ϵϱй/ϱ͘ϮͲϰϬ͘ϵͿĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ;ϭϲ͕ϮϲͿ͘tĞƉŽŽůĞĚƚŚĞŽĚĚƐƌĂƟŽƐŽĨƐĞǀĞƌĂů

ŐƌŽƵƉƐ ŽĨ ƐƚƵĚŝĞƐ͕ ǁŚŝĐŚ ŝƐ ŐƌĂƉŚŝĐĂůůǇ ƉƌĞƐĞŶƚĞĚ ŝŶ &ŝŐƵƌĞ Ϯ͘ tŚĞŶ ƐƚƵĚŝĞƐ ǁŝƚŚ

ĐůŝŶŝĐĂůĐĂƌĚŝŽǀĂƐĐƵůĂƌĞŶĚƉŽŝŶƚƐĂƌĞƉŽŽůĞĚ;ϭϲͲϭϴ͕ϮϭͲϮϰͿ͕ƚŚĞƌĞƐƵůƚĂŶƚŽĚĚƐƌĂƟŽ

ĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝƐϰ͘ϰ;ϵϱй/Ϯ͘ϮͲϴ͘ϳͿ͘/ŶƚŚƌĞĞĐŽŚŽƌƚƐƚƵĚŝĞƐĂĚĚƌĞƐƐŝŶŐ;ƌĞͿ ŽĐĐůƵƐŝŽŶ ĂŌĞƌ ŝŶƚĞƌǀĞŶƟŽŶĂů ƉƌŽĐĞĚƵƌĞƐ ;Ϯϱ͕Ϯϲ͕ϮϴͿ͕ ƚŚĞ ƉŽŽůĞĚ ŽĚĚƐ ƌĂƟŽ ŝƐ Ϯ͘ϰ

;ϵϱй/Ϭ͘ϰͲϭϰ͘ϯͿ͘dŚĞŽĚĚƐƌĂƟŽŽĨŵǇŽŶĞĐƌŽƐŝƐŝƐϯ͘ϭ;ϵϱй/ϭ͘ϲͲϲ͘ϬͿ;Ϯϵ͕ϯϬͿ͘tŚĞŶ

ĂůůƚŚĞƐĞƐƚƵĚŝĞƐĂƌĞĐŽŵďŝŶĞĚ͕ƚŚĞƉŽŽůĞĚŽĚĚƐƌĂƟŽŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞŝƐ

ϯ͘ϴ;ϵϱй/Ϯ͘ϯͲϲ͘ϭͿĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘tĞĂůƐŽƐƚƌĂƟĮĞĚĨŽƌƵƐĞĚĂƐƉŝƌŝŶĚŽƐĂŐĞ͕

ŚŽǁĞǀĞƌ͕ŶŽĚŝīĞƌĞŶĐĞƐďĞƚǁĞĞŶĚŽƐĂŐĞŐƌŽƵƉƐ;чϭϬϬŵŐ͕ϭϬϭͲϮϵϵŵŐĂŶĚшϯϬϬ

ŵŐͿǁĞƌĞĨŽƵŶĚ͘dŚĞƐƚƵĚŝĞƐŶŽƚŝŶĐůƵĚĞĚŝŶƚŚĞĂŶĂůǇƐŝƐ͕ĨŽƌŶŽƚďĞŝŶŐĂĐŽŚŽƌƚƐƚƵĚǇ

ŽƌŶŽƚƌĞƉŽƌƟŶŐƉƌŽƉŽƌƟŽŶƐŽĨƌĞƐŝƐƚĂŶƚĂŶĚŶŽŶͲƌĞƐŝƐƚĂŶƚƉĂƟĞŶƚƐ͕ƐŚŽǁĞĚƐŝŵŝůĂƌ

ƌĞƐƵůƚƐ;dĂďůĞϭͿ;ϭϵ͕ϮϬ͕Ϯϳ͕ϯϭͿ͘

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ϭϮϳ

&ŝŐƵƌĞϮͲ&ŽƌĞƐƚƉůŽƚƐŽĨŽĚĚƐƌĂƟŽƐŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĨƌŽŵ

ĞůŝŐŝďůĞ ƐƚƵĚŝĞƐ͘ /Ŷ ƉĂƌƚ ϭ͕ Ăůů ƐƚƵĚŝĞƐ ǁŝƚŚ ĐůŝŶŝĐĂů ĐĂƌĚŝŽǀĂƐĐƵůĂƌ ĞŶĚƉŽŝŶƚƐ ;ĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ĚĞĂƚŚ͕ ŵǇŽĐĂƌĚŝĂů ŝŶĨĂƌĐƟŽŶ͕ ƐƚƌŽŬĞ͕ ĂĐƵƚĞ ĐŽƌŽŶĂƌǇ ƐǇŶĚƌŽŵĞ ĂŶĚ ƌĞǀĂƐĐƵůĂƌŝǌĂƟŽŶͿ ĂƌĞ

ƉůŽƩĞĚ͖ŝŶƉĂƌƚϮƐƚƵĚŝĞƐƌĞƉŽƌƟŶŐŽŶ;ƌĞͿŽĐĐůƵƐŝŽŶĂŌĞƌďǇƉĂƐƐŐƌĂŌŝŶŐŽƌĂŶŐŝŽƉůĂƐƚǇ͖ĂŶĚ

ŝŶƉĂƌƚϯƐƚƵĚŝĞƐƉƌŽǀŝĚŝŶŐĚĂƚĂŽŶŽĐĐƵƌƌĞŶĐĞŽĨŵǇŽŶĞĐƌŽƐŝƐƌĞƉƌĞƐĞŶƚĞĚďǇĐƌĞĂƟŶĞŬŝŶĂƐĞͲ ŵǇŽĐĂƌĚŝĂů ďĂŶĚ ;<ͲDͿ ĞůĞǀĂƟŽŶ ĂŌĞƌ ƉĞƌĐƵƚĂŶĞŽƵƐ ĐŽƌŽŶĂƌǇ ŝŶƚĞƌǀĞŶƟŽŶ͘ /Ŷ ůĂƐƚ͕ Ăůů

ƐƚƵĚŝĞƐŽŶƚŚĞƐĞĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞƐĂƌĞƉŽŽůĞĚ͘

10.50 (0.59 - 187.48) 0.23 (0.01 - 4.50) 3.54 (1.03 - 12.11) 2.43 (0.41 - 14.29)

3.29 (1.42 - 7.59) 2.85 (1.00 - 8.14) 3.11 (1.62 - 5.98)

3.78 (2.34 - 6.11) 14.53 (5.16 - 40.89) 1.42 (0.60 - 3.36) 1.79 (0.62 - 5.17) 2.86 (0.88 - 9.33) 6.53 (1.46 - 29.33) 6.14 (2.04 - 18.45) 8.50 (3.19 - 22.68) 4.37 (2.19 - 8.73) 1. Composite outcome of clinical ischemic events

Grotemeyer et al,¹⁵ 1993 (180) 24/60 5/114 Buchanan et al,¹⁶ 2000 (289) 15/158 9/131 Andersen et al,¹⁷ 2002 (71) 9/25 11/46 Gum et al,²⁰ 2003 (326) 4/17 30/309 Cotter et al,²¹ 2004 (73) 6/21 3/52 Pamukcu et al,²² 2006 (105) 9/20 10/85 Stejskal et al,²³ 2006 (103) 50/57 21/46 Subtotal (95% Cl) 358 783 Total No. of events 117 89 Test for heterogeneity: χ² = 17.28 (P = .008), I ² = 65.3%

Test for overall effect: z = 4.17 (P < .001)

2. (Re)occlusion

Mueller et al,²⁴ 1997 (100) 8/65 0/35 Ziegler et al,²⁵ 2002 (52) 0/5 13/47 Poston et al,²⁷ 2006 (225) 4/22 12/203 Subtotal (95% Cl) 92 285 Total No. of events 12 25 Test for heterogeneity: χ² = 3.71 (P = .16), I ² = 46.1%

Test for overall effect: z = 0.98 (P = .33)

3. Myonecrosis after PCI

Chen et al,²⁸ 2004 (151) 15/29 30/122 Lev et al,²⁹ 2006 (150) 7/18 23/126 Subtotal (95% Cl) 47 248 Total No. of events 22 53 Test for heterogeneity: χ² = 0.04 (P = .84), I ² = 0%

Test for overall effect: z = 3.40 (P = .007)

Patients With Cardiovascular Events/

Patients With LAR Study or Subcategory

(Study Population, No.)

Patients With Cardiovascular Events/

Patients Without LAR

OR (Random), 95% Cl

6

2

1

Total (95% Cl) 497 1316 Total No. of Events 151 167 Test for heterogeneity: χ² = 21.74 (P = .03), I ² = 49.4%

Test for overall effect: z = 5.43 (P < .001)

11

0.01 0.1 1 10 100

(13)

ϭϮϴ

ŝƐĐƵƐƐŝŽŶ

tĞĐŽŶĚƵĐƚĞĚĂƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁĂŶĚŵĞƚĂͲĂŶĂůǇƐŝƐŝŶŽƌĚĞƌƚŽƋƵĂŶƟĨǇĞǀŝĚĞŶĐĞ

ƌĞŐĂƌĚŝŶŐƚŚĞƋƵĞƐƟŽŶǁŚĞƚŚĞƌƉĂƟĞŶƚƐǁŝƚŚůĂďŽƌĂƚŽƌǇͲĚĞĮŶĞĚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ

ŚĂǀĞĂŚŝŐŚĞƌƌŝƐŬŽĨƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘tĞƐŚŽǁĞĚƚŚĂƚƉĂƟĞŶƚƐǁŝƚŚ

ůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŚĂĚĂŶŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘ŵŽŶŐ

ƐƚƵĚŝĞƐĞůŝŐŝďůĞĨŽƌŵĞƚĂͲĂŶĂůǇƐŝƐ͕ƚŚĞƉŽŽůĞĚŽĚĚƐƌĂƟŽŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞ

ǁĂƐϯ͘ϴ;ϵϱй/Ϯ͘ϯͲϲ͘ϭͿĂŶĚƚŚĞƐƚƵĚŝĞƐŶŽƚŝŶĐůƵĚĞĚŝŶƚŚĞĂŶĂůǇƐŝƐƐŚŽǁĞĚƐŝŵŝůĂƌ

ƌĞƐƵůƚƐ;ϭϵ͖ϮϬ͖Ϯϳ͖ϯϭͿ͘

dŚĞƐƚƵĚŝĞƐŝŶŽƵƌƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁǀĂƌŝĞĚŝŶŵĂŶǇǁĂǇƐ͘dŚĞƉĂƟĞŶƚƐŝŶĐůƵĚĞĚŝŶ

ƚŚĞƐƚƵĚŝĞƐƐƵīĞƌĞĚĨƌŽŵĚŝīĞƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐĂŶĚǁĞƌĞĂŋŝĐƚĞĚǁŝƚŚ

ĂǀĂƌŝĞƚǇŽĨƌŝƐŬƐŽĨƌĞĐƵƌƌĞŶƚĞǀĞŶƚƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ƐƚƵĚŝĞƐĚŝīĞƌĞĚŝŶƵƐĞĚĂƐƉŝƌŝŶ

ĚŽƐĂŐĞ͕ĨŽůůŽǁͲƵƉƟŵĞ͕ůĂďŽƌĂƚŽƌǇŵĞƚŚŽĚƐƚŽĞƐƚĂďůŝƐŚƚŚĞĞīĞĐƚƐŽĨĂƐƉŝƌŝŶĂŶĚ

ĚĞĮŶŝƟŽŶŽĨŽƵƚĐŽŵĞ͘ĞƐƉŝƚĞƚŚĞƐĞĐůŝŶŝĐĂůĂŶĚŵĞƚŚŽĚŽůŽŐŝĐĂůĚŝǀĞƌƐŝƟĞƐ͕ĂůŵŽƐƚĂůů

ŝŶĐůƵĚĞĚƐƚƵĚŝĞƐƐƵŐŐĞƐƚĞĚĂƉŽƐŝƟǀĞĂƐƐŽĐŝĂƟŽŶďĞƚǁĞĞŶƚŚĞƌŝƐŬŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌ

ĞǀĞŶƚƐĂŶĚƚŚĞƉƌĞƐĞŶĐĞŽĨůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘tĞƚŚĞƌĞĨŽƌĞĚĞĐŝĚĞĚƚŚĂƚ

ŝƚĐŽƵůĚďĞŝŶĨŽƌŵĂƟǀĞƚŽƉŽŽůƚŚĞĮŶĚŝŶŐƐĨƌŽŵƚŚĞĐŽŚŽƌƚƐƚƵĚŝĞƐǁŝƚŚĂƌĂŶĚŽŵͲ ĞīĞĐƚƐŵŽĚĞů͕ǁŚŝĐŚƉĂƌƚůǇĂĐĐŽƵŶƚƐĨŽƌƚŚĞŚĞƚĞƌŽŐĞŶĞŝƚǇďĞƚǁĞĞŶƚŚĞƐƚƵĚŝĞƐ;ϭϰͿ͘

ĞƐŝĚĞƚŚĞƐĞŚĞƚĞƌŽŐĞŶĞŝƟĞƐ͕ƐĞǀĞƌĂůŵĞƚŚŽĚŽůŽŐŝĐĂůůŝŵŝƚĂƟŽŶƐŽĨŝŶĐůƵĚĞĚƐƚƵĚŝĞƐ

ƌĞƋƵŝƌĞĐŽŵŵĞŶƚ͘/ŶĂŵĂũŽƌŝƚǇŽĨƐƚƵĚŝĞƐ͕ĞŶĚƉŽŝŶƚƐǁĞƌĞŶŽƚĂĚũƵĚŝĐĂƚĞĚďůŝŶĚĞĚ

ĨŽƌĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͕ŵĂŬŝŶŐƚŚĞŵŵŽƌĞƐƵƐĐĞƉƟďůĞĨŽƌďŝĂƐ;ϭϲ͖ϭϴ͖ϮϯͲϮϲ͖ϮϵͲϯϭͿ͘

/ŶŽŶĞƐƚƵĚǇϰϱƉĂƟĞŶƚƐǁĞƌĞĞǆĐůƵĚĞĚĨŽƌƌĞĂƐŽŶƐƚŚĂƚǁĞƌĞŶŽƚŵĞŶƟŽŶĞĚ;ϮϱͿ͕

ĂŶĚŝŶĂŶŽƚŚĞƌƐƚƵĚǇĂůůŽĐĂƟŽŶƚŽĞŝƚŚĞƌĂƐƉŝƌŝŶŽƌĐůŽƉŝĚŽŐƌĞůǁĂƐŶŽƚƌĂŶĚŽŵŝǌĞĚ

ďƵƚďĂƐĞĚŽŶĐŽŵƉůĂŝŶƚƐ;ϮϲͿ͘DŽƌĞŽǀĞƌ͕ƵƐĞŽĨE^/Ɛ͕ǁŚŝĐŚŵĂǇŚĂǀĞĚŝīĞƌĞĚ

ďĞƚǁĞĞŶƐƚƵĚŝĞƐĂƐŝƚǁĂƐŶŽĨŽƌŵĂůĞǆĐůƵƐŝŽŶĐƌŝƚĞƌŝŽŶŝŶŶŝŶĞƐƚƵĚŝĞƐ;ϭϲͲϭϵ͖ϮϮ͖ϮϲͲ Ϯϴ͖ϯϬ͖ϯϭͿ͕ ĐŽƵůĚ ŚĂǀĞ ŝŶŇƵĞŶĐĞĚ ƚŚĞ ƉƌĞǀĂůĞŶĐĞ ŽĨ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ ;ϯϮͲϯϰͿ͘

&ƵƌƚŚĞƌŵŽƌĞ͕ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞǁĂƐŽŶůǇĚĞƚĞƌŵŝŶĞĚĂƚĂƐŝŶŐƵůĂƌŽĐĐĂƐŝŽŶŝŶĂůůďƵƚ

ĨŽƵƌƐƚƵĚŝĞƐ;Ϯϰ͖Ϯϱ͖Ϯϴ͖ϯϬͿ͕ǁŚŝĐŚŵĂǇŚĂǀĞůĞĂĚƚŽŵŝƐĐůĂƐƐŝĮĐĂƟŽŶ͘͘Ő͕͘ƉĞƌƐŝƐƚĞŶƚ

ƉůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇŵĂǇďĞŵŽƌĞĐŽŵŵŽŶĂŌĞƌĐŽƌŽŶĂƌǇĂƌƚĞƌǇďǇƉĂƐƐŐƌĂŌŝŶŐ͕ĚƵĞ

ƚŽŝŶĐƌĞĂƐĞĚƉůĂƚĞůĞƚƚƵƌŶŽǀĞƌ;ϯϱͿ͘dŚŝƐƚĞŵƉŽƌĂů͚ƌĞƐŝƐƚĂŶĐĞ͛ǁĂƐƌĞĐĞŶƚůǇŽďƐĞƌǀĞĚ

ŝŶĂĐŽƌŽŶĂƌǇďǇƉĂƐƐƉŽƉƵůĂƟŽŶ;ϮϴͿ͘dŚŽƵŐŚŶŽŶͲĐŽŵƉůŝĂŶĐĞŝƐĂŶŝŵƉŽƌƚĂŶƚĐĂƵƐĞ

ŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ;ϮϮ͖ϯϲͿ͕ƉĂƟĞŶƚĂĚŚĞƌĞŶĐĞǁĂƐĂƐƐĞƐƐĞĚŽŶůǇŝŶƚŚƌĞĞƐƚƵĚŝĞƐ

(14)

ϭϮϵ

;ϭϳ͖ϮϮ͖ϮϱͿ͘ ^ŽŵĞ ŚĂǀĞ ƐƵŐŐĞƐƚĞĚ ƚŚĂƚ ĂŌĞƌ ĞǆĐůƵƐŝŽŶ ŽĨ ŶŽŶͲĂĚŚĞƌĞŶƚ ƉĂƟĞŶƚƐ͕

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝƐŶŽůŽŶŐĞƌƌĞůĂƚĞĚƚŽƌĞĐƵƌƌĞŶƚĞǀĞŶƚƐ;ϮϮͿ͘

dŚĞƐƚƌĞŶŐƚŚŽĨŽƵƌƐƚƵĚǇůŝĞƐŝŶƚŚĞƐǇƐƚĞŵĂƟĐŶĂƚƵƌĞŽĨƚŚĞƌĞǀŝĞǁŝŶŐƉƌŽĐĞƐƐ͘Ǉ

ƉƌĞƐƉĞĐŝĨǇŝŶŐŝŶĐůƵƐŝŽŶĐƌŝƚĞƌŝĂĂŶĚĂƐĞŶƐŝƟǀĞƐĞĂƌĐŚƐƚƌĂƚĞŐǇ͕ǁĞǁĞƌĞĐĂƉĂďůĞƚŽ

ƌĞǀŝĞǁĂůůƌĞƚƌŝĞǀĂďůĞƐƚƵĚŝĞƐǁŝƚŚĂŵŝŶŝŵƵŵƌŝƐŬŽĨďŝĂƐ͘dŚƵƐ͕ǁĞǁĞƌĞĂďůĞƚŽ

ƉƌŽǀŝĚĞĂŶĞǆƚĞŶƐŝǀĞĂŶĚƚŽŽƵƌŬŶŽǁůĞĚŐĞĐŽŵƉůĞƚĞŽǀĞƌǀŝĞǁŽĨĂǀĂŝůĂďůĞĚĂƚĂŽŶ

ĐůŝŶŝĐĂůĐŽŶƐĞƋƵĞŶĐĞƐŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝŶƉĂƟĞŶƚƐǁŝƚŚĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘/Ŷ

ĐŽŶƚƌĂƐƚ͕ƉƌĞǀŝŽƵƐƌĞǀŝĞǁƐŝŶĐůƵĚĞĚŽŶůǇƐĞůĞĐƚĞĚƐƚƵĚŝĞƐŽŶĐůŝŶŝĐĂůĐŽŶƐĞƋƵĞŶĐĞƐŽĨ

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘DĂŶǇŝŶĚŝǀŝĚƵĂůƐƚƵĚŝĞƐǁĞƌĞƌĞůĂƟǀĞůǇƐŵĂůů͕ŵĂŬŝŶŐĞǆƚƌĂƉŽůĂƟŽŶ

ĚŝĸĐƵůƚ͘ ,ŽǁĞǀĞƌ͕ ďǇ ƉŽŽůŝŶŐ ĂǀĂŝůĂďůĞ ƐƚƵĚŝĞƐ͕ ǁĞ ĨŽƵŶĚ Ă ƐƚƌŽŶŐ ĂƐƐŽĐŝĂƟŽŶ

ďĞƚǁĞĞŶůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂŶĚƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘

ƐŝŶĂůůƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁƐ͕ŽƵƌƌĞƐƵůƚƐŵĂǇďĞŝŶŇƵĞŶĐĞĚďǇƐĞǀĞƌĂůĨŽƌŵƐŽĨďŝĂƐ͘tĞ

ŚŽǁĞǀĞƌƚƌŝĞĚƚŽŵŝŶŝŵŝǌĞƐĞůĞĐƟŽŶďŝĂƐďǇĂƉƉůǇŝŶŐŶŽĨŽƌŵĂůůĂŶŐƵĂŐĞƌĞƐƚƌŝĐƟŽŶ

ĂŶĚŝŶĐůƵĚŝŶŐďŽƚŚĨƵůůͲƚĞǆƚĂƌƟĐůĞƐĂŶĚŵĞĞƟŶŐĂďƐƚƌĂĐƚƐ͘&ƵƌƚŚĞƌŵŽƌĞ͕ŝŶĂĨƵŶŶĞů

ƉůŽƚƚŚĞƌĞǁĂƐŶŽŝŶǀĞƌƐĞƌĞůĂƟŽŶƐŚŝƉďĞƚǁĞĞŶƐŝǌĞŽĨŝŶĚŝǀŝĚƵĂůƐƚƵĚŝĞƐĂŶĚŽĚĚƐ

ƌĂƟŽƐŽĨĐĂƌĚŝŽǀĂƐĐƵůĂƌŽƵƚĐŽŵĞƐ͕ǁŚŝĐŚĂƌŐƵĞƐĂŐĂŝŶƐƚĞǆŝƐƚĞŶĐĞŽĨƉƵďůŝĐĂƟŽŶĂŶĚ

ƌĞƉŽƌƟŶŐďŝĂƐ͘,ŽǁĞǀĞƌ͕ďŝĂƐƚŚĞƐĞĨŽƌŵƐŽĨďŝĂƐĐŽƵůĚŶŽƚďĞĐŽŵƉůĞƚĞůǇĞǆĐůƵĚĞĚ

ĚƵĞ ƚŽ ƚŚĞ ƌĞůĂƟǀĞůǇ ƐŵĂůů ŶƵŵďĞƌ ŽĨ ŝŶĐůƵĚĞĚ ƐƚƵĚŝĞƐ͘ DŽƌĞŽǀĞƌ͕ ǁĞ ĂƐƐƵŵĞĚ

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞƚŽďĞĐĂƚĞŐŽƌŝĐĂůǀĂƌŝĂďůĞ͘dŚŝƐŵĂǇŶŽƚďĞƚŚĞĐĂƐĞƐŝŶĐĞƚŚĞƌĞ

ŝƐŶŽƐƚĂŶĚĂƌĚŝǌĞĚĚĞĮŶŝƟŽŶŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘,ŽǁĞǀĞƌ͕ĞǀĞŶǁŚĞŶƌĞƐŝƐƚĂŶĐĞ

ƐŚŽƵůĚďĞƐĞĞŶĂƐĂĐŽŶƟŶƵŽƵƐǀĂƌŝĂďůĞ͕ŝƚŝƐůŝŬĞůǇƚŚĂƚĂĐĂƚĞŐŽƌŝĐĂůĚĞĮŶŝƟŽŶǁŽƵůĚ

ďĞĂůƐŽƉƌĞĚŝĐƟǀĞĂŶĚƚŚĂƚũƵƐƚƚŚĞƐƚƌĞŶŐƚŚŽĨƚŚĞƌĞůĂƟŽŶŵŝŐŚƚĚŝīĞƌ͘

/ŶĐŽŶĐůƵƐŝŽŶ͕ŽƵƌƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁĂŶĚŵĞƚĂͲĂŶĂůǇƐŝƐŝŶĚŝĐĂƚĞƚŚĂƚůĂďŽƌĂƚŽƌǇĂƐƉŝƌŝŶ

ƌĞƐŝƐƚĂŶĐĞ ŝƐ Ă ĐůŝŶŝĐĂůůǇ ŝŵƉŽƌƚĂŶƚ ƉŚĞŶŽŵĞŶŽŶ͘ WĂƟĞŶƚƐ ďŝŽĐŚĞŵŝĐĂůůǇ ůĂďĞůĞĚ

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶƚĂƌĞůŝŬĞůǇƚŽďĞĂůƐŽ͞ĐůŝŶŝĐĂůůǇƌĞƐŝƐƚĂŶƚ͟ĂƐƚŚĞǇĞǆŚŝďŝƚĂƐƚƌŽŶŐůǇ

ŝŶĐƌĞĂƐĞĚƌŝƐŬŽĨƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͕ĐŽŵƉĂƌĞĚǁŝƚŚƉĂƟĞŶƚƐƚŚĂƚĂƌĞ

ůĂďĞůĞĚƐĞŶƐŝƟǀĞ͘ƐĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƐĂƌĞǀĞƌǇƉƌĞǀĂůĞŶƚĂŶĚĂƐƐŽĐŝĂƚĞĚǁŝƚŚ

ůĂƌŐĞŵŽƌƚĂůŝƚǇĂŶĚŵŽƌďŝĚŝƚǇ͕ƚŚĞƌĞŝƐĂĐůĞĂƌŶĞĞĚĨŽƌĨƵƚƵƌĞƐƚƵĚŝĞƐƚŽƚŚŽƌŽƵŐŚůǇ

ĞǀĂůƵĂƚĞŝŶĚŝǀŝĚƵĂůĚĞƚĞƌŵŝŶĂŶƚƐŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͕ƉƌĞĚŝĐƟǀĞǀĂůƵĞŽĨƚŚĞǀĂƌŝŽƵƐ

ůĂďŽƌĂƚŽƌǇŵĞƚŚŽĚƐĂŶĚƉŽƐƐŝďůĞƐŽůƵƟŽŶƐĨŽƌŝŶĚŝǀŝĚƵĂůƉĂƟĞŶƚƐ͘

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ϭϯϬ

ZĞĨĞƌĞŶĐĞƐ

ϭ͘ dŚŽŵd͕,ĂĂƐĞE͕ZŽƐĂŵŽŶĚtĞƚĂů͘,ĞĂƌƚŝƐĞĂƐĞĂŶĚ^ƚƌŽŬĞ^ƚĂƟƐƟĐƐͲͲϮϬϬϲhƉĚĂƚĞ͗

ZĞƉŽƌƚ &ƌŽŵ ƚŚĞ ŵĞƌŝĐĂŶ ,ĞĂƌƚ ƐƐŽĐŝĂƟŽŶ ^ƚĂƟƐƟĐƐ ŽŵŵŝƩĞĞ ĂŶĚ ^ƚƌŽŬĞ

^ƚĂƟƐƟĐƐ^ƵďĐŽŵŵŝƩĞĞ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϲ͖ϭϭϯ͗ĞϴϱͲϭϱϭ͘

Ϯ͘ ZƵŐŐĞƌŝD͘WůĂƚĞůĞƚƐŝŶĂƚŚĞƌŽƚŚƌŽŵďŽƐŝƐ͘EĂƚDĞĚ͘ϮϬϬϮ͖ϴ͗ϭϮϮϳͲϯϰ͘

ϯ͘ WĂƚƌŽŶŽ ͕ 'ĂƌĐŝĂ ZŽĚƌŝŐƵĞǌ >͕ >ĂŶĚŽůĮ Z͕ ĂŝŐĞŶƚ ͘ >ŽǁͲŽƐĞ ƐƉŝƌŝŶ ĨŽƌ ƚŚĞ

WƌĞǀĞŶƟŽŶŽĨƚŚĞƌŽƚŚƌŽŵďŽƐŝƐ͘EŶŐů:DĞĚ͘ϮϬϬϱ͖ϯϱϯ͗ϮϯϳϯͲϴϯ͘

ϰ͘ ĂƚĞůůĂͲ>ĂǁƐŽŶ&͘sĂƐĐƵůĂƌďŝŽůŽŐǇŽĨƚŚƌŽŵďŽƐŝƐ͗WůĂƚĞůĞƚͲǀĞƐƐĞůǁĂůůŝŶƚĞƌĂĐƟŽŶƐĂŶĚ

ĂƐƉŝƌŝŶĞīĞĐƚƐ͘EĞƵƌŽůŽŐǇ͘ϮϬϬϭ͖ϱϳ͗ϱ^Ͳϳ͘

ϱ͘ ŶƟƚŚƌŽŵďŽƟĐ dƌŝĂůŝƐƚƐ͛ ŽůůĂďŽƌĂƟŽŶ͘ ŽůůĂďŽƌĂƟǀĞ ŵĞƚĂͲĂŶĂůǇƐŝƐ ŽĨ ƌĂŶĚŽŵŝƐĞĚ

ƚƌŝĂůƐŽĨĂŶƟƉůĂƚĞůĞƚƚŚĞƌĂƉǇĨŽƌƉƌĞǀĞŶƟŽŶŽĨĚĞĂƚŚ͕ŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶ͕ĂŶĚƐƚƌŽŬĞ

ŝŶŚŝŐŚƌŝƐŬƉĂƟĞŶƚƐ͘D:͘ϮϬϬϮ͖ϯϮϰ͗ϳϭͲϴϲ͘

ϲ͘ tĞďĞƌ͕WƌǌǇƚƵůƐŬŝ͕^ĐŚĂŶǌ͕,ŽŚůĨĞůĚd͕^ĐŚƌŽƌ<͘dŽǁĂƌĚƐĂĚĞĮŶŝƟŽŶŽĨĂƐƉŝƌŝŶ

ƌĞƐŝƐƚĂŶĐĞ͗ĂƚǇƉŽůŽŐŝĐĂůĂƉƉƌŽĂĐŚ͘WůĂƚĞůĞƚƐ͘ϮϬϬϮ͖ϭϯ͗ϯϳͲϰϬ͘

ϳ͘ WĂƚƌŽŶŽ͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͗ĚĞĮŶŝƟŽŶ͕ŵĞĐŚĂŶŝƐŵƐĂŶĚĐůŝŶŝĐĂůƌĞĂĚͲŽƵƚƐ͘:dŚƌŽŵď

,ĂĞŵŽƐƚ͘ϮϬϬϯ͖ϭ͗ϭϳϭϬͲϭϯ͘

ϴ͘ ,ĂŶŬĞǇ':͕ŝŬĞůďŽŽŵ:t͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘D:͘ϮϬϬϰ͖ϯϮϴ͗ϰϳϳͲϳϵ͘

ϵ͘ DŝĐŚĞůƐŽŶ͕ĂƩĂŶĞŽD͕ŝŬĞůďŽŽŵ:tĞƚĂů͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͗ƉŽƐŝƟŽŶƉĂƉĞƌŽĨ

ƚŚĞtŽƌŬŝŶŐ'ƌŽƵƉŽŶƐƉŝƌŝŶZĞƐŝƐƚĂŶĐĞ͘:dŚƌŽŵď,ĂĞŵŽƐƚ͘ϮϬϬϱ͖ϯ͗ϭϯϬϵͲϭϭ͘

ϭϬ͘ ^ĂŶĚĞƌƐŽŶ^͕ŵĞƌǇ:͕ĂŐůŝŶd͕<ŝŶŵŽŶƚŚ>͘EĂƌƌĂƟǀĞƌĞǀŝĞǁ͗ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂŶĚ

ŝƚƐĐůŝŶŝĐĂůŝŵƉůŝĐĂƟŽŶƐ͘ŶŶ/ŶƚĞƌŶDĞĚ͘ϮϬϬϱ͖ϭϰϮ͗ϯϳϬͲϴϬ͘

ϭϭ͘ ,ĂŶŬĞǇ':͕ŝŬĞůďŽŽŵ:t͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘>ĂŶĐĞƚ͘ϮϬϬϲ͖ϯϲϳ͗ϲϬϲͲϭϳ͘

ϭϮ͘ WŽůůĂĐŬ͕͘&ŽƌƐŽŵĞ͕ƐƉŝƌŝŶŵĂǇŶŽƚŚĞůƉŚĞĂƌƚƐ͘EĞǁzŽƌŬ͕EĞǁzŽƌŬdŝŵĞƐ͕:ƵůǇϮϬ͕

ϮϬϬϰ͘

ϭϯ͘ ,ŽǀĞŶƐDD͕^ŶŽĞƉ:͕ŝŬĞŶďŽŽŵ::͕ǀĂŶĚĞƌŽŵ:'͕DĞƌƚĞŶƐ:͕,ƵŝƐŵĂŶDs͘

WƌĞǀĂůĞŶĐĞŽĨƉĞƌƐŝƐƚĞŶƚƉůĂƚĞůĞƚƌĞĂĐƟǀŝƚǇĚĞƐƉŝƚĞƵƐĞŽĨĂƐƉŝƌŝŶ͗ĂƐǇƐƚĞŵĂƟĐƌĞǀŝĞǁ͘

ŵ,ĞĂƌƚ:͘ϮϬϬϳ͖ϭϱϯ͗ϭϳϱͲϴ͘

ϭϰ͘ Ğƌ^ŝŵŽŶŝĂŶZ͕>ĂŝƌĚE͘DĞƚĂͲĂŶĂůǇƐŝƐŝŶĐůŝŶŝĐĂůƚƌŝĂůƐ͘ŽŶƚƌŽůůŝŶdƌŝĂůƐ͘ϭϵϴϲ͖ϳ͗ϭϳϳͲ ϴϴ͘

ϭϱ͘ ŐŐĞƌD͕^ŵŝƚŚ'͕^ĐŚŶĞŝĚĞƌD͕DŝŶĚĞƌ͘ŝĂƐŝŶŵĞƚĂͲĂŶĂůǇƐŝƐĚĞƚĞĐƚĞĚďǇĂƐŝŵƉůĞ͕

ŐƌĂƉŚŝĐĂůƚĞƐƚ͘D:͘ϭϵϵϳ͖ϯϭϱ͗ϲϮϵͲϯϰ͘

(16)

ϭϯϭ

ϭϲ͘ 'ƌŽƚĞŵĞǇĞƌ<,͕^ĐŚĂƌĂĮŶƐŬŝ,t͕,ƵƐƐƚĞĚƚ/t͘dǁŽͲǇĞĂƌĨŽůůŽǁͲƵƉŽĨĂƐƉŝƌŝŶƌĞƐƉŽŶĚĞƌ

ĂŶĚĂƐƉŝƌŝŶŶŽŶƌĞƐƉŽŶĚĞƌ͘ƉŝůŽƚͲƐƚƵĚǇŝŶĐůƵĚŝŶŐϭϴϬƉŽƐƚͲƐƚƌŽŬĞƉĂƟĞŶƚƐ͘dŚƌŽŵď

ZĞƐ͘ϭϵϵϯ͖ϳϭ͗ϯϵϳͲϰϬϯ͘

ϭϳ͘ ƵĐŚĂŶĂŶDZ͕^ĐŚǁĂƌƚǌ>͕ŽƵƌĂƐƐĂD͕ƌŝƐƚĞƌ^:͕WĞŶŝƐƚŽŶD͘ZĞƐƵůƚƐŽĨƚŚĞZd

ƐƚƵĚǇͲͲĂƉŝůŽƚƐƚƵĚǇŝŶǀĞƐƟŐĂƟŶŐƚŚĞƉŽƐƐŝďůĞƐŝŐŶŝĮĐĂŶĐĞŽĨ^ŶŽŶƌĞƐƉŽŶƐŝǀĞŶĞƐƐ

ŽŶƚŚĞďĞŶĞĮƚƐĂŶĚƌŝƐŬƐŽĨ^ŽŶƚŚƌŽŵďŽƐŝƐŝŶƉĂƟĞŶƚƐƵŶĚĞƌŐŽŝŶŐĐŽƌŽŶĂƌǇĂƌƚĞƌǇ

ďǇƉĂƐƐƐƵƌŐĞƌǇ͘ĂŶ:ĂƌĚŝŽů͘ϮϬϬϬ͖ϭϲ͗ϭϯϴϱͲϵϬ͘

ϭϴ͘ ŶĚĞƌƐĞŶ<͕,ƵƌůĞŶD͕ƌŶĞƐĞŶ,͕^ĞůũĞŇŽƚ/͘ƐƉŝƌŝŶŶŽŶͲƌĞƐƉŽŶƐŝǀĞŶĞƐƐĂƐŵĞĂƐƵƌĞĚ

ďǇW&ͲϭϬϬŝŶƉĂƟĞŶƚƐǁŝƚŚĐŽƌŽŶĂƌǇĂƌƚĞƌǇĚŝƐĞĂƐĞ͘dŚƌŽŵďZĞƐ͘ϮϬϬϮ͖ϭϬϴ͗ϯϳͲϰϮ͘

ϭϵ͘ ŝŬĞůďŽŽŵ:t͕,ŝƌƐŚ:͕tĞŝƚǌ:/͕:ŽŚŶƐƚŽŶD͕zŝY͕zƵƐƵĨ^͘ƐƉŝƌŝŶͲƌĞƐŝƐƚĂŶƚƚŚƌŽŵďŽǆĂŶĞ

ďŝŽƐǇŶƚŚĞƐŝƐĂŶĚƚŚĞƌŝƐŬŽĨŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶ͕ƐƚƌŽŬĞ͕ŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĚĞĂƚŚŝŶ

ƉĂƟĞŶƚƐĂƚŚŝŐŚƌŝƐŬĨŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϮ͖ϭϬϱ͗ϭϲϱϬͲϱϱ͘

ϮϬ͘ 'ƌƵŶĚŵĂŶŶ <͕ :ĂƐĐŚŽŶĞŬ <͕ <ůĞŝŶĞ ͕ ŝĐŚŐĂŶƐ :͕ dŽƉŬĂ ,͘ ƐƉŝƌŝŶ ŶŽŶͲƌĞƐƉŽŶĚĞƌ

ƐƚĂƚƵƐŝŶƉĂƟĞŶƚƐǁŝƚŚƌĞĐƵƌƌĞŶƚĐĞƌĞďƌĂůŝƐĐŚĞŵŝĐĂƩĂĐŬƐ͘:EĞƵƌŽů͘ϮϬϬϯ͖ϮϱϬ͗ϲϯͲϲϲ͘

Ϯϭ͘ 'Ƶŵ W͕ <ŽƩŬĞͲDĂƌĐŚĂŶƚ <͕ tĞůƐŚ W͕ tŚŝƚĞ :͕ dŽƉŽů :͘ ƉƌŽƐƉĞĐƟǀĞ͕ ďůŝŶĚĞĚ

ĚĞƚĞƌŵŝŶĂƟŽŶŽĨƚŚĞŶĂƚƵƌĂůŚŝƐƚŽƌǇŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂŵŽŶŐƐƚĂďůĞƉĂƟĞŶƚƐǁŝƚŚ

ĐĂƌĚŝŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞ͘:ŵŽůůĂƌĚŝŽů͘ϮϬϬϯ͖ϰϭ͗ϵϲϭͲϲϱ͘

ϮϮ͘ ŽƩĞƌ '͕ ^ŚĞŵĞƐŚ ͕ ĞŚĂǀŝ D Ğƚ Ăů͘ >ĂĐŬ ŽĨ ĂƐƉŝƌŝŶ ĞīĞĐƚ͗ ĂƐƉŝƌŝŶ ƌĞƐŝƐƚĂŶĐĞ Žƌ

ƌĞƐŝƐƚĂŶĐĞƚŽƚĂŬŝŶŐĂƐƉŝƌŝŶ͍ŵ,ĞĂƌƚ:͘ϮϬϬϰ͖ϭϰϳ͗ϮϵϯͲϯϬϬ͘

Ϯϯ͘ WĂŵƵŬĐƵ͕KŇĂǌ,͕KŶĐƵůĞƚĂů͘dŚĞƌŽůĞŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŽŶŽƵƚĐŽŵĞŝŶƉĂƟĞŶƚƐ

ǁŝƚŚĂĐƵƚĞĐŽƌŽŶĂƌǇƐǇŶĚƌŽŵĞĂŶĚƚŚĞĞīĞĐƚŽĨĐůŽƉŝĚŽŐƌĞůƚŚĞƌĂƉǇŝŶƚŚĞƉƌĞǀĞŶƟŽŶ

ŽĨŵĂũŽƌĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐ͘:dŚƌŽŵďdŚƌŽŵďŽůǇƐŝƐ͘ϮϬϬϲ͖sϮϮ͗ϭϬϯͲϭϬ͘

Ϯϰ͘ ^ƚĞũƐŬĂů͕sĂĐůĂǀŝŬ:͕>ĂĐŶĂŬ͕WƌŽƐŬŽǀĂ:͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŵĞĂƐƵƌĞĚďǇĐĂƟŽŶŝĐ

ƉƌŽƉǇůŐĂůůĂƚĞƉůĂƚĞůĞƚĂŐŐƌĞŐŽŵĞƚƌǇĂŶĚƌĞĐƵƌƌĞŶƚĐĂƌĚŝŽǀĂƐĐƵůĂƌĞǀĞŶƚƐĚƵƌŝŶŐϰ΀ŶŽͲ ďƌĞĂŬƐƉĂĐĞ΁ǇĞĂƌƐŽĨĨŽůůŽǁͲƵƉ͘Ƶƌ:/ŶƚĞƌŶDĞĚ͘ϮϬϬϲ͖ϭϳ͗ϯϰϵͲϱϰ͘

Ϯϱ͘ DƵĞůůĞƌDZ͕^ĂůĂƚ͕^ƚĂŶŐůWĞƚĂů͘sĂƌŝĂďůĞƉůĂƚĞůĞƚƌĞƐƉŽŶƐĞƚŽůŽǁͲĚŽƐĞ^ĂŶĚ

ƚŚĞƌŝƐŬŽĨůŝŵďĚĞƚĞƌŝŽƌĂƟŽŶŝŶƉĂƟĞŶƚƐƐƵďŵŝƩĞĚƚŽƉĞƌŝƉŚĞƌĂůĂƌƚĞƌŝĂůĂŶŐŝŽƉůĂƐƚǇ͘

dŚƌŽŵď,ĂĞŵŽƐƚ͘ϭϵϵϳ͖ϳϴ͗ϭϬϬϯͲϬϳ͘

Ϯϲ͘ ŝĞŐůĞƌ^͕DĂĐĂd͕ůƚ͕^ƉĞŝƐĞƌt͕^ĐŚŶĞŝĚĞƌ͕DŝŶĂƌ͘DŽŶŝƚŽƌŝŶŐŽĨĂŶƟƉůĂƚĞůĞƚ

ƚŚĞƌĂƉǇǁŝƚŚƚŚĞW&ͲϭϬϬŝŶƉĞƌŝƉŚĞƌĂůĂŶŐŝŽƉůĂƐƚǇƉĂƟĞŶƚƐ͘WůĂƚĞůĞƚƐ͘ϮϬϬϮ͖ϭϯ͗ϰϵϯͲ ϵϳ͘

Ϯϳ͘ zŝůŵĂǌD͕ĂůďĂǇz͕ĂůĚŝƌsĞƚĂů͘>ĂƚĞƐĂƉŚĞŶŽƵƐǀĞŝŶŐƌĂŌŽĐĐůƵƐŝŽŶŝŶƉĂƟĞŶƚƐǁŝƚŚ

ĐŽƌŽŶĂƌǇďǇƉĂƐƐ͗ƉŽƐƐŝďůĞƌŽůĞŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞ͘dŚƌŽŵďZĞƐ͘ϮϬϬϱ͖ϭϭϱ͗ϮϱͲϮϵ͘

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ϭϯϮ

Ϯϴ͘ WŽƐƚŽŶZ^͕'Ƶ:͕ƌŽǁŶ:DĞƚĂů͘ŶĚŽƚŚĞůŝĂůŝŶũƵƌǇĂŶĚĂĐƋƵŝƌĞĚĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂƐ

ƉƌŽŵŽƚĞƌƐŽĨƌĞŐŝŽŶĂůƚŚƌŽŵďŝŶĨŽƌŵĂƟŽŶĂŶĚĞĂƌůǇǀĞŝŶŐƌĂŌĨĂŝůƵƌĞĂŌĞƌĐŽƌŽŶĂƌǇ

ĂƌƚĞƌǇďǇƉĂƐƐŐƌĂŌŝŶŐ͘:dŚŽƌĂĐĂƌĚŝŽǀĂƐĐ^ƵƌŐ͘ϮϬϬϲ͖ϭϯϭ͗ϭϮϮͲϯϬ͘

Ϯϵ͘ ŚĞŶt,͕>ĞĞWz͕EŐt͕dƐĞ,&͕>ĂƵW͘ƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŝƐĂƐƐŽĐŝĂƚĞĚǁŝƚŚĂŚŝŐŚ

ŝŶĐŝĚĞŶĐĞ ŽĨ ŵǇŽŶĞĐƌŽƐŝƐ ĂŌĞƌ ŶŽŶͲƵƌŐĞŶƚ ƉĞƌĐƵƚĂŶĞŽƵƐ ĐŽƌŽŶĂƌǇ ŝŶƚĞƌǀĞŶƟŽŶ

ĚĞƐƉŝƚĞĐůŽƉŝĚŽŐƌĞůƉƌĞƚƌĞĂƚŵĞŶƚ͘:ŵŽůůĂƌĚŝŽů͘ϮϬϬϰ͖ϰϯ͗ϭϭϮϮͲϮϲ͘

ϯϬ͘ >Ğǀ/͕WĂƚĞůZd͕DĂƌĞƐŚ<:ĞƚĂů͘ƐƉŝƌŝŶĂŶĚĐůŽƉŝĚŽŐƌĞůĚƌƵŐƌĞƐƉŽŶƐĞŝŶƉĂƟĞŶƚƐ

ƵŶĚĞƌŐŽŝŶŐƉĞƌĐƵƚĂŶĞŽƵƐĐŽƌŽŶĂƌǇŝŶƚĞƌǀĞŶƟŽŶ͗ƚŚĞƌŽůĞŽĨĚƵĂůĚƌƵŐƌĞƐŝƐƚĂŶĐĞ͘:ŵ

ŽůůĂƌĚŝŽů͘ϮϬϬϲ͖ϰϳ͗ϮϳͲϯϯ͘

ϯϭ͘ ŚĞŶŐy͕ŚĞŶt,͕>ĞĞWz͕EŐt͕<ǁŽŬzz͕>ĂƵW͘WƌĞǀĂůĞŶĐĞ͕ƉƌŽĮůĞ͕ƉƌĞĚŝĐƚŽƌƐ͕ĂŶĚ

ŶĂƚƵƌĂůŚŝƐƚŽƌǇŽĨĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞŵĞĂƐƵƌĞĚďǇƚŚĞƵůƚĞŐƌĂƌĂƉŝĚƉůĂƚĞůĞƚĨƵŶĐƟŽŶ

ĂƐƐĂǇͲ^ŝŶƉĂƟĞŶƚƐǁŝƚŚĐŽƌŽŶĂƌǇŚĞĂƌƚĚŝƐĞĂƐĞ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϱ͖ϭϭϭ͗ϯϯϵ͘

ϯϮ͘ ĂƚĞůůĂͲ>ĂǁƐŽŶ &͕ ZĞŝůůǇ DW͕ <ĂƉŽŽƌ ^ Ğƚ Ăů͘ ǇĐůŽŽǆǇŐĞŶĂƐĞ /ŶŚŝďŝƚŽƌƐ ĂŶĚ ƚŚĞ

ŶƟƉůĂƚĞůĞƚīĞĐƚƐŽĨƐƉŝƌŝŶ͘EŶŐů:DĞĚ͘ϮϬϬϭ͖ϯϰϱ͗ϭϴϬϵͲϭϳ͘

ϯϯ͘ ĂƉŽŶĞD>͕^ĐŝƵůůŝD'͕dĂĐĐŽŶĞůůŝ^ĞƚĂů͘WŚĂƌŵĂĐŽĚǇŶĂŵŝĐŝŶƚĞƌĂĐƟŽŶŽĨŶĂƉƌŽǆĞŶ

ǁŝƚŚůŽǁͲĚŽƐĞĂƐƉŝƌŝŶŝŶŚĞĂůƚŚǇƐƵďũĞĐƚƐ͘:ŵŽůůĂƌĚŝŽů͘ϮϬϬϱ͖ϰϱ͗ϭϮϵϱͲϯϬϭ͘

ϯϰ͘ DĂĐŽŶĂůĚdD͕tĞŝ>͘īĞĐƚŽĨŝďƵƉƌŽĨĞŶŽŶĐĂƌĚŝŽƉƌŽƚĞĐƟǀĞĞīĞĐƚŽĨĂƐƉŝƌŝŶ͘>ĂŶĐĞƚ͘

ϮϬϬϯ͖ϯϲϭ͗ϱϳϯͲϳϰ͘

ϯϱ͘ ŝŵŵĞƌŵĂŶŶE͕tĞŶŬ͕<ŝŵhĞƚĂů͘&ƵŶĐƟŽŶĂůĂŶĚďŝŽĐŚĞŵŝĐĂůĞǀĂůƵĂƟŽŶŽĨƉůĂƚĞůĞƚ

ĂƐƉŝƌŝŶƌĞƐŝƐƚĂŶĐĞĂŌĞƌĐŽƌŽŶĂƌǇĂƌƚĞƌǇďǇƉĂƐƐƐƵƌŐĞƌǇ͘ŝƌĐƵůĂƟŽŶ͘ϮϬϬϯ͖ϭϬϴ͗ϱϰϮͲϰϳ͘

ϯϲ͘ ^ĐŚǁĂƌƚǌ<͕^ĐŚǁĂƌƚǌ͕'ŚŽƐŚĞŚ<͕ZĞĞǀĞƐD:͕ĂƌďĞƌ<͕Ğ&ƌĂŶĐŽ͘ŽŵƉůŝĂŶĐĞ

ĂƐĂĐƌŝƟĐĂůĐŽŶƐŝĚĞƌĂƟŽŶŝŶƉĂƟĞŶƚƐǁŚŽĂƉƉĞĂƌƚŽďĞƌĞƐŝƐƚĂŶƚƚŽĂƐƉŝƌŝŶĂŌĞƌŚĞĂůŝŶŐ

ŽĨŵǇŽĐĂƌĚŝĂůŝŶĨĂƌĐƟŽŶ͘ŵ:ĂƌĚŝŽů͘ϮϬϬϱ͖ϵϱ͗ϵϳϯͲϳϱ͘

ϯϳ͘ 'ƌŽƚĞŵĞǇĞƌ <,͘ dŚĞ ƉůĂƚĞůĞƚͲƌĞĂĐƟǀŝƚǇͲƚĞƐƚͲͲĂ ƵƐĞĨƵů ͞ďǇͲƉƌŽĚƵĐƚ͟ ŽĨ ƚŚĞ ďůŽŽĚͲ ƐĂŵƉůŝŶŐƉƌŽĐĞĚƵƌĞ͍dŚƌŽŵďZĞƐ͘ϭϵϵϭ͖ϲϭ͗ϰϮϯͲϯϭ͘

ϯϴ͘ dŚĞ ,ĞĂƌƚ KƵƚĐŽŵĞƐ WƌĞǀĞŶƟŽŶ ǀĂůƵĂƟŽŶ ^ƚƵĚǇ /ŶǀĞƐƟŐĂƚŽƌƐ͘ īĞĐƚƐ ŽĨ ĂŶ

ŶŐŝŽƚĞŶƐŝŶͲŽŶǀĞƌƟŶŐͲŶǌǇŵĞ/ŶŚŝďŝƚŽƌ͕ZĂŵŝƉƌŝů͕ŽŶĂƌĚŝŽǀĂƐĐƵůĂƌǀĞŶƚƐŝŶ,ŝŐŚͲ ZŝƐŬWĂƟĞŶƚƐ͘EŶŐů:DĞĚ͘ϮϬϬϬ͖ϯϰϮ͗ϭϰϱͲϱϯ͘

ϯϵ͘ dŚĞ ,ĞĂƌƚ KƵƚĐŽŵĞƐ WƌĞǀĞŶƟŽŶ ǀĂůƵĂƟŽŶ ^ƚƵĚǇ /ŶǀĞƐƟŐĂƚŽƌƐ͘ sŝƚĂŵŝŶ

^ƵƉƉůĞŵĞŶƚĂƟŽŶ ĂŶĚ ĂƌĚŝŽǀĂƐĐƵůĂƌ ǀĞŶƚƐ ŝŶ ,ŝŐŚͲZŝƐŬ WĂƟĞŶƚƐ͘ E ŶŐů : DĞĚ͘

ϮϬϬϬ͖ϯϰϮ͗ϭϱϰͲϲϬ͘