Conditions: Subarachnoid Hemorrhage, Aneurysmal Vasospasm, Cerebral
Keywords: acetazolamide challenge cerebral vasospasm aneurysmal subarachnoid hemorrhage
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 11
Healthy volunteers: no

Brief summary:
The investigators propose a technique using cone beam CT perfusion (CBCTP) imaging with an acetazolamide challenge as a potential diagnostic tool to detect a defect in cerebral autoregulation at a time when it has not yet caused clinically apparent signs or symptoms. 30 participants will be enrolled at the University of Wisconsin - Madison and can expect to be on study for about 2 weeks.

Detailed description:
Acetazolamide or vasodilatory challenge should identify subjects having a abnormal cerebrovascular reactivity capacity. More specifically, after receiving the drug there will not be the expected increase in cerebral blood flow (CBF) in some of the subjects because they are already suffering from a disturbance in the vasculature's ability to respond to the signal for vasodilation. The investigators believe the presence of this deficit will be helpful in identifying patients who are at risk for potential brain ischemia due to this decreased capacity to autoregulate if/when clinically significant vasospasm occurs. The investigators predict that acetazolamide-activated regional cerebral blood flow studies will be more sensitive in the detection of mild cerebral vasospasm and will not just detect changes in cerebral blood flow as does standard perfusion imaging, but will provide information regarding changes in cerebrovascular reactivity. Under these circumstances, a better predictor of those patients at risk of cerebral infarction due to delayed vasospasm would be delineated. Identifying this "high-risk cohort" prior to the onset of clinically apparent symptoms would result in the institution of preventative measures such as triple H therapy.

The objective of this proposal is to conduct a feasibility study of acetazolamide activated C-arm cone beam CT perfusion (CBCTP) to determine its application in the prediction of symptomatic cerebral vasospasm (i.e. ischemia or stroke) in patients with aneurysmal subarachnoid hemorrhage. The initial plan is to obtain C-arm CBCTP pre- and post-intravenous infusion of 1g acetazolamide within 24 hours of symptom onset in aneurysmal subarachnoid hemorrhage patients. The hypothesis is that some of these patients that will later develop clinical vasospasm of a degree sufficient to cause cerebral ischemia. The investigators believe this cohort of patients will demonstrate altered cerebrovascular reactivity during the acetazolamide challenge at a time before there is either angiographic evidence of vasospasm or clinical evidence of abnormal perfusion.

Arms:
arm 1: Participants entered into the study as a cohort, will because of their participation, undergo only two additional digital subtraction angiogram (DSA) imaging acquisitions. These will be done in conjunction with their standard diagnostic DSA evaluation and consist of two CBCTPs, one before and one after administration of 1 g acetazolamide through a peripheral IV line. Each CBCTP will require administration of 75-100 mL iodinated contrast medium also through an intravenous line. Neither of these imaging studies will be used for clinical decision making, but would be processed and evaluated at later date for a formal analysis of the results. Following completion of diagnostic imaging subjects will receive the usual standard of care for treatment of their ruptured aneurysm i.e. endovascular embolization or open surgical clipping.

Interventions: intervention 1: Acetazolamide
Intervention descriptions: intervention 1: 1 g acetazolamide through a peripheral IV line

Protocol document:
Prot_SAP_000.pdf: 
C-arm Cone Beam CTA and CTP with Acetazolamide Challenge in Aneurysmal
Subarachnoid Hemorrhage: 
Evaluating Predictability for Early Ischemia in Cerebral Vasospasm 
NCT03377049 
W/͗ǌĂŵŚŵĞĚ͕D
ϰͬϮϴͬϮϬϮϬ


C-arm Cone Beam CTA and CTP with Acetazolamide Challenge in Aneurysmal
Subarachnoid Hemorrhage: 
Evaluating Predictability for Early Ischemia in Cerebral Vasospasm 
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Project Summary 
 
ĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵĐĂŶďĞĂĚĞǀĂƐƚĂƚŝŶŐƐĞƋƵĞůĂŽĨĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚ
ŚĞŵŽƌƌŚĂŐĞ͘ƵƌƌĞŶƚůǇ͕ƚŚĞƌĞŝƐŶĞŝƚŚĞƌĂƐĂƚŝƐĨĂĐƚŽƌǇƉƌĞĚŝĐƚŽƌŽĨŝƚƐůŝŬĞůŝŚŽŽĚŶŽƌĂ
ƐƚĂŶĚĂƌĚŝǌĞĚƉƌŽƚŽĐŽůĨŽƌŝƚƐĞĂƌůǇĚĞƚĞĐƚŝŽŶ͘ŝĂŐŶŽƐƚŝĐŵĞƚŚŽĚƐƚǇƉŝĐĂůůǇĞŵƉůŽǇĞĚŝŶĐůƵĚĞ
ƚƌĂŶƐĐƌĂŶŝĂůŽƉƉůĞƌŝŵĂŐŝŶŐ;dͿ͕dĂŶŐŝŽŐƌĂƉŚǇ;dͿ͕dƉĞƌĨƵƐŝŽŶ;dWͿ͕ĂŶĚĚŝŐŝƚĂů
ƐƵďƚƌĂĐƚŝŽŶĂŶŐŝŽŐƌĂƉŚǇ;^Ϳ͘dŝƐƚŚĞůĞĂƐƚŝŶǀĂƐŝǀĞƚĞĐŚŶŝƋƵĞďƵƚ͕ŚĂƐůŝŵŝƚĂƚŝŽŶƐďĞĐĂƵƐĞ
ŵĂŶǇƐƵďũĞĐƚƐĚŽŶŽƚŚĂǀĞĂŶĂĐŽƵƐƚŝĐĂůǁŝŶĚŽǁƚŚƌŽƵŐŚƚŚĞƐŬƵůů͘ϭdWƉƌŽǀŝĚĞƐďŽƚŚ
ǀŽůƵŵĞƚƌŝĐŝŵĂŐŝŶŐĂŶĚǁĞůůǀĂůŝĚĂƚĞĚŵĞĂƐƵƌĞŵĞŶƚƐŽĨďƌĂŝŶƉĞƌĨƵƐŝŽŶ͕ŚŽǁĞǀĞƌ͕ŝƚƐƐĞŶƐŝƚŝǀŝƚǇ
ŝƐŶŽƚĂĚĞƋƵĂƚĞƚŽĚĞƚĞĐƚĞĂƌůǇƌĞĚƵĐƚŝŽŶƐŝŶƉĞƌĨƵƐŝŽŶϭ͕Ϯ͘^ĂůůŽǁƐĞǆĐĞůůĞŶƚǀŝƐƵĂůŝǌĂƚŝŽŶŽĨ
ĐŚĂŶŐĞƐŝŶůĂƌŐĞǀĞƐƐĞůĐĂůŝďĞƌďƵƚŽĨƚĞŶĚŽĞƐŶŽƚĐŽƌƌĞůĂƚĞǁŝƚŚƚŚĞĚĞŐƌĞĞŽĨŚĞŵŽĚǇŶĂŵŝĐ
ĐŽŵƉƌŽŵŝƐĞ͖ŝƚŝƐĂůƐŽĂŵŽƌĞŝŶǀĂƐŝǀĞƐƚƵĚǇƚŚĂŶƚŚĞŽƚŚĞƌŵŽĚĂůŝƚŝĞƐϭ͘
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ĨůŽǁ;&ͿĂŶĚĐĞƌĞďƌĂůďůŽŽĚǀŽůƵŵĞ;sͿƌĞůĂƚŝǀĞůǇĐŽŶƐƚĂŶƚŽǀĞƌĂǁŝĚĞƌĂŶŐĞŽĨƐǇƐƚĞŵŝĐ
ďůŽŽĚƉƌĞƐƐƵƌĞƐďǇŵĞĂŶƐŽĨĐŽŵƉůĞǆƉŚǇƐŝŽůŽŐŝĐĂůŵĞĐŚĂŶŝƐŵƐŝŶƌĞƐƉŽŶƐĞƚŽĐŚĂŶŐĞƐŝŶ
ƉĞƌĨƵƐŝŽŶƉƌĞƐƐƵƌĞĂŶĚĚĞŵĂŶĚ͘/ƚƉůĂǇƐŝŶĂŶŝŵƉŽƌƚĂŶƚƌŽůĞŝŶĚĞůŝǀĞƌŝŶŐďůŽŽĚĐŽŶƚĂŝŶŝŶŐ
ŽǆǇŐĞŶĂŶĚŶƵƚƌŝĞŶƚƐƚŽƚŚĞďƌĂŝŶƚŝƐƐƵĞƚŽŵĞĞƚŝƚƐŵĞƚĂďŽůŝĐŶĞĞĚƐ͘dŚŝƐĂĚĂƉƚĂƚŝŽŶŽĨ
ĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞƐŝƐƚĂŶĐĞƚŚƌŽƵŐŚǀĂƐŽĚŝůĂƚŝŽŶŽƌǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶĂĚũƵƐƚƐ&ĂŶĚsƚŽ
ŶŽƌŵĂůǀĂůƵĞƐŽǀĞƌĂǁŝĚĞƌĂŶŐĞŽĨƉĞƌĨƵƐŝŽŶƉƌĞƐƐƵƌĞƐ͘ĞůŽǁĐĞƌƚĂŝŶůĞǀĞůƐŽĨƉĞƌĨƵƐŝŽŶ
ƉƌĞƐƐƵƌĞ͕ŚŽǁĞǀĞƌ͕ĂƵƚŽƌĞŐƵůĂƚŝŽŶĨĂŝůƐ͘dŚŝƐƌĞƐƵůƚƐŝŶŝƐĐŚĞŵŝĂĂŶĚŝŶũƵƌǇƚŽƚŚĞďƌĂŝŶƚŝƐƐƵĞ͘
dŚĞĞǆƚĞŶƚĂŶĚĚĞŐƌĞĞŽĨŝŶũƵƌǇǀĂƌǇǁŝƚŚƚŚĞůĞŶŐƚŚŽĨƚŝŵĞĂŶĚĞǆƚĞŶƚƚŽǁŚŝĐŚƚŝƐƐƵĞ
ƉĞƌĨƵƐŝŽŶŝƐŝŶĂĚĞƋƵĂƚĞ͘
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tĞƉƌŽƉŽƐĞĂƚĞĐŚŶŝƋƵĞƵƐŝŶŐĐŽŶĞďĞĂŵƉĞƌĨƵƐŝŽŶ;dWͿǁŝƚŚĂŶĂĐĞƚĂǌŽůĂŵŝĚĞ
ĐŚĂůůĞŶŐĞĂƐĂƉŽƚĞŶƚŝĂůĚŝĂŐŶŽƐƚŝĐƚŽŽůƚŽĚĞƚĞĐƚĂĚĞĨĞĐƚŝŶĐĞƌĞďƌĂůĂƵƚŽƌĞŐƵůĂƚŝŽŶĂƚĂƚŝŵĞ
ǁŚĞŶŝƚŚĂƐŶŽƚǇĞƚĐĂƵƐĞĚĐůŝŶŝĐĂůůǇĂƉƉĂƌĞŶƚƐŝŐŶƐŽƌƐǇŵƉƚŽŵƐ͘ĐĞƚĂǌŽůĂŵŝĚĞŝƐĂĐĂƌďŽŶŝĐ
ĂŶŚǇĚƌĂƐĞŝŶŚŝďŝƚŽƌǁŚŝĐŚǁŽƌŬƐƚŽŝŶĐƌĞĂƐĞƚŚĞĂƌƚĞƌŝĂůĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨĐĂƌďŽŶĚŝŽǆŝĚĞ͘
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ǀĂƐŽĚŝůĂƚŽƌ͘ĐĞƚĂǌŽůĂŵŝĚĞŽƌǀĂƐŽĚŝůĂƚŽƌǇĐŚĂůůĞŶŐĞƐŚŽƵůĚŝĚĞŶƚŝĨǇƐƵďũĞĐƚƐŚĂǀŝŶŐĂŶ
ĂďŶŽƌŵĂůĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞĂĐƚŝǀŝƚǇĐĂƉĂĐŝƚǇ͘DŽƌĞƐƉĞĐŝĨŝĐĂůůǇ͕ĂĨƚĞƌƌĞĐĞŝǀŝŶŐƚŚĞĚƌƵŐƚŚĞƌĞ
ǁŝůůŶŽƚďĞƚŚĞĞǆƉĞĐƚĞĚŝŶĐƌĞĂƐĞ&ŝŶƐŽŵĞŽĨƚŚĞƐƵďũĞĐƚƐďĞĐĂƵƐĞƚŚĞǇĂƌĞĂůƌĞĂĚǇ
ƐƵĨĨĞƌŝŶŐĨƌŽŵĂĚŝƐƚƵƌďĂŶĐĞŝŶƚŚĞǀĂƐĐƵůĂƚƵƌĞ͛ƐĂďŝůŝƚǇƚŽƌĞƐƉŽŶĚƚŽƚŚĞƐŝŐŶĂůĨŽƌ
ǀĂƐŽĚŝůĂƚŝŽŶ͘tĞƵůƚŝŵĂƚĞůǇďĞůŝĞǀĞƚŚĞƉƌĞƐĞŶĐĞŽĨƚŚŝƐĚĞĨŝĐŝƚǁŝůůďĞŚĞůƉĨƵůŝŶŝĚĞŶƚŝĨǇŝŶŐ
ƉĂƚŝĞŶƚƐǁŚŽĂƌĞĂƚƌŝƐŬĨŽƌƉŽƚĞŶƚŝĂůďƌĂŝŶŝƐĐŚĞŵŝĂĚƵĞƚŽƚŚŝƐĚĞĐƌĞĂƐĞĚĐĂƉĂĐŝƚǇƚŽ
ĂƵƚŽƌĞŐƵůĂƚĞŝĨͬǁŚĞŶĐůŝŶŝĐĂůůǇƐŝŐŶŝĨŝĐĂŶƚǀĂƐŽƐƉĂƐŵŽĐĐƵƌƐ͘tĞƉƌĞĚŝĐƚƚŚĂƚĂĐĞƚĂǌŽůĂŵŝĚĞͲ
ĂĐƚŝǀĂƚĞĚƌĞŐŝŽŶĂůĐĞƌĞďƌĂůďůŽŽĚĨůŽǁƐƚƵĚŝĞƐǁŝůůďĞŵŽƌĞƐĞŶƐŝƚŝǀĞŝŶƚŚĞĚĞƚĞĐƚŝŽŶŽĨŵŝůĚ
ĐĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵĂŶĚǁŝůůŶŽƚũƵƐƚĚĞƚĞĐƚĐŚĂŶŐĞƐŝŶĐĞƌĞďƌĂůďůŽŽĚĨůŽǁĂƐĚŽĞƐƐƚĂŶĚĂƌĚ
ƉĞƌĨƵƐŝŽŶŝŵĂŐŝŶŐ͕ďƵƚǁŝůůƉƌŽǀŝĚĞŝŶĨŽƌŵĂƚŝŽŶƌĞŐĂƌĚŝŶŐĐŚĂŶŐĞƐŝŶĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞĂĐƚŝǀŝƚǇ͘
hŶĚĞƌƚŚĞƐĞĐŝƌĐƵŵƐƚĂŶĐĞƐ͕ǁĞǁŽƵůĚŚĂǀĞĂďĞƚƚĞƌƉƌĞĚŝĐƚŽƌŽĨƚŚŽƐĞƉĂƚŝĞŶƚƐĂƚƌŝƐŬŽĨ
ĐĞƌĞďƌĂůŝŶĨĂƌĐƚŝŽŶĚƵĞƚŽĚĞůĂǇĞĚǀĂƐŽƐƉĂƐŵ͘/ĚĞŶƚŝĨǇŝŶŐƚŚŝƐ͞ŚŝŐŚͲƌŝƐŬĐŽŚŽƌƚ͟ƉƌŝŽƌƚŽƚŚĞ
ŽŶƐĞƚŽĨĐůŝŶŝĐĂůůǇĂƉƉĂƌĞŶƚƐǇŵƉƚŽŵƐǁŽƵůĚƌĞƐƵůƚŝŶƚŚĞŝŶƐƚŝƚƵƚŝŽŶŽĨƉƌĞǀĞŶƚĂƚŝǀĞŵĞĂƐƵƌĞƐ
ƐƵĐŚĂƐƚƌŝƉůĞ,ƚŚĞƌĂƉǇϯ͘
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Background and Significance 
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ZƵƉƚƵƌĞĚĂŶĞƵƌǇƐŵƐĂƌĞƌĞƐƉŽŶƐŝďůĞĨŽƌĂƉƉƌŽǆŝŵĂƚĞůǇϴϬͲϴϱйŽĨŶŽŶͲƚƌĂƵŵĂƚŝĐ
ƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞĂŶĚŝŶƚƌĂĐƌĂŶŝĂůĂŶĞƵƌǇƐŵƐ;/ƐͿĂƌĞƉƌĞƐĞŶƚŝŶϭͲϮйŽĨĂĚƵůƚƐŝŶƚŚĞ
hŶŝƚĞĚ^ƚĂƚĞƐϰ͘Ŷ/ŝƐĂƉĂƚŚŽůŽŐŝĐĂůĚŝůĂƚŝŽŶĂŶĚƚŚŝŶŶŝŶŐŽĨĂƉŽƌƚŝŽŶŽĨƚŚĞǁĂůůŽĨĂŶ
ŝŶƚƌĂĐƌĂŶŝĂůĂƌƚĞƌǇ͘tŚŝůĞƚŚĞŽǀĞƌĂůůƌŝƐŬŽĨƌƵƉƚƵƌĞŽĨĂŶ/ŝƐƋƵŝƚĞůŽǁ͕ǁŚĞŶƌƵƉƚƵƌĞŽĐĐƵƌƐ
ƚŚĞĞĨĨĞĐƚŝƐĚĞǀĂƐƚĂƚŝŶŐǁŝƚŚŵŽƌƚĂůŝƚǇĂŶĚŵŽƌďŝĚŝƚǇƌĂƚĞƐƚŚĂƚĂƉƉƌŽĂĐŚϱϬйĂŶĚϯϬй͕
ƌĞƐƉĞĐƚŝǀĞůǇ͘ŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞŝƐŽŶĞŽĨƚŚĞŵŽƐƚĚĞĂĚůǇĂŶĚŵŽƌďŝĚ
ƚǇƉĞƐŽĨƐƚƌŽŬĞƐĂŶĚƌĞƉƌĞƐĞŶƚƐĂƉƉƌŽǆŝŵĂƚĞůǇϯйŽĨĂůůƐƚƌŽŬĞƐϱ͘KŶĞƚŚŝƌĚŽĨƚŚĞƐĞĚĞĂƚŚƐ
ŽĐĐƵƌŝŶƚŚĞĨŝƌƐƚϯϬĚĂǇƐϲ͘ĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵŽƌĚĞůĂǇĞĚĐĞƌĞďƌĂůŝƐĐŚĞŵŝĂŝƐĂŵĂũŽƌĐĂƵƐĞŽĨ
ŵŽƌďŝĚŝƚǇĂŶĚŵŽƌƚĂůŝƚǇŝŶƉĂƚŝĞŶƚƐǁŚŽƐƵƌǀŝǀĞƚŚĞŝŶŝƚŝĂůŚĞŵŽƌƌŚĂŐĞ͘ŶŐŝŽŐƌĂƉŚŝĐ
ǀĂƐŽƐƉĂƐŵŝƐĞǀŝĚĞŶƚŝŶϯϬͲϳϬйŽĨƉĂƚŝĞŶƚƐĂŶĚĐĂŶĐĂƵƐĞƉĞƌŵĂŶĞŶƚŵŽƌďŝĚŝƚǇŽƌŵŽƌƚĂůŝƚǇŝŶ
ƵƉƚŽϮϬйŽĨƚŚĞƐĞƉĂƚŝĞŶƚƐϳ͘ĂƌůǇƉƌĞĚŝĐƚŝŽŶŽĨƉĂƚŝĞŶƚƐĂƚƌŝƐŬĨŽƌĚĞǀĞůŽƉŵĞŶƚŽĨĐĞƌĞďƌĂů
ǀĂƐŽƐƉĂƐŵĐĂŶŚĞůƉŐƵŝĚĞƚŚĞĂŐŐƌĞƐƐŝǀĞŶĞƐƐŽĨďŽƚŚŵĞĚŝĐĂůĂŶĚĞŶĚŽǀĂƐĐƵůĂƌƚƌĞĂƚŵĞŶƚƚŽ
ƉƌĞǀĞŶƚŝƌƌĞǀĞƌƐŝďůĞĐĞƌĞďƌĂůŝŶĨĂƌĐƚŝŽŶ͘
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dŚĞŵĞĐŚĂŶŝƐŵďĞŚŝŶĚĐĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵŝƐŶŽƚĐŽŵƉůĞƚĞůǇƵŶĚĞƌƐƚŽŽĚ͘/ƚŝƐ
ƐƵŐŐĞƐƚĞĚƚŚĂƚƚŚĞƌĞŝƐŐůŽďĂůǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶŝŶƌĞƐƉŽŶƐĞƚŽƚŚĞƉƌĞƐĞŶĐĞŽĨďůŽŽĚŝŶƚŚĞ
ƐƵďĂƌĂĐŚŶŽŝĚƐƉĂĐĞ͘KŶĞƚŚĞŽƌǇŝƐƚŚĞĚĞŐƌĂĚĂƚŝŽŶŽĨŚĞŵŽŐůŽďŝŶƌĞƐƵůƚƐŝŶĨŽƌŵĂƚŝŽŶŽĨĨƌĞĞ
ƌĂĚŝĐĂůƐĂŶĚĐŽŶƐƵŵƉƚŝŽŶŽĨŶŝƚƌŝĐŽǆŝĚĞ͘ŶĞŶǀŝƌŽŶŵĞŶƚǁŝƚŚůŽǁĐŽŶĐĞŶƚƌĂƚŝŽŶƐŽĨŶŝƚƌŝĐ
ŽǆŝĚĞĐĂŶƉƌŽĚƵĐĞďŽƚŚůŽĐĂůĂŶĚŐůŽďĂůǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶŽĨƚŚĞĐĞƌĞďƌĂůǀĞƐƐĞůƐϴ͘dŚĞĐĞƌĞďƌĂů
ďůŽŽĚƐƵƉƉůǇŝƐƵŶŝƋƵĞŝŶƚŚĂƚŝƐƌĞůŝĞƐŚĞĂǀŝůǇŽŶĂƵƚŽƌĞŐƵůĂƚŝŽŶ͘hŶĚĞƌĐŽŶĚŝƚŝŽŶƐŽĨ
ŝŶĚŝƐĐƌŝŵŝŶĂƚĞǀĂƐŽĐŽŶƐƚƌŝĐƚŝŽŶƚŚĞƌĞĐĂŶďĞŝŵƉĂŝƌĞĚĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞĂĐƚŝǀŝƚǇŽƌĂďŝůŝƚǇƚŽ
ŝŶĐƌĞĂƐĞĐĞƌĞďƌĂůďůŽŽĚĨůŽǁƚŚƌŽƵŐŚǀĂƐŽĚŝůĂƚŝŽŶŝŶƌĞƐƉŽŶƐĞƚŽĞŝƚŚĞƌŝŶƚƌŝŶƐŝĐŽƌ
ƉŚĂƌŵĂĐŽůŽŐŝĐƐŝŐŶĂůƐƚŽŝŶĐƌĞĂƐĞ&͘
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WŽƐŶĞƌĂŶĚWůƵŵŝŶϭϵϲϬĨŝƌƐƚŝŶĐŝĚĞŶƚĂůůǇŽďƐĞƌǀĞĚƚŚĂƚƚŚĞƌĞŝƐĂĐŽŶƐŝĚĞƌĂďůĞŝŶĐƌĞĂƐĞ
ŝŶĐĞƌĞďƌĂůďůŽŽĚĨůŽǁĂĨƚĞƌŝŶƚƌĂǀĞŶŽƵƐĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨĂĐĞƚĂǌŽůĂŵŝĚĞĚƵƌŝŶŐĂŶ
ŝŶǀĞƐƚŝŐĂƚŝŽŶŽĨƚŚĞĞĨĨĞĐƚƐŽĨĂĐĞƚĂǌŽůĂŵŝĚĞŝŶŚĞƉĂƚŝĐĞŶĐĞƉŚĂůŽƉĂƚŚǇϵ͘ĐĞƚĂǌŽůĂŵŝĚĞŝƐĂ
ƌĞǀĞƌƐŝďůĞĐĂƌďŽŶŝĐĂŶŚǇĚƌĂƐĞŝŶŚŝďŝƚŽƌǁŚŝĐŚƉƌĞǀĞŶƚƐĐŽŶǀĞƌƐŝŽŶŽĨĐĂƌďŽŶĚŝŽǆŝĚĞƚŽǁĂƚĞƌ
ĂŶĚĐĂƌďŽŶŝĐĂĐŝĚ͕ƌĞƐƵůƚŝŶŐŝŶĂŶŝŶĐƌĞĂƐĞĚĐŽŶĐĞŶƚƌĂƚŝŽŶŽĨĂƌƚĞƌŝĂůĐĂƌďŽŶĚŝŽǆŝĚĞ͘ZĞŐƵůĂƚŝŽŶ
ŽĨĐĞƌĞďƌĂůĐŝƌĐƵůĂƚŝŽŶŝƐƉĂƌƚůǇŵĞĚŝĂƚĞĚďǇĐĂƌďŽŶĚŝŽǆŝĚĞǁŚŝĐŚƐĞƌǀĞƐĂƐĂƉŽƚĞŶƚǀĂƐŽĚŝůĂƚŽƌ
ƌĞƐƵůƚŝŶŐŝŶŝŶĐƌĞĂƐĞĚĐĞƌĞďƌĂůďůŽŽĚĨůŽǁ͘hŶĚĞƌŶŽƌŵĂůƉŚǇƐŝŽůŽŐŝĐĂůĐŽŶĚŝƚŝŽŶƐ
ĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨĂĐĞƚĂǌŽůĂŵŝĚĞĐĂŶƌĞƐƵůƚŝŶĨƵƌƚŚĞƌĚŝůĂƚŝŽŶŽĨƚŚĞĐĞƌĞďƌĂůĂƌƚĞƌŝŽůĞƐ͕
ƚŚĞƌĞĨŽƌĞŝŶĐƌĞĂƐŝŶŐĐĞƌĞďƌĂůďůŽŽĚĨůŽǁϭϬ͘^ĞǀĞƌĂůƐƚƵĚŝĞƐŚĂǀĞĚŽĐƵŵĞŶƚĞĚƚŚŝƐƉŚĞŶŽŵĞŶŽŶ
ďŽƚŚŝŶŶŽƌŵĂůƐƵďũĞĐƚƐĂŶĚŝŶƉĂƚŝĞŶƚƐǁŝƚŚǀĂƌǇŝŶŐĚĞŐƌĞĞƐŽĨǀĂƐĐƵůĂƌƉĂƚŚŽůŽŐǇŝŶĐůƵĚŝŶŐ
ƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞĂŶĚǀĂƐĐƵůĂƌŝŶƐƵĨĨŝĐŝĞŶĐǇŽƌŽĐĐůƵƐŝŽŶϭ͕Ϯ͕ϭϬʹϭϰ͘,ŽǁĞǀĞƌ͕ŝĨĐĞƌĞďƌĂů
ƉĞƌĨƵƐŝŽŶŚĂƐďĞĞŶƌĞĚƵĐĞĚĚƵĞƚŽǀĂƐŽƐƉĂƐŵ͕ƚŚĞĐĞƌĞďƌĂůĂƌƚĞƌŝŽůĞƐĐŽƌƌĞůĂƚŝŶŐƚŽƚŚĞ
ĚŝƐĞĂƐĞĚƚĞƌƌŝƚŽƌǇŚĂǀĞĂůƌĞĂĚǇůŽƐƚƚŚĞŝƌĂďŝůŝƚǇƚŽĚŝůĂƚĞĂŶĚǁŝůůŶŽƚŚĂǀĞƚŚĞĞǆƉĞĐƚĞĚ
ŝŶĐƌĞĂƐĞŝŶĐĞƌĞďƌĂůďůŽŽĚĨůŽǁĂƐĂĚŝƌĞĐƚƌĞƐƉŽŶƐĞƚŽĂĐĞƚĂǌŽůĂŵŝĚĞĂĚŵŝŶŝƐƚƌĂƚŝŽŶ͘^ŝŵƉůǇ
ƉƵƚĂĐĞƚĂǌŽůĂŵŝĚĞƐŚŽƵůĚŚĂǀĞŶŽĂĚĚŝƚŝŽŶĂůĞĨĨĞĐƚŽŶĐĞƌĞďƌĂůďůŽŽĚĨůŽǁŝŶĂŶĂƌĞĂǁŚĞƌĞ


ǀĂƐŽƌĞŐƵůĂƚŽƌǇƌĞƐƉŽŶƐĞƐĂƌĞŝŵƉĂŝƌĞĚ͘/ŶĂĚĚŝƚŝŽŶ͕ĂĐĞƚĂǌŽůĂŵŝĚĞŚĂƐďĞĞŶƌĞƉŽƌƚĞĚƚŽŚĂǀĞ
ďĞĞŶŝŶũĞĐƚĞĚŝŶƚƌĂǀĞŶŽƵƐůǇǁŝƚŚŶŽƐĞƌŝŽƵƐĐŽŵƉůŝĐĂƚŝŽŶƐŝŶƉƌŝŽƌ&ƐƚƵĚŝĞƐŝŶŶŽƌŵĂů
ƐƵďũĞĐƚƐĂŶĚŝŶƉĂƚŝĞŶƚƐǁŝƚŚǀĂƐĐƵůĂƌƉĂƚŚŽůŽŐǇϭϰ͘
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ĂƐĞĚŽŶƚŚĞƉƌŝŶĐŝƉůĞƐŽĨĂƵƚŽƌĞŐƵůĂƚŝŽŶ͕ĐĞƌĞďƌĂůďůŽŽĚĨůŽǁǁŝůůŶŽƚĚĞĐƌĞĂƐĞƵŶƚŝůƚŚĞ
ĐŽŵƉĞŶƐĂƚŽƌǇĐĂƉĂĐŝƚǇŽĨƚŚĞĐĞƌĞďƌĂůǀĂƐĐƵůĂƚƵƌĞŚĂƐďĞĞŶĞǆŚĂƵƐƚĞĚ͘^ŽŝĚĞĂůůǇ͕ƚŚĞƌĞŝƐĂ
ǁŝŶĚŽǁŽĨŽƉƉŽƌƚƵŶŝƚǇĨŽƌƚŚĞƌĂƉĞƵƚŝĐŝŶƚĞƌǀĞŶƚŝŽŶďĞƚǁĞĞŶƌĞĚƵĐƚŝŽŶŝŶĐĞƌĞďƌĂůƉĞƌĨƵƐŝŽŶ
ƉƌĞƐƐƵƌĞĂŶĚŝƐĐŚĞŵŝĐŶĞƵƌŽůŽŐŝĐĂůƐǇŵƉƚŽŵƐĚƵĞƚŽƌĞĚƵĐĞĚĐĞƌĞďƌĂůďůŽŽĚĨůŽǁ͘We 
hypothesize that using CBCTP combined with an acetazolamide challenge would be able to 
identify abnormalities in the cerebrovascular autoregulation prior to reductions in cerebral 
blood flow and therefore prior to ischemic insult.^ĞǀĞƌĂůƐƚƵĚŝĞƐŚĂǀĞĂůƌĞĂĚǇĚĞŵŽŶƐƚƌĂƚĞĚĂ
ƐŝŐŶŝĨŝĐĂŶƚŝŶĐƌĞĂƐĞŝŶĐĞƌĞďƌĂůďůŽŽĚĨůŽǁŝŶƌĞƐƉŽŶƐĞƚŽŝŶƚƌĂǀĞŶŽƵƐŝŶũĞĐƚŝŽŶŽĨĂĐĞƚĂǌŽůĂŵŝĚĞ
ďƵƚŝƚƐĂƉƉůŝĐĂƚŝŽŶƚŽƉĂƚŝĞŶƚƐǁŝƚŚƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞĂƚƌŝƐŬŽĨĚĞǀĞůŽƉŵĞŶƚŽĨ
ǀĂƐŽƐƉĂƐŵŚĂƐďĞĞŶůŝŵŝƚĞĚϵ͕ϭϬ͕ϭϮ͕ϭϱ͕ϭϲ͘
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ͲĂƌŵdŝƐĂƚĞĐŚŶŽůŽŐǇƚŚĂƚĂůůŽǁƐĨŽƌdŝŵĂŐĞƐŽĨƚŚĞǀĂƐĐƵůĂƚƵƌĞ͕ďŽŶĞ͕ĂŶĚƐŽĨƚ
ƚŝƐƐƵĞƐƚŽďĞŐĞŶĞƌĂƚĞĚƵƚŝůŝǌŝŶŐƚŚĞĨůĂƚĚĞƚĞĐƚŽƌƐŽĨŵŽĚĞƌŶĂŶŐŝŽŐƌĂƉŚǇŵĂĐŚŝŶĞƐ͘dŚŝƐŝƐ
ĂĐĐŽŵƉůŝƐŚĞĚǁŝƚŚŚŝŐŚƐƉĞĞĚƌŽƚĂƚŝŽŶŽĨƚŚĞͲĂƌŵĂƌŽƵŶĚĂƐƵƉŝŶĞůǇƉŽƐŝƚŝŽŶĞĚƉĂƚŝĞŶƚǁŚŝůĞ
ĐŽůůĞĐƚŝŶŐĂŶĂƌƌĂǇŽĨϮͲĚŝŵĞŶƐŝŽŶĂůǆͲƌĂǇƉƌŽũĞĐƚŝŽŶƐ͘^ĞƉĂƌĂƚĞůǇ^DZdͲZKEĂůŐŽƌŝƚŚŵƐĂƌĞ
ƵƐĞĚƚŽƌĞĐŽŶƐƚƌƵĐƚƚŚĞƉƌŽũĞĐƚŝŽŶƐŝŶĂŶĂƚŽŵŝĐƉůĂŶĞƐĐŽŵƉĂƌĂďůĞƚŽdŝŵĂŐĞƐ͘tŝƚŚƌĞĐĞŶƚ
ĂĚǀĂŶĐĞƐŝŶƚĞĐŚŶŽůŽŐǇƚŚĞƉŽƐƚͲƉƌŽĐĞƐƐŝŶŐŽĨŝŵĂŐĞƐĐĂŶƉƌŽǀŝĚĞďŽƚŚĂŶĂƚŽŵŝĐĂŶĚ
ƉŚǇƐŝŽůŽŐŝĐ;ƉĞƌĨƵƐŝŽŶͿŝŶĨŽƌŵĂƚŝŽŶƵƐŝŶŐĂŶŝŶƚƌĂǀĞŶŽƵƐŝŶũĞĐƚŝŽŶŽĨĐŽŶƚƌĂƐƚĚǇĞ͘dŚŝƐŚŝŐŚͲ
ƋƵĂůŝƚǇͲĂŵdĂŶŐŝŽŐƌĂƉŚǇƵƚŝůŝǌĞƐϭͬϯŽĨƚŚĞƌĂĚŝĂƚŝŽŶĚŽƐĞĐƵƌƌĞŶƚůǇƵƐĞĚŝŶŽƵƌĐůŝŶŝĐĂů
ƉƌĂĐƚŝĐĞƵŶĚĞƌĐŽŶǀĞŶƚŝŽŶĂůdŝŵĂŐŝŶŐƚĞĐŚŶŽůŽŐǇ͘dŚŝƐƚĞĐŚŶŝƋƵĞŚĂƐďĞĞŶǀĂůŝĚĂƚĞĚďǇŽƵƌ
ƉƌĞǀŝŽƵƐůǇƉƵďůŝƐŚĞĚǁŽƌŬϭϳʹϭϵ͘
 
Study Objective 
 
dŚĞŽďũĞĐƚŝǀĞŽĨƚŚŝƐƉƌŽƉŽƐĂůŝƐƚŽĐŽŶĚƵĐƚĂĨĞĂƐŝďŝůŝƚǇƐƚƵĚǇŽĨĂĐĞƚĂǌŽůĂŵŝĚĞĂĐƚŝǀĂƚĞĚ
ͲĂƌŵdWƚŽĚĞƚĞƌŵŝŶĞŝƚƐĂƉƉůŝĐĂƚŝŽŶŝŶƚŚĞƉƌĞĚŝĐƚŝŽŶŽĨƐǇŵƉƚŽŵĂƚŝĐĐĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵ
ŝŶƉĂƚŝĞŶƚƐǁŝƚŚĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞ͘KƵƌŝŶŝƚŝĂůƉůĂŶŝƐƚŽŽďƚĂŝŶͲĂƌŵ
dWƉƌĞͲĂŶĚƉŽƐƚͲŝŶƚƌĂǀĞŶŽƵƐŝŶĨƵƐŝŽŶŽĨϭŐƌĂŵĂĐĞƚĂǌŽůĂŵŝĚĞǁŝƚŚŝŶϮϰŚŽƵƌƐŽĨƐǇŵƉƚŽŵ
ŽŶƐĞƚŝŶĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞƉĂƚŝĞŶƚƐ͘KƵƌŚǇƉŽƚŚĞƐŝƐŝƐƚŚĂƚƐŽŵĞŽĨƚŚĞƐĞ
ƉĂƚŝĞŶƚƐƚŚĂƚǁŝůůůĂƚĞƌĚĞǀĞůŽƉĐůŝŶŝĐĂůǀĂƐŽƐƉĂƐŵŽĨĂĚĞŐƌĞĞƐƵĨĨŝĐŝĞŶƚƚŽĐĂƵƐĞĐĞƌĞďƌĂů
ŝƐĐŚĞŵŝĂ͘tĞďĞůŝĞǀĞƚŚŝƐĐŽŚŽƌƚŽĨƉĂƚŝĞŶƚƐǁŝůůĚĞŵŽŶƐƚƌĂƚĞĂůƚĞƌĞĚĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞĂĐƚŝǀŝƚǇ
ĚƵƌŝŶŐƚŚĞĂĐĞƚĂǌŽůĂŵŝĚĞĐŚĂůůĞŶŐĞĂƚĂƚŝŵĞďĞĨŽƌĞƚŚĞƌĞŝƐĞŝƚŚĞƌĂŶŐŝŽŐƌĂƉŚŝĐĞǀŝĚĞŶĐĞŽĨ
ǀĂƐŽƐƉĂƐŵŽƌĐůŝŶŝĐĂůĞǀŝĚĞŶĐĞŽĨĂďŶŽƌŵĂůƉĞƌĨƵƐŝŽŶ͘dŚƵƐĨĂƌŝŶƚŚĞƉŝůŽƚƐƚƵĚǇǁĞŚĂǀĞ
ĞŶƌŽůůĞĚĂƚŽƚĂůŽĨϭϬƉĂƚŝĞŶƚƐĂŶĚĂƌĞŶŽǁƉůĂŶŶŝŶŐƚŽĞǆƉĂŶĚĞŶƌŽůůŵĞŶƚƚŽϯϬƉĂƚŝĞŶƚƐ͘dŚĞ
ĚĂƚĂǁĞŚĂǀĞĐŽůůĞĐƚĞĚĨƌŽŵƚŚĞƌĞƐĞĂƌĐŚƐĐĂŶƐŚĂǀĞƚŚƵƐĨĂƌďĞĞŶƌĞƉƌŽĚƵĐŝďůĞĂŶĚĐŽůůĞĐƚĞĚ
ǁŝƚŚĐůŝŶŝĐĂůĞĂƐĞ͘dŚĞƌĞŚĂǀĞďĞĞŶŶŽĐŽŵƉůŝĐĂƚŝŽŶƐǁŝƚŚŝŵĂŐŝŶŐĂĐƋƵŝƐŝƚŝŽŶĂŶĚƚŚĞƌĞŚĂǀĞ
ďĞĞŶŶŽƐĂĨĞƚǇĐŽŶĐĞƌŶƐĨŽƌƉĂƚŝĞŶƚƐ͘,ĂǀŝŶŐƐŽĨĂƌĂĐŚŝĞǀĞĚŽƵƌŽďũĞĐƚŝǀĞƐǁŝƚŚƚŚĞŝŶŝƚŝĂůϭϬ
ƉĂƚŝĞŶƚƐǁĞŶŽǁŚŽƉĞƚŽĂŵĞŶĚƚŚĞƉƌŽƚŽĐŽůƚŽĂůůŽǁĨŽƌƚŚĞůĂƌŐĞƌĐŽŚŽƌƚŽĨϯϬƐƵďũĞĐƚƐ͘tŝƚŚ
ƚŚŝƐůĂƌŐĞƌƐĂŵƉůĞƐŝǌĞǁĞǁŝůůŶŽƚŽŶůǇĐŽŶƚŝŶƵĞƚŽĂƐƐĞƐƐƐĂĨĞƚǇĂŶĚƌĞƉƌŽĚƵĐŝďŝůŝƚǇ͕ďƵƚĂůƐŽ
ǁŝůůŚŽƉĞƚŽĐĂƉƚƵƌĞĂůĂƌŐĞŶƵŵďĞƌŽĨƉĂƚŝĞŶƚƐǁŚŽĚĞǀĞůŽƉǀĂƐŽƐƉĂƐŵŝŶŽƌĚĞƌĨƵƌƚŚĞƌĂƐƐĞƐƐ


ƚŚĞƵƚŝůŝƚǇŽĨƚŚĞƌĞƐĞĂƌĐŚƐƚƵĚǇŝŶŝƚƐĂƉƉůŝĐĂƚŝŽŶĂƐĂƐĐƌĞĞŶŝŶŐĚŝĂŐŶŽƐƚŝĐƚŽŽůƚŽƉƌĞĚŝĐƚƚŚĞ
ƐƵďƐĞƋƵĞŶƚŽĐĐƵƌƌĞŶĐĞŽĨĚĞůĂǇĞĚǀĂƐŽƐƉĂƐŵŝŶƐƵďũĞĐƚƐǁŝƚŚĂŶĂĐƵƚĞĂŶĞƵƌǇƐŵĂů
ƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞ͘
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Study Methods 
 
/ŶĐůƵƐŝŽŶĐƌŝƚĞƌŝĂ͗
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ƚŽƚĂůŽĨϯϬƐƵďũĞĐƚƐǁŝůůďĞĞŶƌŽůůĞĚŝŶƚŚŝƐƉŝůŽƚĨĞĂƐŝďŝůŝƚǇƐƚƵĚǇ͘dŚĞĨŽůůŽǁŝŶŐƉĂƚŝĞŶƚƐǁŝůůďĞ
ƚĂƌŐĞƚĞĚĨŽƌĞŶƌŽůůŵĞŶƚ͗
ϭ͘ WĂƚŝĞŶƚƐǁŝƚŚĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞƉƌĞƐĞŶƚŝŶŐƚŽŽƵƌŝŶƐƚŝƚƵƚŝŽŶǁŝƚŚŝŶ
ϮϰŚŽƵƌƐŽĨƐǇŵƉƚŽŵŽŶƐĞƚ͘
Ϯ͘ ĚƵůƚƐ͕ϭϴǇĞĂƌƐŽĨĂŐĞŽƌŽůĚĞƌ
ϯ͘ tŽŵĞŶŽĨĐŚŝůĚďĞĂƌŝŶŐƉŽƚĞŶƚŝĂůŵƵƐƚŶŽƚďĞƉƌĞŐŶĂŶƚ;ƵƌŝŶĞƉƌĞŐŶĂŶĐǇƚĞƐƚǁŝůůďĞ
ƌĞƋƵŝƌĞĚĂƐŝƐĂůƌĞĂĚǇĚŽŶĞĂƐƉĂƌƚŽĨƐƚĂŶĚĂƌĚŽĨĐĂƌĞͿ
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ǆĐůƵƐŝŽŶĐƌŝƚĞƌŝĂ͗
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tŚĞƚŚĞƌƐƵďũĞĐƚƐǁŝůůďĞŝŶǀŝƚĞĚƚŽƉĂƌƚŝĐŝƉĂƚĞŝŶƚŚŝƐƌĞƐĞĂƌĐŚǁŝůůďĞďĂƐĞĚŽŶƚŚĞƉĂƚŝĞŶƚ͛Ɛ
ŵĞĚŝĐĂůĐŽŶĚŝƚŝŽŶĂŶĚǁŝůůďĞĂƚƚŚĞĚŝƐĐƌĞƚŝŽŶŽĨƚŚĞƚƌĞĂƚŝŶŐƉŚǇƐŝĐŝĂŶ͘dŚĞĨŽůůŽǁŝŶŐƉĂƚŝĞŶƚƐ
ǁŝůůďĞĞǆĐůƵĚĞĚĂƵƚŽŵĂƚŝĐĂůůǇ͗
ϭ͘ ŽŶƚƌĂŝŶĚŝĐĂƚŝŽŶƚŽĂĐĞƚĂǌŽůĂŵŝĚĞ;ŝ͘Ğ͘ƐƵůĨŽŶĂŵŝĚĞĂůůĞƌŐǇ͕ƌĞŶĂůŽƌůŝǀĞƌĨĂŝůƵƌĞͿ
Ϯ͘ ŽŶƚƌĂŝŶĚŝĐĂƚŝŽŶƚŽĐŽŶƚƌĂƐƚŵĞĚŝĂ;ůůĞƌŐǇŽƌĂďŶŽƌŵĂůƐĞƌƵŵƌĂŶĚͬŽƌ'&ZďĂƐĞĚŽŶ
ĐƵƌƌĞŶƚhtŐƵŝĚĞůŝŶĞƐĨŽƌ/sĐŽŶƚƌĂƐƚƐĞĞƉƉĞŶĚŝǆͿ
ϯ͘ ZĞŶĂůŝŶƐƵĨĨŝĐŝĞŶĐǇ͕ŚŝƐƚŽƌǇŽĨƌĞŶĂůĨĂŝůƵƌĞŽƌƌĞŶĂůƚƌĂŶƐƉůĂŶƚ
ϰ͘ ,ƵŶƚĂŶĚ,ĞƐƐŐƌĂĚĞϭĂŶĚϱ;^ĞĞƉƉĞŶĚŝǆ͕ĂƐ'ƌĂĚĞϭŚĂǀĞůŽǁĞƌǇŝĞůĚĨŽƌ
ǀĂƐŽƐƉĂƐŵĂŶĚ'ƌĂĚĞϱĂƌĞďǇĚĞĨŝŶŝƚŝŽŶĐƌŝƚŝĐĂůůǇŝůůĂŶĚƵŶƐƚĂďůĞƉĂƚŝĞŶƚƐͿ
ϱ͘ ƌŝƚŝĐĂůůǇŝůůƉĂƚŝĞŶƚƐǁŚŽĂƌĞƵŶƐƚĂďůĞĂŶĚǁŚŽĐĂŶŶŽƚƵŶĚĞƌŐŽƐĐĂŶƐǁŝƚŚŝŶƚŚĞ
ƉƌŽƉŽƐĞĚƚŝŵĞůŝŶĞŝ͘Ğ͘ǁŝƚŚŝŶϮϰŚŽƵƌƐŽĨƚŚĞŽŶƐĞƚŽĨƚŚĞŝƌƐǇŵƉƚŽŵƐ͘
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WĂƚŝĞŶƚŝĚĞŶƚŝĨŝĐĂƚŝŽŶͬZĞĐƌƵŝƚŵĞŶƚͬŽŶƐĞŶƚ͗
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WĂƚŝĞŶƚƐƚĂƌŐĞƚĞĚĨŽƌĞŶƌŽůůŵĞŶƚǁŝůůďĞƚŚŽƐĞƌĞĨĞƌƌĞĚƚŽƚŚĞĞƉĂƌƚŵĞŶƚŽĨ
EĞƵƌŽƐƵƌŐĞƌǇĂŶĚEĞƵƌŽĞŶĚŽǀĂƐĐƵůĂƌ^ƵƌŐĞƌǇĂƚhŶŝǀĞƌƐŝƚǇŽĨtŝƐĐŽŶƐŝŶŵĞĞƚŝŶŐƚŚĞŝŶĐůƵƐŝŽŶ
ĐƌŝƚĞƌŝĂ͘ůŝŐŝďůĞĐĂŶĚŝĚĂƚĞƐǁŝůůďĞŝĚĞŶƚŝĨŝĞĚďǇƚŚĞŶĞƵƌŽĞŶĚŽǀĂƐĐƵůĂƌŽƌŶĞƵƌŽƐƵƌŐŝĐĂů
ĂƚƚĞŶĚŝŶŐƉŚǇƐŝĐŝĂŶĂŶĚǁŝůůďĞŝŶǀŝƚĞĚƚŽƉĂƌƚŝĐŝƉĂƚĞďǇĂĐůŝŶŝĐĂůĐĂƌĞƚĞĂŵŵĞŵďĞƌ͘/ĨƉĂƚŝĞŶƚƐ
ůĂĐŬĐĂƉĂĐŝƚǇƚŽƉƌŽǀŝĚĞŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚŽŶƚŚĞŝƌŽǁŶďĞŚĂůĨ͕ƚŚĞĐĂƌĞƚĞĂŵǁŝůůŝŶĐůƵĚĞƚŚĞ
ŶĞǆƚŽĨŬŝŶŝŶƚŚĞĐŽŶƐĞŶƚŝŶŐƉƌŽĐĞƐƐ͘^ƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞƉĂƚŝĞŶƚƐƚŚĂƚƉƌĞƐĞŶƚǁŝƚŚĂ
ŵĞĚŝĐĂůůǇƵŶƐƚĂďůĞĐŽŶĚŝƚŝŽŶǁŝůůŶŽƚďĞĐŽŶƐŝĚĞƌĞĚĨŽƌƚŚŝƐƐƚƵĚǇ͘
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ĂƉĂĐŝƚǇĨŽƌƉƌŽǀŝĚŝŶŐŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚǁŝůůďĞĚĞƚĞƌŵŝŶĞĚĂŶĚĚŽĐƵŵĞŶƚĞĚŝŶ
ĂĐĐŽƌĚĂŶĐĞǁŝƚŚƚŚĞŝŶƐƚŝƚƵƚŝŽŶĂůƉŽůŝĐǇĨŽƌƚŚĞŝŶĐůƵƐŝŽŶŽĨƉĂƚŝĞŶƚƐŝŶŶŽŶͲƚŚĞƌĂƉĞƵƚŝĐƌĞƐĞĂƌĐŚ
ƚŚĂƚƉƌĞƐĞŶƚƐŵŽƌĞƚŚĂŶŵŝŶŝŵĂůƌŝƐŬ͘dŚŝƐĚĞƚĞƌŵŝŶĂƚŝŽŶǁŝůůŽĐĐƵƌďǇĚŝƌĞĐƚĞǀĂůƵĂƚŝŽŶďǇƚŚĞ
ĐůŝŶŝĐĂůĐĂƌĞƚĞĂŵďĂƐĞĚŽŶŝŶƚĞƌĂĐƚŝŽŶǁŝƚŚƚŚĞƉĂƚŝĞŶƚ͕ĞǆŝƐƚŝŶŐůĞŐĂůĚŽĐƵŵĞŶƚĂƚŝŽŶŝŶƚŚĞ


ŵĞĚŝĐĂůƌĞĐŽƌĚŝŶƌĞŐĂƌĚƐƚŽĂůĞŐĂůŐƵĂƌĚŝĂŶ͕ŚĞĂůƚŚĐĂƌĞƉŽǁĞƌŽĨĂƚƚŽƌŶĞǇ͕ŽƌƉƌĞͲĞǆŝƐƚŝŶŐ
ĚŝƐĞĂƐĞƚŚĂƚĂĨĨĞĐƚƐĚĞĐŝƐŝŽŶĂůĐĂƉĂĐŝƚǇ͘dŚĞhŶŝǀĞƌƐŝƚǇŽĨtŝƐĐŽŶƐŝŶ,ŽƐƉŝƚĂůƐĂŶĚůŝŶŝĐƐ
ůŝŶŝĐĂůWŽůŝĐǇŽŶ/ŶĨŽƌŵĞĚŽŶƐĞŶƚǁŝůůďĞĨŽůůŽǁĞĚ;ƉƉĞŶĚŝǆͿ͘dŚŽƐĞƐƵďũĞĐƚƐůĂĐŬŝŶŐĨŽƌŵĂů
ĐĂƉĂĐŝƚǇǁŝůůƐƚŝůůďĞŝŶĐůƵĚĞĚŝŶƚŚĞĐŽŶƐĞŶƚŝŶŐƉƌŽĐĞƐƐĂŶĚǁŝůůďĞĂƐŬĞĚƚŽƉƌŽǀŝĚĞĂƐƐĞŶƚƚŽ
ƉĂƌƚŝĐŝƉĂƚĞ͘ŶǇƐŝŐŶŽĨĚŝƐƐĞŶƚďǇƚŚĞƐƵďũĞĐƚǁŝůůďĞŚŽŶŽƌĞĚďǇƚŚĞƌĞƐĞĂƌĐŚƚĞĂŵĞǀĞŶŝĨĂ
ƐƵƌƌŽŐĂƚĞŚĂƐƉƌŽǀŝĚĞĚĐŽŶƐĞŶƚŽŶƚŚĞŝƌďĞŚĂůĨ͘/ĨĂƐƵďũĞĐƚƌĞŐĂŝŶƐĐĂƉĂĐŝƚǇƉƌŝŽƌƚŽŚŽƐƉŝƚĂů
ĚŝƐĐŚĂƌŐĞ͕ĂƌĞƐĞĂƌĐŚƚĞĂŵŵĞŵďĞƌǁŝůůƌĞǀŝĞǁƚŚĞĐŽŶƐĞŶƚ͕ƌĞƐĞĂƌĐŚƉƌŽĐĞĚƵƌĞƐƚŚĂƚŚĂǀĞ
ďĞĞŶĐŽŶĚƵĐƚĞĚ͕ĂŶĚǁŝůůŽďƚĂŝŶŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚĨŽƌĐŽŶƚŝŶƵĞĚƉĂƌƚŝĐŝƉĂƚŝŽŶŝŶƚŚĞƌĞƐĞĂƌĐŚ͘
&ŽƌƉĂƚŝĞŶƚƐƚŚĂƚŚĂǀĞďĞĞŶĚĞƚĞƌŵŝŶĞĚƚŽŚĂǀĞĐĂƉĂĐŝƚǇƚŽƉƌŽǀŝĚĞŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚ͕Ă
ƌĞƐĞĂƌĐŚƚĞĂŵŵĞŵďĞƌǁŝůůĂĚŵŝŶŝƐƚĞƌĂĨŽƵƌͲƋƵĞƐƚŝŽŶĂƐƐĞƐƐŵĞŶƚƚŽĐŽŶĨŝƌŵƵŶĚĞƌƐƚĂŶĚŝŶŐŽĨ
ƚŚĞŝŵƉůŝĐĂƚŝŽŶƐŽĨƉĂƌƚŝĐŝƉĂƚŝŶŐŝŶƚŚŝƐƌĞƐĞĂƌĐŚ;ƉƉĞŶĚŝǆͿ͘/ĨƚŚĞƐƵďũĞĐƚŽƌůĞŐĂůŚĞĂůƚŚĐĂƌĞ
ƌĞƉƌĞƐĞŶƚĂƚŝǀĞŝƐƵŶĂďůĞƚŽƉƌŽǀŝĚĞŝŶĨŽƌŵĞĚĐŽŶƐĞŶƚ͕ƚŚĞŶƚŚĞƉĂƚŝĞŶƚǁŝůůďĞĞǆĐůƵĚĞĚĨƌŽŵ
ƉĂƌƚŝĐŝƉĂƚŝŽŶ͘
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^ĐĂŶƉƌŽĐĞĚƵƌĞ͗
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KǀĞƌǀŝĞǁŽĨŝŵĂŐŝŶŐƉƌŽƚŽĐŽů͗WƌŝŽƌƚŽĐĂƚŚĞƚĞƌĂŶŐŝŽŐƌĂƉŚǇ͕ƚŚĞĚŝĂŐŶŽƐƚŝĐĞǀĂůƵĂƚŝŽŶƐŽĨ
ƐƵďũĞĐƚƐĞŶƚĞƌĞĚŝŶƚŽƚŚŝƐƉƌŽƚŽĐŽůǁŝůůŶŽƚǀĂƌǇĨƌŽŵƚŚĂƚƵƐĞĚŽŶŽƚŚĞƌƐǁŚŽĂƌĞŶŽƚĞůŝŐŝďůĞŽƌ
ǁŚŽĚŽŶŽƚǁŝƐŚƚŽƉĂƌƚŝĐŝƉĂƚĞŝŶƚŚĞƐƚƵĚǇ͘^ƵďũĞĐƚƐĞŶƚĞƌĞĚŝŶƚŽƚŚĞƐƚƵĚǇ͕ǁŝůůďĞĐĂƵƐĞŽĨ
ƚŚĞŝƌƉĂƌƚŝĐŝƉĂƚŝŽŶ͕ƵŶĚĞƌŐŽŽŶůǇƚǁŽĂĚĚŝƚŝŽŶĂů^ŝŵĂŐŝŶŐĂĐƋƵŝƐŝƚŝŽŶƐ͘dŚĞƐĞǁŝůůďĞĚŽŶĞŝŶ
ĐŽŶũƵŶĐƚŝŽŶǁŝƚŚƚŚĞŝƌƐƚĂŶĚĂƌĚĚŝĂŐŶŽƐƚŝĐ^ĞǀĂůƵĂƚŝŽŶĂŶĚĐŽŶƐŝƐƚŽĨƚǁŽdWƐ͕ŽŶĞ
ďĞĨŽƌĞĂŶĚŽŶĞĂĨƚĞƌĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨϭŐĂĐĞƚĂǌŽůĂŵŝĚĞƚŚƌŽƵŐŚĂƉĞƌŝƉŚĞƌĂů/sůŝŶĞ͘ĂĐŚ
dWǁŝůůƌĞƋƵŝƌĞĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨϳϱͲϭϬϬŵ>ŝŽĚŝŶĂƚĞĚĐŽŶƚƌĂƐƚŵĞĚŝƵŵĂůƐŽƚŚƌŽƵŐŚĂŶ/s
ůŝŶĞ͘EĞŝƚŚĞƌŽĨƚŚĞƐĞŝŵĂŐŝŶŐƐƚƵĚŝĞƐǁŝůůďĞƵƐĞĚĨŽƌĐůŝŶŝĐĂůĚĞĐŝƐŝŽŶŵĂŬŝŶŐ͕ďƵƚǁŽƵůĚďĞ
ƉƌŽĐĞƐƐĞĚĂŶĚĞǀĂůƵĂƚĞĚĂƚůĂƚĞƌĚĂƚĞĨŽƌĂĨŽƌŵĂůĂŶĂůǇƐŝƐŽĨƚŚĞƌĞƐƵůƚƐ͘&ŽůůŽǁŝŶŐĐŽŵƉůĞƚŝŽŶ
ŽĨĚŝĂŐŶŽƐƚŝĐŝŵĂŐŝŶŐƐƵďũĞĐƚƐǁŝůůƌĞĐĞŝǀĞƚŚĞƵƐƵĂůƐƚĂŶĚĂƌĚŽĨĐĂƌĞĨŽƌƚƌĞĂƚŵĞŶƚŽĨƚŚĞŝƌ
ƌƵƉƚƵƌĞĚĂŶĞƵƌǇƐŵŝ͘Ğ͘ĞŶĚŽǀĂƐĐƵůĂƌĞŵďŽůŝǌĂƚŝŽŶŽƌŽƉĞŶƐƵƌŐŝĐĂůĐůŝƉƉŝŶŐ͘
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ĞƚĂŝůƐŽĨĞǆƉĞƌŝŵĞŶƚĂůŝŵĂŐŝŶŐ͗ŶŝŶŝƚŝĂůdWĂĐƋƵŝƐŝƚŝŽŶǁŝůůďĞĚŽŶĞŝŶĐŽŶũƵŶĐƚŝŽŶǁŝƚŚ
ŝŶũĞĐƚŝŽŶŽĨŝŽĚŝŶĂƚĞĚĐŽŶƚƌĂƐƚŵĞĚŝƵŵƚŚƌŽƵŐŚĂƉĞƌŝƉŚĞƌĂů/s;ϳϱͲϭϬϬŵ>ŝŽƉĂŵŝĚŽů͕/ƐŽǀƵĞ
ϯϳϬ͖ƌĂĐĐŽŝĂŐŶŽƐƚŝĐƐ͕WƌŝŶĐĞƚŽŶ͕E:Ϳ͘Ŷ/sŝƐƉůĂĐĞĚĨŽƌŶŽƌŵĂůƐƚĂŶĚĂƌĚͲŽĨͲĐĂƌĞĨŽƌƚŚŝƐ
ĚŝƐĞĂƐĞƉƌŽĐĞƐƐ͘ĨƚĞƌƚŚŝƐϭŐŽĨĂĐĞƚĂǌŽůĂŵŝĚĞǁŝůůďĞŐŝǀĞŶƚŚƌŽƵŐŚƚŚĞ/sůŝŶĞ͘&ŽůůŽǁŝŶŐĂ
ϮϬͲŵŝŶƵƚĞĚĞůĂǇĂƐĞĐŽŶĚdWĂĐƋƵŝƐŝƚŝŽŶǁŝůůďĞĐŽŵƉůĞƚĞĚĂŐĂŝŶŝŶĐŽŶũƵŶĐƚŝŽŶǁŝƚŚ
ŝŶũĞĐƚŝŽŶŽĨŝŽĚŝŶĂƚĞĚĐŽŶƚƌĂƐƚŵĞĚŝƵŵĂƚĂĚŽƐĞŝĚĞŶƚŝĐĂůƚŽƚŚĂƚƵƐĞĚĨŽƌƚŚĞĨŝƌƐƚdW
ĂĐƋƵŝƐŝƚŝŽŶ͘ĂĐŚŽĨƚŚĞdWĂĐƋƵŝƐŝƚŝŽŶƐƚĂŬĞůĞƐƐƚŚĂŶϮŵŝŶƵƚĞƐƐŽ͕ĞǆĐĞƉƚĨŽƌƚŚĞϮϬͲ
ŵŝŶƵƚĞƉĞƌŝŽĚĨŽůůŽǁŝŶŐĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨƚŚĞĂĐĞƚĂǌŽůĂŵŝĚĞƚŚĞƌĞǁŝůůďĞŶŽĚĞůĂǇŝŶƚŚĞ
ƐƵďũĞĐƚƐ͛ĚŝĂŐŶŽƐŝƐŽƌƚƌĞĂƚŵĞŶƚ͘
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ŽŶƚƌĂƐƚ͗ͲĂƌŵdWǁŝůůďĞƉĞƌĨŽƌŵĞĚǁŝƚŚŝŶƚƌĂǀĞŶŽƵƐŝŶũĞĐƚŝŽŶŽĨĐŽŶƚƌĂƐƚĚǇĞ;ŝŽƉĂŵŝĚŽů͕
/ƐŽǀƵĞϯϳϬ͖ƌĂĐĐŽŝĂŐŶŽƐƚŝĐƐ͕WƌŝŶĐĞƚŽŶ͕E:ͿĂƚĂƌĂƚĞŽĨϰŵ>ͬƐĂŶĚĂŵĂǆŝŵƵŵĚŽƐĞƌĂŶŐĞŽĨ
ϳϱͲϭϬϬŵ>͘dŚĞĐŽŶƚƌĂƐƚďŽůƵƐŵĂǇďĞĨŽůůŽǁĞĚďǇĂϱϬͲŵ>ƐĂůŝŶĞƉƵƐŚĂƚĂƌĂƚĞŽĨϰŵ>ͬƐ͘dŚĞ
ĚĞůĂǇǁŝůůďĞĐĂůĐƵůĂƚĞĚĨƌŽŵƚŚĞĐŽŶǀĞŶƚŝŽŶĂůdͬdWƚŚĂƚǁĂƐƉĞƌĨŽƌŵĞĚƉƌŝŽƌ͘dŚĞĐŽŶƚƌĂƐƚ
ĂĚŵŝŶŝƐƚĞƌĞĚĚƵƌŝŶŐƚŚĞĐŽŶǀĞŶƚŝŽŶĂůdŚĞĂĚĂŶĚŶĞĐŬǁŝƚŚƉĞƌĨƵƐŝŽŶƉĞƌĨŽƌŵĞĚƉƌŝŽƌǁŝůů
ďĞϭϮϬŵ>͘dŚĞƌĞĨŽƌĞ͕ƚŚĞŵĂǆŝŵƵŵĂŵŽƵŶƚŽĨ/sĐŽŶƚƌĂƐƚŵĞĚŝĂƚŚĂƚǁŽƵůĚďĞĂĚŵŝŶŝƐƚĞƌĞĚ


ǁŝƚŚŝŶĂϮϰͲŚŽƵƌƉĞƌŝŽĚĨŽƌƚŚŝƐƐƚƵĚǇŝƐϯϮϬŵ>͘ŽŶƚƌĂƐƚŵĞĚŝĂĂĚŵŝŶŝƐƚƌĂƚŝŽŶŝƐĂŶŝŵƉŽƌƚĂŶƚ
ĐŽŶƐŝĚĞƌĂƚŝŽŶĂƐĂĐĂƵƐĞŽĨŝĂƚƌŽŐĞŶŝĐĂĐƵƚĞŬŝĚŶĞǇŝŶũƵƌǇ͕ďƵƚŝƚƐŚŽƵůĚďĞĞŵƉŚĂƐŝǌĞĚƚŚĂƚƚŚĞ
ůĂƌŐĞŵĂũŽƌŝƚǇŽĨƚŚĞƐĞĐĂƐĞƐĂƌĞŵŝŶŽƌ͘hŶĚĞƌŽƵƌƉƌŽƚŽĐŽůƉƌĞͲĂŶĚƉŽƐƚͲƉƌŽĐĞĚƵƌĞƐĞƌƵŵ
ĐƌĞĂƚŝŶŝŶĞůĞǀĞůƐǁŝůůďĞŵŽŶŝƚŽƌĞĚĐůŽƐĞůǇĂŶĚƉĂƚŝĞŶƚƐǁŝůůƌĞĐĞŝǀĞĂĚĞƋƵĂƚĞŚǇĚƌĂƚŝŽŶ͘
/ŽƉĂŵŝĚŽůŝƐĞǆĐƌĞƚĞĚŵĂŝŶůǇƚŚƌŽƵŐŚƚŚĞŬŝĚŶĞǇƐĂŶĚŝŶƚŚĞĂďƐĞŶĐĞŽĨƌĞŶĂůĚǇƐĨƵŶĐƚŝŽŶϯϱͲ
ϱϬйŽĨƚŚĞĐŽŶƚƌĂƐƚŵĞĚŝĂŝƐĞǆĐƌĞƚĞĚǁŝƚŚŝŶϲϬŵŝŶƵƚĞƐĂŶĚϴϬͲϵϬйǁŝƚŚŝŶϴŚŽƵƌƐ͘dŚĞƌĞǁŝůů
ďĞĂƚůĞĂƐƚĂϭŚŽƵƌƉĞƌŝŽĚďĞƚǁĞĞŶĐŽŶƚƌĂƐƚůŽĂĚŝŶŐĨƌŽŵƚŚĞĐŽŶǀĞŶƚŝŽŶĂůdͬdWĂŶĚƚŚĞ
ƐƚƵĚǇͲĂƌŵdWƐĐĂŶƐ͘
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^DZdZKE͗dŚŝƐƐŽĨƚǁĂƌĞƵƚŝůŝǌĞƐƚŚĞŝŵĂŐĞƐĂĐƋƵŝƌĞĚĚƵƌŝŶŐƌŽƚĂƚŝŽŶĂůĂŶŐŝŽŐƌĂƉŚǇƚŽ
ĐƌĞĂƚĞĂŶĂŶŐŝŽŐƌĂƉŚŝĐd͘dŚĞǀŽůƵŵĞƐĞƚŝƐƌĞĐŽŶƐƚƌƵĐƚĞĚŽŶƚŚĞƐǇŶŐŽDƵůƚŝDŽĚĂůŝƚǇ
tŽƌŬƉůĂĐĞĂŶĚĂǀĂŝůĂďůĞĨŽƌĂƐƐĞƐƐŵĞŶƚŝŶůĞƐƐƚŚĂŶϭŵŝŶƵƚĞŝŶƚŚĞŝŶƚĞƌǀĞŶƚŝŽŶĂůƐƵŝƚĞ͘
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ĂƚĂĐƋƵŝƐŝƚŝŽŶ͗WĞƌĨƵƐŝŽŶŵĂƉƐĨƌŽŵƚŚĞƐƚĂŶĚĂƌĚŵƵůƚŝͲƌŽǁdWǁŝůůďĞĞǀĂůƵĂƚĞĚǁŝƚŚƚŚĞ
^ŝĞŵĞŶƐdWƐŽĨƚǁĂƌĞĂĨƚĞƌƚŚĞƉƌŽĐĞĚƵƌĞ͘WĞƌĨƵƐŝŽŶŵĂƉƐĨƌŽŵƚŚĞͲĂƌŵdǁŝůůďĞ
ĞǀĂůƵĂƚĞĚĂƚĂŶŝŶĚĞƉĞŶĚĞŶƚǁŽƌŬƐƚĂƚŝŽŶǁŝƚŚ^DZdZKE͘DĂƚĐŚŝŶŐƌĞŐŝŽŶƐŽĨŝŶƚĞƌĞƐƚ
;ZK/͛ƐͿǁŝůůďĞƉůĂĐĞĚŝŶĞĂĐŚŚĞŵŝƐƉŚĞƌĞŝŶŵŝƌƌŽƌŝŵĂŐĞƉŽƐŝƚŝŽŶƐ͘dŚĞZK/͛ƐŝĚĞŶƚŝĨŝĞĚŽŶĞĂĐŚ
ƉĂƚŝĞŶƚ͛ƐƐƚĂŶĚĂƌĚdWǁŝůůďĞĐŽŵƉĂƌĞĚƚŽŽŶĞƐƐĞůĞĐƚĞĚŝŶƚŚĞƉŽƐƚͲƉƌŽĐĞƐƐŝŶŐƉŚĂƐĞ͘
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ĐĞƚĂǌŽůĂŵŝĚĞŝŶũĞĐƚŝŽŶ͗ϭŐŝŶƚƌĂǀĞŶŽƵƐĂĐĞƚĂǌŽůĂŵŝĚĞǁŝůůďĞĂĚŵŝŶŝƐƚĞƌĞĚďǇƉĞƌŝƉŚĞƌĂů/s͘
ůŽŽĚƉƌĞƐƐƵƌĞ͕ƌĞƐƉŝƌĂƚŽƌǇƌĂƚĞ͕ŚĞĂƌƚƌĂƚĞĂŶĚƉƵůƐĞŽǆŝŵĞƚƌǇǁŝůůďĞŵŽŶŝƚŽƌĞĚďĞĨŽƌĞ͕
ĚƵƌŝŶŐ͕ĂŶĚĂĨƚĞƌƚŚŝƐŝŶũĞĐƚŝŽŶďǇƚŚĞĂĚŵŝŶŝƐƚĞƌŝŶŐŶƵƌƐĞ͘dŚĞǁĂŝƚƉĞƌŝŽĚĂĨƚĞƌĚƌƵŐ
ĂĚŵŝŶŝƐƚƌĂƚŝŽŶǁŝůůďĞƐƚĂŶĚĂƌĚŝǌĞĚƚŽϮϬŵŝŶƵƚĞƐƉƌŝŽƌƚŽŽďƚĂŝŶŝŶŐƚŚĞĨŽůůŽǁƵƉƉĞƌĨƵƐŝŽŶ
ƐƚƵĚǇ͘
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ƌƵŐ/ŶĨŽƌŵĂƚŝŽŶ͗
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ƌƵŐĨŽƌŵƵůĂƚŝŽŶ͗^ŽůƵƚŝŽŶZĞĐŽŶƐƚŝƚƵƚĞĚ͕/ŶũĞĐƚŝŽŶ
^ŽƵƌĐĞ͗ƌƵŐŝƐŽŶht,ĨŽƌŵƵůĂƌǇĂŶĚǁŽƵůĚďĞĂǀĂŝůĂďůĞƚŚƌŽƵŐŚƚŚĞŝŶƉĂƚŝĞŶƚƉŚĂƌŵĂĐǇ
^ƚŽƌĂŐĞĂŶĚƐƚĂďŝůŝƚǇ͗^ƚŽƌĞŝŶƚĂĐƚǀŝĂůƐĂƚϮϬͲϮϱ;ϲϴͲϳϳ&Ϳ͘^ƚŽƌĞƌĞĐŽŶƐƚŝƚƵƚĞĚƐŽůƵƚŝŽŶƐĨŽƌϯ
ĚĂǇƐƵŶĚĞƌƌĞĨƌŝŐĞƌĂƚŝŽŶĂƚϮͲϴ;ϯϲͲϰϲ&Ϳ͕ŽƌϭϮŚŽƵƌƐĂƚƌŽŽŵƚĞŵƉĞƌĂƚƵƌĞ;ϮϬͲϮϱŽƌϲϴͲϳϳ
&Ϳ͘
WƌĞƉĂƌĂƚŝŽŶ͗&ŽƌŝŶũĞĐƚŝŽŶƌĞĐŽŶƐƚŝƚƵƚĞǁŝƚŚĂƚůĞĂƐƚϱŵ>ƐƚĞƌŝůĞǁĂƚĞƌƚŽƉƌŽǀŝĚĞƐŽůƵƚŝŽŶ
ĐŽŶƚĂŝŶŝŶŐŶŽƚŵŽƌĞƚŚĂŶϭϬϬŵŐͬŵ>͘
ŽƐĂŐĞͬĚŵŝŶŝƐƚƌĂƚŝŽŶ͗ϭŐƌĂŵ͕ŝŶƚƌĂǀĞŶŽƵƐ
&ŽƌĂĐŽŵƉůĞƚĞůŝƐƚŝŶŐŽĨĚƌƵŐŝŶƚĞƌĂĐƚŝŽŶƐ͕ĐŽŶƚƌĂŝŶĚŝĐĂƚŝŽŶƐ͕ĂŶĚĂĚǀĞƌƐĞƌĞĂĐƚŝŽŶƐƉůĞĂƐĞƐĞĞ͗
ŚƚƚƉƐ͗ͬͬŽŶůŝŶĞ͘ůĞǆŝ͘ĐŽŵͬůĐŽͬĂĐƚŝŽŶͬĚŽĐͬƌĞƚƌŝĞǀĞͬĚŽĐŝĚͬƵŽĨǁŝƐĐŽŶƐŝŶͺĨͬϯϲϴϬϮϴϬ
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ĐĞƚĂǌŽůĂŵŝĚĞŽƌƚŚĞďƌĂŶĚŶĂŵĞŝĂŵŽǆŝƐĂŶ&ͲĂƉƉƌŽǀĞĚŵĞĚŝĐĂƚŝŽŶǁŝƚŚůĂďĞůĞĚ
ŝŶĚŝĐĂƚŝŽŶƐŝŶĐůƵĚŝŶŐŐůĂƵĐŽŵĂ͕ĞĚĞŵĂ͕ĂůƚŝƚƵĚĞƐŝĐŬŶĞƐƐ͕ĂŶĚĞƉŝůĞƉƐǇ͘KƵƌƉƌŽƚŽĐŽůǁŝůůƵƚŝůŝǌĞ
ŝŶƚƌĂǀĞŶŽƵƐĨŽƌŵƵůĂƚŝŽŶŽŶůǇ͘WƌŝŽƌƐƚƵĚŝĞƐŝŶƚŚĞůŝƚĞƌĂƚƵƌĞĂƐƐĞƐƐŝŶŐĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞƐĞƌǀĞ
ƵƐĞĚƌĂƉŝĚϭŐŝŶƚƌĂǀĞŶŽƵƐŝŶũĞĐƚŝŽŶŽǀĞƌůĞƐƐƚŚĂŶϭŵŝŶƵƚĞϭϭ͘ŽƐĞƐŽĨϱϬϬŵŐǁĞƌĞƌĞƉŽƌƚĞĚ
ƚŽďĞŝŶƐƵĨĨŝĐŝĞŶƚĨŽƌĂĚĞƋƵĂƚĞĐĂƌďŽŶŝĐĂŶŚǇĚƌĂƐĞŝŶŚŝďŝƚŝŽŶϭϮ͘ĐĞƚĂǌŽůĂŵŝĚĞŝƐ


ĐŽŶƚƌĂŝŶĚŝĐĂƚĞĚŝŶƉĂƚŝĞŶƚƐǁŝƚŚŵĂƌŬĞĚƌĞŶĂůŝŵƉĂŝƌŵĞŶƚ͕ĐŝƌƌŚŽƐŝƐŽƌůŝǀĞƌĚŝƐĞĂƐĞ͕
ƐƵůĨŽŶĂŵŝĚĞĂůůĞƌŐǇ͕ĂĚƌĞŶŽĐŽƌƚŝĐĂůŝŶƐƵĨĨŝĐŝĞŶĐǇ͕ŽƌŚǇƉĞƌĐŚůŽƌĞŵŝĐĂĐŝĚŽƐŝƐ͘
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ZŝƐŬƐ͗
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dŚŝƐĨĞĂƐŝďŝůŝƚǇƐƚƵĚǇƉƌĞƐĞŶƚƐŵŝŶŝŵĂůƌŝƐŬƐƚŽƉĂƌƚŝĐŝƉĂŶƚƐ͘^ƵďũĞĐƚƐĞŶƚĞƌŝŶŐƚŚŝƐƐƚƵĚǇ
ǁŝůůŶŽƚŚĂǀĞƚŚĞƚŝŵŝŶŐŽĨƚŚĞŝƌƚŚĞƌĂƉǇ͕ǁŚĞƚŚĞƌƚŚĂƚďĞĞŶĚŽǀĂƐĐƵůĂƌŽƌŽƉĞŶƐƵƌŐĞƌǇ͕ĂůƚĞƌĞĚ
ŝŶĂŶǇǁĂǇƚŚĂƚǁŽƵůĚĚŝĨĨĞƌĨƌŽŵƚŚĞƐƚĂŶĚĂƌĚŽĨĐĂƌĞŽĨĨĞƌĞĚĂƚŽƵƌŝŶƐƚŝƚƵƚŝŽŶ͘dŚĞƉŽƚĞŶƚŝĂů
ƌŝƐŬƐĨƌŽŵƉĂƌƚŝĐŝƉĂƚŝŶŐŝŶƚŚŝƐƐƚƵĚǇŝŶĐůƵĚĞĐŽŶƚƌĂƐƚĂŶĚƌĂĚŝĂƚŝŽŶĞǆƉŽƐƵƌĞ͕ƐŝĚĞĞĨĨĞĐƚƐŽƌ
ĂĚǀĞƌƐĞƌĞĂĐƚŝŽŶƐƚŽĂĐĞƚĂǌŽůĂŵŝĚĞĂŶĚƚŚĞƌŝƐŬŽĨďƌĞĂĐŚŽĨĐŽŶĨŝĚĞŶƚŝĂůŝƚǇ͘
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dŚĞŵĂŝŶƌŝƐŬƐĂƌĞĂůůĞƌŐŝĐƌĞĂĐƚŝŽŶĂŶĚĐŽŶƚƌĂƐƚͲŝŶĚƵĐĞĚŶĞƉŚƌŽƉĂƚŚǇ;/EͿ͘WƌŝŽƌƚŽ
ƌĞĐĞŝǀŝŶŐƚŚĞĂĚĚŝƚŝŽŶĂůĐŽŶƚƌĂƐƚŵĞĚŝĂƌĞƋƵŝƌĞĚďǇŽƵƌƐƚƵĚǇƐĐĂŶƐƵďũĞĐƚƐǁŝůůŚĂǀĞĂůƌĞĂĚǇ
ďĞĞŶŐŝǀĞŶĂƉƌŝŽƌĚŽƐĞŽĨƚŚĞƐĂŵĞĐŽŶƚƌĂƐƚŵĞĚŝƵŵĨŽƌƚŚĞŝƌƐƚĂŶĚĂƌĚŽĨĐĂƌĞĐŽŶǀĞŶƚŝŽŶĂů
d͘/ƚǁŝůůƚŚƵƐďĞĐůĞĂƌƚŽƌĞƐĞĂƌĐŚĞƌƐǁŚĞƚŚĞƌƚŚĞƐƵďũĞĐƚƐĂƌĞĂďůĞƚŽƚŽůĞƌĂƚĞƚŚĞĂŐĞŶƚ͘/Ĩ
ĂŶǇƉĂƚŝĞŶƚŝƐĞǆƉĞƌŝĞŶĐŝŶŐĂŶǇƐŝŐŶŽĨĐŽŶƚƌĂƐƚƌĞĂĐƚŝŽŶĂƚƚŚĞĐŽŶĐůƵƐŝŽŶŽĨƚŚĞĐůŝŶŝĐĂůd͕
ƚŚĞǇǁŝůůďĞǁŝƚŚĚƌĂǁŶĨƌŽŵƚŚŝƐƌĞƐĞĂƌĐŚƐƚƵĚǇ͘
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ƐŝƚƉĞƌƚĂŝŶƐƚŽ/E͕ƚŚĞƐƚĂŶĚĂƌĚŵĂǆŝŵƵŵĚŽƐĞĨŽƌĂŐŝǀĞŶƐƚƵĚǇŝƐϮϱϬŵ>ĂŶĚƚŚĞ
ƚŽƚĂůĚŽƐĞĨŽƌƐƵďũĞĐƚƐƉĂƌƚŝĐŝƉĂƚŝŶŐŝŶŽƵƌƌĞƐĞĂƌĐŚƐĐĂŶƐǁŝůůďĞůĞƐƐƚŚĂŶƚŚŝƐ͘/ŶĂƐƚƵĚǇŽĨ
ϭϭ͕ϱϴϴƉĂƚŝĞŶƚƐƵŶĚĞƌŐŽŝŶŐdƐĐĂŶƐǁŝƚŚŽƌǁŝƚŚŽƵƚĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨĐŽŶƚƌĂƐƚŵĞĚŝƵŵ͕ƌƵĐĞ
ĂŶĚĐŽůůĞĂŐƵĞƐĂƚhtͲDĂĚŝƐŽŶĐŽŶĐůƵĚĞĚ͗͞tĞŝĚĞŶƚŝĨŝĞĚĂŚŝŐŚŝŶĐŝĚĞŶĐĞŽĨĂĐƵƚĞŬŝĚŶĞǇ
ŝŶũƵƌǇĂŵŽŶŐĐŽŶƚƌŽůƐƵďũĞĐƚƐƵŶĚĞƌŐŽŝŶŐunenhanced d͘dŚĞŝŶĐŝĚĞŶĐĞŽĨĐƌĞĂƚŝŶŝŶĞĞůĞǀĂƚŝŽŶ
ŝŶƚŚŝƐŐƌŽƵƉǁĂƐƐƚĂƚŝƐƚŝĐĂůůǇƐŝŵŝůĂƌƚŽƚŚĂƚŝŶƚŚĞŝƐŽͲŽƐŵŽůĂƌĐŽŶƚƌĂƐƚŵĞĚŝƵŵŐƌŽƵƉĨŽƌĂůů
ďĂƐĞůŝŶĞĐƌĞĂƚŝŶŝŶĞǀĂůƵĞƐĂŶĚĂůůƐƚĂŐĞƐŽĨĐŚƌŽŶŝĐŬŝĚŶĞǇĚŝƐĞĂƐĞ͘dŚĞƐĞĨŝŶĚŝŶŐƐƐƵŐŐĞƐƚƚŚĂƚ
ƚŚĞĂĚĚŝƚŝŽŶĂůƌŝƐŬŽĨĂĐƵƚĞŬŝĚŶĞǇŝŶũƵƌǇĂĐĐŽŵƉĂŶǇŝŶŐĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨĐŽŶƚƌĂƐƚŵĞĚŝƵŵ
;ĐŽŶƚƌĂƐƚͲŝŶĚƵĐĞĚŶĞƉŚƌŽƚŽǆŝĐŝƚǇͿŵĂǇďĞŽǀĞƌƐƚĂƚĞĚĂŶĚƚŚĂƚŵƵĐŚŽĨƚŚĞĐƌĞĂƚŝŶŝŶĞĞůĞǀĂƚŝŽŶ
ŝŶƚŚĞƐĞƉĂƚŝĞŶƚƐŝƐĂƚƚƌŝďƵƚĂďůĞƚŽďĂĐŬŐƌŽƵŶĚĨůƵĐƚƵĂƚŝŽŶ͕ƵŶĚĞƌůǇŝŶŐĚŝƐĞĂƐĞ͕ŽƌƚƌĞĂƚŵĞŶƚ͘͘͟
/ŶĂŶŽƚŚĞƌƐƚƵĚǇŽĨϭ͕ϬϳϱƉĂƚŝĞŶƚƐƌĞĐĞŝǀŝŶŐƌŽƵƚŝŶĞdĂŶŐŝŽŐƌĂƉŚǇĂŶĚdƉĞƌĨƵƐŝŽŶ͕
:ŽƐĞƉŚƐŽŶĂŶĚĐŽůůĞĂŐƵĞƐϱϮƉĂƚŝĞŶƚƐŚĂĚĂĐƌĞĂƚŝŶŝŶĞƌŝƐĞŽĨхŽƌсƚŽϬ͘ϱŵŐͬĚ>͘/Ŷϰ;Ϭ͘ϯϳйͿ
ƚŚĞĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨ/sĐŽŶƚƌĂƐƚŵĞĚŝƵŵƉŽƐƐŝďůǇĐŽŶƚƌŝďƵƚĞĚƚŽƌĞŶĂůĨĂŝůƵƌĞ͘dŚĞǇĐŽŶĐůƵĚĞĚ
ƚŚĂƚ͞dŚĞŝŶĐŝĚĞŶĐĞŽĨĐŽŶƚƌĂƐƚŶĞƉŚƌŽƉĂƚŚǇŝŶŶĞƵƌŽǀĂƐĐƵůĂƌƉĂƚŝĞŶƚƐŝƐůŽǁ͘͟dŚƵƐ͕ďŽƚŚŽƵƌ
ĞǆƉĞƌŝĞŶĐĞĂŶĚĂĚĚŝƚŝŽŶĂůůŝƚĞƌĂƚƵƌĞƐƵƉƉŽƌƚŽƵƌďĞůŝĞĨƚŚĂƚƚŚŝƐƐŵĂůůĂŵŽƵŶƚŽĨĂĚĚĞĚĐŽŶƚƌĂƐƚ
ĚŽƐĞƉŽƐĞƐǀŝƌƚƵĂůůǇŶŽĂĚĚĞĚƌŝƐŬƚŽƚŚĞƐĞƐƵďũĞĐƚƐǁŚĞŶƵƐĞĚĂƐĚĞƐĐƌŝďĞĚŝŶƚŚŝƐƉƌŽƚŽĐŽůϮϭ͕ϮϮ͘
ĚĚŝƚŝŽŶĂůůǇ͕ŝŶƚŚĞϮϬϭϳŵĞƌŝĐĂŶŽůůĞŐĞŽĨZĂĚŝŽůŽŐǇDĂŶƵĂůŽŶŽŶƚƌĂƐƚDĞĚŝĂƚŚĞǇƌĞƉŽƌƚ
ƚŚĂƚƚŚĞƌĞŝƐŶŽƚƐƵĨĨŝĐŝĞŶƚĞǀŝĚĞŶĐĞƚŽƐƉĞĐŝĨŝĐĂůůǇĞŶĚŽƌƐĞƚŚĞĚĞĐŝƐŝŽŶƚŽǁŝƚŚŚŽůĚĂƌĞƉĞĂƚ
ĐŽŶƚƌĂƐƚŵĞĚŝƵŵŝŶũĞĐƚŝŽŶƵŶƚŝůŵŽƌĞƚŚĂŶϮϰŚŽƵƌƐŚĂǀĞƉĂƐƐĞĚŶŽƌƚŽƌĞĐŽŵŵĞŶĚĂƐƉĞĐŝĨŝĐ
ƚŚƌĞƐŚŽůĚŽĨĐŽŶƚƌĂƐƚŵĞĚŝƵŵǀŽůƵŵĞďĞǇŽŶĚǁŚŝĐŚĂĚĚŝƚŝŽŶĂůĐŽŶƚƌĂƐƚŵĞĚŝĂƐŚŽƵůĚŶŽƚďĞ
ŐŝǀĞŶǁŝƚŚŝŶĂƚϮϰͲŚŽƵƌƉĞƌŝŽĚ͘
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ZĂĚŝĂƚŝŽŶĞǆƉŽƐƵƌĞ͗
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dŚĞŵĞƌŝĐĂŶƐƐŽĐŝĂƚŝŽŶŽĨWŚǇƐŝĐŝƐƚƐŝŶDĞĚŝĐŝŶĞ;WDͿŝƐƚŚĞƉƌŽĨĞƐƐŝŽŶĂůƐŽĐŝĞƚǇ
ŵŽƐƚŝŶǀŽůǀĞĚŝŶǁŽƌŬƚŽƌĞĚƵĐĞƌĂĚŝĂƚŝŽŶĞǆƉŽƐƵƌĞĨƌŽŵŵĞĚŝĐĂůĂŶĚŽƚŚĞƌƐŽƵƌĐĞƐĂŶĚƚŽ
ĞǀĂůƵĂƚĞƚŚĞƉŽƚĞŶƚŝĂůƌŝƐŬƐŽĨƌĂĚŝĂƚŝŽŶĞǆƉŽƐƵƌĞ͘dŚĞŝƌĐƵƌƌĞŶƚƉŽƐŝƚŝŽŶƐƚĂƚĞŵĞŶƚƌĞŐĂƌĚŝŶŐ
ƚŚĞƌŝƐŬƐĨƌŽŵŵĞĚŝĐĂůŝŵĂŐŝŶŐƉƌŽĐĞĚƵƌĞƐƐƚĂƚĞƐ͗͞ZŝƐŬƐŽĨŵĞĚŝĐĂůŝŵĂŐŝŶŐĂƚĞĨĨĞĐƚŝǀĞĚŽƐĞƐ
ďĞůŽǁϱϬŵ^ǀĨŽƌƐŝŶŐůĞƉƌŽĐĞĚƵƌĞƐŽƌϭϬϬŵ^ǀĨŽƌŵƵůƚŝƉůĞƉƌŽĐĞĚƵƌĞƐŽǀĞƌƐŚŽƌƚƚŝŵĞƉĞƌŝŽĚƐ
ĂƌĞƚŽŽůŽǁƚŽďĞĚĞƚĞĐƚĂďůĞĂŶĚŵĂǇďĞŶŽŶĞǆŝƐƚĞŶƚ͘WƌĞĚŝĐƚŝŽŶƐŽĨŚǇƉŽƚŚĞƚŝĐĂůĐĂŶĐĞƌ
ŝŶĐŝĚĞŶĐĞĂŶĚĚĞĂƚŚƐŝŶƉĂƚŝĞŶƚƉŽƉƵůĂƚŝŽŶƐĞǆƉŽƐĞĚƚŽƐƵĐŚůŽǁĚŽƐĞƐĂƌĞŚŝŐŚůǇƐƉĞĐƵůĂƚŝǀĞ
ĂŶĚƐŚŽƵůĚďĞĚŝƐĐŽƵƌĂŐĞĚ͘͟
ŚƚƚƉ͗ͬͬǁǁǁ͘ĨĚĂ͘ŐŽǀͬZĂĚŝĂƚŝŽŶŵŝƚƚŝŶŐWƌŽĚƵĐƚƐͬZĂĚŝĂƚŝŽŶŵŝƚƚŝŶŐWƌŽĚƵĐƚƐĂŶĚWƌŽĐĞĚƵƌĞƐͬDĞ
ĚŝĐĂů/ŵĂŐŝŶŐͬDĞĚŝĐĂůyͲZĂǇƐͬƵĐŵϭϭϱϯϮϵ͘Śƚŵ͘
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dŚĞƌĂĚŝĂƚŝŽŶĞǆƉŽƐƵƌĞƌĞĐĞŝǀĞĚďǇƐƵďũĞĐƚƐǁŚŽĂƌĞĞŶƌŽůůĞĚŝŶŽƵƌƌĞƐĞĂƌĐŚŝƐϴ͘ϴŵ^ǀ͕
ǁŚŝĐŚŝƐĨĂƌďĞůŽǁƚŚĞĚŽƐĞƐĚĞƐĐƌŝďĞĚĂďŽǀĞ;ϭϬϬŵ^ǀĨŽƌŵƵůƚŝƉůĞƉƌŽĐĞĚƵƌĞƐͿ͘ĚĚŝƚŝŽŶĂůůǇ͕
ƚŚŝƐĞĨĨĞĐƚŝǀĞĚŽƐĞŽĨƚŚĞƌĞƐĞĂƌĐŚŝŵĂŐŝŶŐŝƐŽŶůǇϭͬϯƚŚĂƚŽĨƚŚĞƐƚĂŶĚĂƌĚŽĨĐĂƌĞdĚŽƐĞĂŶĚ͕
ĨƵƌƚŚĞƌŵŽƌĞ͕ƚŚŝƐĚŽƐĞŝƐĞƋƵŝǀĂůĞŶƚƚŽũƵƐƚŽǀĞƌϭǇĞĂƌŽĨŶĂƚƵƌĂůďĂĐŬŐƌŽƵŶĚƌĂĚŝĂƚŝŽŶ͘/ƚ
ǁŽƵůĚƚŚƵƐƐĞĞŵƚŚĂƚƚŚŝƐĚŽƐĞ͕ĞƋƵŝǀĂůĞŶƚƚŽƚŚĂƚƌĞĐĞŝǀĞĚĨƌŽŵďĂĐŬŐƌŽƵŶĚƌĂĚŝĂƚŝŽŶǁŽƵůĚ
ĨĂůůǁŝƚŚŝŶƚŚĞĂĐĐĞƉƚĂďůĞƌŝƐŬƐĨŽƌ͞DŝŶŝŵĂůZŝƐŬ͘͟/ŶŽƚŚĞƌǁŽƌĚƐ͕ƚŚĞĂĚĚĞĚĞǆƉŽƐƵƌĞƌĞĐĞŝǀĞĚ
ďǇƚŚĞƐƵďũĞĐƚƐƉĂƌƚŝĐŝƉĂƚŝŶŐŝŶŽƵƌƌĞƐĞĂƌĐŚŝƐĞƋƵŝǀĂůĞŶƚƚŽƚŚĂƚƚŚĞǇǁŽƵůĚƌĞĐĞŝǀĞĨƌŽŵ
ďĂĐŬŐƌŽƵŶĚƌĂĚŝĂƚŝŽŶŝŶƚŚĞŝƌĚĂŝůǇůŝĨĞ͘
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ĐĞƚĂǌŽůĂŵŝĚĞƌŝƐŬƐ͗
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ĐĞƚĂǌŽůĂŵŝĚĞŝƐĂůƌĞĂĚǇĂŶ&ͲĂƉƉƌŽǀĞĚŵĞĚŝĐĂƚŝŽŶ͘^ƵůůŝǀĂŶĞƚĂůƚĞƐƚĞĚ
ĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞĂĐƚŝǀŝƚǇŝŶŶŽƌŵĂůƐƵďũĞĐƚƐŝŶƌĞƐƉŽŶƐĞƚŽĂĐĞƚĂǌŽůĂŵŝĚĞĐŚĂůůĞŶŐĞĂŶĚĨŽƵŶĚ
ƚŚĞŵŽƐƚĐŽŵŵŽŶĂĚǀĞƌƐĞƌĞĂĐƚŝŽŶƚŽďĞŶƵŵďŶĞƐƐĂŶĚƚŝŶŐůŝŶŐǁŚŝĐŚǁĂƐƚƌĂŶƐŝĞŶƚŽǀĞƌƚŚĞ
ĐŽƵƌƐĞŽĨƐĞǀĞƌĂůŚŽƵƌƐ͘ƉƉƌŽǆŝŵĂƚĞůǇŚĂůĨŽĨƐƵďũĞĐƚƐĞǆƉĞƌŝĞŶĐĞĚŚĞĂĚĂĐŚĞĂŶĚŐĞŶĞƌĂůŝǌĞĚ
ĨĂƚŝŐƵĞ͘,ŽǁĞǀĞƌ͕ƚŚĞƌĞǁĞƌĞŶŽƐĞƌŝŽƵƐŽƌůŝĨĞͲƚŚƌĞĂƚĞŶŝŶŐƌĞĂĐƚŝŽŶƐŝŶĂŶǇŽĨƚŚĞƐƵďũĞĐƚƐϭϬ͘
,ŽůůĞƚĂůĚĞŵŽŶƐƚƌĂƚĞĚƵƐĞŽĨŝŶƚƌĂǀĞŶŽƵƐĂĐĞƚĂǌŽůĂŵŝĚĞŝŶďŽƚŚŶŽƌŵĂůƐƵďũĞĐƚƐĂŶĚƐƵďũĞĐƚƐ
ǁŝƚŚŵĂũŽƌĐĞƌĞďƌĂůŽĐĐůƵƐŝŽŶŚĂĚŶŽƐĞƌŝŽƵƐĐŽŵƉůŝĐĂƚŝŽŶƐ͘dŚĞǇĚŽƌĞƉŽƌƚƚŚĂƚƚŚĞƌĞǁĂƐĂ
ĐŽŶƐŝƐƚĞŶƚůǇƉƌŽĚƵĐĞĚƌŝƐĞŝŶŝŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞƐ;/WͿŝŶƉĂƚŝĞŶƚƐǁŝƚŚĂůƌĞĂĚǇĚŝƐƚƵƌďĞĚ
ĐĞƌĞďƌĂůƐƉŝŶĂůĨůƵŝĚ;^&ͿĐŝƌĐƵůĂƚŝŽŶ͕ďƵƚƚŚŝƐŝŶĐƌĞĂƐĞǁĂƐƚƌĂŶƐŝĞŶƚĂŶĚŝŶƚŚĞŝƌĐŽŚŽƌƚŝƚǁĂƐ
ƐǇŵƉƚŽŵĂƚŝĐŝŶŽŶůǇŽŶĞƉĂƚŝĞŶƚǁŚŽĞǆƉĞƌŝĞŶĐĞĚĂŚĞĂĚĂĐŚĞϭϱ͕ϮϬ͘/ŶŽƵƌƉŽƉƵůĂƚŝŽŶŝĨƚŚĞƌĞŝƐ
ĐŽŶĐĞƌŶĨŽƌŝŶĐƌĞĂƐĞĚ/WƚŚĞƌĞǁŽƵůĚďĞĂŶŝŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞŵŽŶŝƚŽƌƚŚĂƚǁŽƵůĚďĞ
ƉƌŽǀŝĚŝŶŐ^&ĚŝǀĞƌƐŝŽŶƚŽƌĞĚƵĐĞ/WĂƐĂƐƚĂŶĚĂƌĚŽĨĐĂƌĞƉůĂĐĞĚƉƌŝŽƌƚŽĂĚŵŝŶŝƐƚƌĂƚŝŽŶŽĨƚŚĞ
ĚƌƵŐ͘dŚĞƌĞĨŽƌĞ͕ƚŚŝƐĐĂƵƐĞƐĞƐƐĞŶƚŝĂůŶŽĐůŝŶŝĐĂůƌŝƐŬƚŽƚŚŝƐƉĂƚŝĞŶƚƉŽƉƵůĂƚŝŽŶ͘
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WƌŝǀĂĐǇͬŽŶĨŝĚĞŶƚŝĂůŝƚǇƉƌŽƚĞĐƚŝŽŶƐĂŶĚƐŚĂƌŝŶŐŽĨĚĂƚĂ͗
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ĂƚĂŐĂƚŚĞƌĞĚĨƌŽŵƚŚŝƐƐƚƵĚǇǁŝůůďĞƉŽƐƚͲƉƌŽĐĞƐƐĞĚĂŶĚĞǀĂůƵĂƚĞĚďǇƚŚĞƐƚƵĚǇ
ŶĞƵƌŽĞŶĚŽǀĂƐĐƵůĂƌƉŚǇƐŝĐŝĂŶŝŶĂĐĐŽƌĚĂŶĐĞǁŝƚŚƚŚĞƉƌŽƚŽĐŽůŽƵƚůŝŶĞĚĂďŽǀĞ͘/ŵĂŐŝŶŐĚĂƚĂǁŝůů
ďĞƐƚƌŝƉƉĞĚŽĨĂůůĚŝƌĞĐƚƉĂƚŝĞŶƚŝĚĞŶƚŝĨŝĞƌƐĂŶĚƐƚŽƌĞĚŽŶĂĚĞĚŝĐĂƚĞĚW^ƐǇƐƚĞŵĐŽŶƚƌŽůůĞĚďǇ
ht,͘ƌ͘^ƚƌŽƚŚĞƌ͕ǁŝůůŵĂŝŶƚĂŝŶƚŚĞŵĂƐƚĞƌůŝƐƚůŝŶŬŝŶŐĐŽĚĞĚĚĂƚĂƚŽŵĞĚŝĐĂůƌĞĐŽƌĚŶƵŵďĞƌƐ͘
dŚĞƌĞƐĞĂƌĐŚǁŽƌŬƐƚĂƚŝŽŶƚŚĂƚǁŝůůďĞƵƐĞĚďǇĂŶĂůǇƐŝƐŝƐƉĂƐƐǁŽƌĚƉƌŽƚĞĐƚĞĚĂŶĚƵƐĞƐ
ĚĞƉĂƌƚŵĞŶƚĂůƐĞƌǀĞƌƐƚŚĂƚĂƌĞďĂĐŬĞĚƵƉďǇƚŚĞht,ĨŝƌĞǁĂůů͘ŽĚĞĚĚĂƚĂ͕ŝŶĐůƵĚŝŶŐŝŵĂŐĞƐ͕


ĐŽůůĞĐƚĞĚĨƌŽŵƚŚŝƐƌĞƐĞĂƌĐŚǁŝůůďĞƐŚĂƌĞĚǁŝƚŚŵĂŶƵĨĂĐƚƵƌĞƌŽĨͲĂƌŵd͕^ŝĞŵĞŶƐDĞĚŝĐĂů
^ŽůƵƚŝŽŶƐĨŽƌĨƵƌƚŚĞƌƌĞĨŝŶĞŵĞŶƚƐŝŶŚĂƌĚǁĂƌĞĂŶĚƉƌŽƚŽƚǇƉĞƐŽĨƚǁĂƌĞƚŽŝŵƉƌŽǀĞŝŵĂŐŝŶŐ͘EŽ
ĚŝƌĞĐƚůǇŝĚĞŶƚŝĨŝĂďůĞŝŵĂŐĞƐŽƌĚĂƚĂǁŝůůďĞĚŝƐĐůŽƐĞĚŽƵƚƐŝĚĞŽĨht,͘ůůĚĂƚĂŽďƚĂŝŶĞĚĨƌŽŵ
ƚŚĞŵĞĚŝĐĂůƌĞĐŽƌĚǁŝůůďĞƐƚŽƌĞĚŝŶĂ,/WĐŽŵƉůŝĂŶƚŵĂŶŶĞƌ͘
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WĂƚŝĞŶƚ&ŽůůŽǁhƉ͗
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WĂƚŝĞŶƚƐǁŝůůƌĞĐĞŝǀĞĨŽůůŽǁƵƉĐĂƌĞďǇƚŚĞƉƌŝŵĂƌǇƚƌĞĂƚŝŶŐŶĞƵƌŽƐƵƌŐĞŽŶŽƌ
ŶĞƵƌŽĞŶĚŽǀĂƐĐƵůĂƌƐƵƌŐĞŽŶŝŶĂŵĂŶŶĞƌƚŚĂƚŝƐĐŽŶƐŝƐƚĞŶƚǁŝƚŚƐƚĂŶĚĂƌĚĐůŝŶŝĐĂůĐĂƌĞ͘^ƵďũĞĐƚƐ
ǁŝůůďĞŝŶƉĂƚŝĞŶƚƐĂŶĚƚŚĞŝƌƌĞĐŽǀĞƌǇĨŽůůŽǁĞĚƉƌŝŵĂƌŝůǇďǇĞŝƚŚĞƌƚŚĞŶĞƵƌŽƐƵƌŐĞƌǇŽƌ
ŶĞƵƌŽĞŶĚŽǀĂƐĐƵůĂƌƚĞĂŵƐĚƵƌŝŶŐƚŚĞŝƌĂĐƵƚĞŚŽƐƉŝƚĂůŝǌĂƚŝŽŶ͘
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/ŶĨŽƌŵĂƚŝŽŶŽůůĞĐƚĞĚĨƌŽŵDĞĚŝĐĂůZĞĐŽƌĚƐ
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ĂƚĂĐŽůůĞĐƚĞĚĨƌŽŵŵĞĚŝĐĂůƌĞĐŽƌĚƐǁŝůůŝŶĐůƵĚĞ͗
ϭ͘ ŐĞ͕ƐĞǆ͕ŵĞĚŝĐĂůŚŝƐƚŽƌǇ͕ƉŚǇƐŝĐĂůĞǆĂŵ͕ůĂďŽƌĂƚŽƌǇĂŶĚŝŵĂŐŝŶŐƐƚƵĚŝĞƐ
Ϯ͘ ,ƵŶƚĂŶĚ,ĞƐƐ'ƌĂĚĞ
ϯ͘ &ŝƐŚĞƌ'ƌĂĚĞ
ϰ͘ /ŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞ
ϱ͘ >ŽĐĂƚŝŽŶŽĨĂŶĞƵƌǇƐŵƌĞƐƉŽŶƐŝďůĞĨŽƌďůĞĞĚŝŶŐ
ϲ͘ dƌĞĂƚŵĞŶƚŵŽĚĂůŝƚǇĨŽƌĂŶĞƵƌǇƐŵ;ĞŵďŽůŝǌĂƚŝŽŶǀĞƌƐƵƐĐůŝƉƉŝŶŐͿ
ϳ͘ ŶĞƐƚŚĞƐŝĂƌĞĐŽƌĚ
ϴ͘ WƌĞƐĞŶĐĞŽĨǀĂƐŽƐƉĂƐŵŽƌĚĞůĂǇĞĚĐĞƌĞďƌĂůŝƐĐŚĞŵŝĂ
Ă͘ ůŝŶŝĐĂů͗ĚĞƚĞƌŝŽƌĂƚŝŽŶǁŚĞŶŽƚŚĞƌĐĂƵƐĞƐŚĂǀĞďĞĞŶƌƵůĞĚŽƵƚŝŶĐůƵĚŝŶŐ
ŚǇĚƌŽĐĞƉŚĂůƵƐ͕ƌĞͲďůĞĞĚ͕ŽƌŵĞƚĂďŽůŝĐĂďŶŽƌŵĂůŝƚŝĞƐ
ď͘ ZĂĚŝŽŐƌĂƉŚŝĐ͗ĚĞƚĞĐƚŝŽŶŽĨŶĞǁŝŶĨĂƌĐƚŽŶŝŵĂŐŝŶŐŶŽƚǀŝƐŝďůĞŽŶƚŚĞĂĚŵŝƐƐŝŽŶŽƌ
ŝŵŵĞĚŝĂƚĞƉŽƐƚͲƚƌĞĂƚŵĞŶƚƐĐĂŶŽƌďŽƚŚ
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&ŽŶƐŝĚĞƌĂƚŝŽŶƐ͗
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ͲĂƌŵdW͗^ŝĞŵĞŶƐͲĂƌŵdƐŽĨƚǁĂƌĞĐƵƌƌĞŶƚůǇŚĂƐϱϭϬ;ŬͿ;^ĞƉƚĞŵďĞƌϮϬϬϰͿ
ĐůĞĂƌĂŶĐĞ͘dŚĞŝŶŶŽǀĂƚŝǀĞͲĂƌŵdWƐŽĨƚǁĂƌĞŝƐƵƐĞĚƚŽĐŽŶƐĞĐƵƚŝǀĞůǇƉĞƌĨŽƌŵϭϬdƐǁĞĞƉƐ
ǁŝƚŚŽŶĞƐŝŶŐůĞŝŶƚƌĂǀĞŶŽƵƐĐŽŶƚƌĂƐƚŝŶũĞĐƚŝŽŶ͘tĞĂƌĞƌĞƋƵĞƐƚŝŶŐĂ͕͞ŶŽŶͲƐŝŐŶŝĨŝĐĂŶƚƌŝƐŬ͟
ĚĞƚĞƌŵŝŶĂƚŝŽŶďǇƚŚĞ/ZĨŽƌƚŚĞƵƐĞŽĨƚŚŝƐŶŽǀĞůƐŽĨƚǁĂƌĞ͘EŽƚĞƚŚĂƚͲĂƌŵdĂĐƋƵŝƐŝƚŝŽŶƐ
ĂƌĞƌŽƵƚŝŶĞůǇĂŶĚĨƌĞƋƵĞŶƚůǇƵƚŝůŝǌĞĚŝŶŽƵƌĐůŝŶŝĐĂůƉƌĂĐƚŝĐĞĂŶĚǁĞĚŽŶŽƚĨŽƌĞƐĞĞĂŶǇƉŽƚĞŶƚŝĂů
ƌŝƐŬƐ͘dŚĞƉĂĐŬĂŐĞŽĨƚĞŶͲĂƌŵdƐǁĞĞƉƐĂŶĚƚŚĞŝŶŶŽǀĂƚŝǀĞĚĂƚĂƉƌŽĐĞƐƐŝŶŐƐŽĨƚǁĂƌĞ
^DZdZKE͕ĂƌĞŶŽƚ&ĂƉƉƌŽǀĞĚƐŝŶĐĞƚŚĞǇĂƌĞŝŶĞǆƉĞƌŝŵĞŶƚĂůǀĂůŝĚĂƚŝŽŶƌĞƐĞĂƌĐŚƐƚĂŐĞ
ĂƉƉƌŽǀĞĚďǇƚŚĞE/,Ăƚht͘dŚĞĚĂƚĂŽďƚĂŝŶĞĚĨƌŽŵƚŚŝƐƐƚƵĚǇŵĂǇƐƵƉƉŽƌƚƚŚĞĂƉƉůŝĐĂƚŝŽŶĂŶĚ
ĂƉƉƌŽǀĂůŽĨƚŚĞhtƐŽĨƚǁĂƌĞŝŶƚŚĞĨƵƚƵƌĞ͘,ŽǁĞǀĞƌ͕ƚŚĞŚĂƌĚǁĂƌĞ;^ŝĞŵĞŶƐĂŶŐŝŽŐƌĂƉŚŝĐ
ŵĂĐŚŝŶĞͿƚŽŽďƚĂŝŶƚŚĞͲĂƌŵdƉĞƌĨƵƐŝŽŶĚĂƚĂĚŽĞƐŶŽƚŝŶƚƌŽĚƵĐĞĂŶǇŶĞǁƉŽƚĞŶƚŝĂůƐĂĨĞƚǇ
ƌŝƐŬƐĂŶĚŝƐĞƋƵŝǀĂůĞŶƚƚŽĂŶĚƉĞƌĨŽƌŵƐŝŶƚŚĞƐĂŵĞĨĂƐŚŝŽŶĂƐƐƚĂŶĚĂƌĚͲĂƌŵd͘
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Data and Safety Monitoring Plan 
 


ůůƌĞƐĞĂƌĐŚĞƌƐĂŶĚƌĞƐĞĂƌĐŚƐƚĂĨĨŝŶǀŽůǀĞĚŝŶƚŚŝƐƉƌŽũĞĐƚŚĂǀĞĐŽŵƉůĞƚĞĚ,ƵŵĂŶ
^ƵďũĞĐƚƐĂŶĚ,/WƚƌĂŝŶŝŶŐĂŶĚĂƌĞĨĂŵŝůŝĂƌǁŝƚŚĂůůƉƌŽĐĞĚƵƌĞƐ͘dŚĞW/ĂŶĚĐŽͲŝŶǀĞƐƚŝŐĂƚŽƌƐ
ǁŝůůƌĞǀŝĞǁƚŚĞĚĂƚĂĐŽůůĞĐƚĞĚĂĨƚĞƌƚŚĞŝŶŝƚŝĂůƉĂƚŝĞŶƚƐŚĂǀĞďĞĞŶƚƌĞĂƚĞĚĂŶĚŽƵƚĐŽŵĞĚĂƚĂ
ďĞĐŽŵĞƐĂǀĂŝůĂďůĞ͘ĚǀĞƌƐĞĞǀĞŶƚƐŽƌƉƌŽďůĞŵƐǁŝůůďĞƌĞǀŝĞǁĞĚďǇƚŚĞW/ĂŶĚĐŽͲŝŶǀĞƐƚŝŐĂƚŽƌƐ
ĂƐƚŚĞǇŽĐĐƵƌĂŶĚǁŝůůďĞƌĞƉŽƌƚĞĚƚŽƚŚĞ/ZďǇƚŚĞW/ŝŶĂĐĐŽƌĚĂŶĐĞǁŝƚŚƉŽƐƚĞĚŐƵŝĚĞůŝŶĞƐ͘
dŚĞW/ĂŶĚƚŚĞĐŽͲŝŶǀĞƐƚŝŐĂƚŽƌƐǁŝůůŵĞĞƚƌĞŐƵůĂƌůǇƚŽƌĞǀŝĞǁƚŚĞĚĂƚĂ͕ĂĚŚĞƌĞŶĐĞƚŽƚŚĞ
ƉƌŽƚŽĐŽůĂŶĚ/ZŐƵŝĚĞůŝŶĞƐ͘ĂƚĂĂŶĚƐĂĨĞƚǇŵŽŶŝƚŽƌŝŶŐǁŝůůŽĐĐƵƌŽŶĂĐŽŶƚŝŶƵŽƵƐďĂƐŝƐďǇƚŚĞ
ƌĞƐĞĂƌĐŚƐƚĂĨĨ͘dŚĞƐƚƵĚǇƚĞĂŵǁŝůůŵĞĞƚƌĞŐƵůĂƌůǇƚŽƌĞǀŝĞǁƐƚƵĚǇƉƌŽŐƌĞƐƐŝŶĐůƵĚŝŶŐ
ƌĞĐƌƵŝƚŵĞŶƚ͕ĚĂƚĂĐŽůůĞĐƚŝŽŶ͕ĂŶĚƚŚĞǇǁŝůůĂĚĚƌĞƐƐĂŶǇĐŽŶĐĞƌŶƐŽƌĐŚĂůůĞŶŐĞƐƚŚĂƚŵĂǇĂƌŝƐĞ͘/Ĩ
ŝŶŝƚŝĂůƉŝůŽƚĚĂƚĂƐŚŽǁƐƚŚĂƚƚŚŝƐƚĞĐŚŶŝƋƵĞŝƐǀĂůŝĚĂƚĞĚĂĨŽƌŵĂůƐƚƵĚǇǁŝůůďĞƉƌŽƉŽƐĞĚƚŽƚŚĞ
/Z͘
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Statistical Considerations 
 
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dŚĞŝŶŝƚŝĂůƉŝůŽƚƐƚƵĚǇǁĂƐĐŽŶĚƵĐƚĞĚĂƐĂĨĞĂƐŝďŝůŝƚǇƐƚƵĚǇĂŶĚŶŽƌŽďƵƐƚƐƚĂƚŝƐƚŝĐĂů
ĞǀĂůƵĂƚŝŽŶŝƐƉŽƐƐŝďůĞ͘^ŝŶĐĞǁĞŚĂǀĞĚĞƚĞƌŵŝŶĞĚƚŚĂƚƚŚĞƌĞƐĞĂƌĐŚŝŵĂŐŝŶŐĐĂŶďĞĂĐŚŝĞǀĞĚ
ƐĂĨĞůǇĂŶĚĚĂƚĂƌĞƉƌŽĚƵĐŝďůǇĐŽůůĞĐƚĞĚ͕ǁĞŶŽǁŚŽƉĞƚŽĂŵĞŶĚƚŚĞĐŽŚŽƌƚƚŽĂƚŽƚĂůŽĨϯϬ
ƉĂƚŝĞŶƚƐƐŽƚŚĂƚǁĞĐĂŶĐĂƉƚƵƌĞŵŽƌĞƉĂƚŝĞŶƚƐǁŝƚŚǀĂƐŽƐƉĂƐŵŝŶŽƌĚĞƌƚŽŚĂǀĞĂŵŽƌĞƌŽďƵƐƚ
ĂŶĂůǇƐŝƐŽĨƚŚĞĐŽƌƌĞůĂƚŝŽŶďĞƚǁĞĞŶƉĞƌĐĞŶƚĐŚĂŶŐĞŝŶ&ƚŽŝĂŵŽǆĂŶĚƚŚĞĨƵƚƵƌĞ
ĚĞǀĞůŽƉŵĞŶƚŽĨĐĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵ͘
 
IRB Concerns 
 
dŚĞŐŽůĚƐƚĂŶĚĂƌĚĨŽƌĚĞƚĞƌŵŝŶŝŶŐŝĨĂƉĂƚŝĞŶƚŚĂƐǀĂƐŽƐƉĂƐŵŝƐƚŚĞĐůŝŶŝĐĂůŶĞƵƌŽůŽŐŝĐĂů
ĞǆĂŵ͘dŚĞƌĞŝƐŶŽĐƵƌƌĞŶƚůǇĂĐĐĞƉƚĞĚƌĂĚŝŽŐƌĂƉŚŝĐŵĞƚŚŽĚŽƌƉƌŽĐĞĚƵƌĞĨŽƌƉƌĞĚŝĐƚŝŶŐ
ǀĂƐŽƐƉĂƐŵ͘dŚĞƌĞĨŽƌĞ͕ǁŚĞŶĐŽŵƉĂƌŝŶŐƚŚŝƐƉƌŽƉŽƐĞĚdĂƉƉƌŽĂĐŚƚŽƚŚĞĐŽŵƉĞƚŝŶŐ
ŵĞƚŚŽĚǁĞǁŽƵůĚďĞĐŽŵƉĂƌŝŶŐŝƚƚŽƚŚĞĐůŝŶŝĐĂůŶĞƵƌŽůŽŐŝĐĂůĞǆĂŵ͘ĚĚŝƚŝŽŶĂůůǇ͕ĐŽŵƉĂƌŝƐŽŶƐ
ĂƌĞďĞŝŶŐŵĂĚĞƚŽĐƵƌƌĞŶƚŵĞƚŚŽĚƐŽĨƉƌĞĚŝĐƚŝŶŐǀĂƐŽƐƉĂƐŵŝŶĐůƵĚŝŶŐdƐ͕ŵƵůƚŝĚĞƚĞĐƚŽƌ
dͬdW͕ĂŶĚĂŶŐŝŽŐƌĂƉŚǇ͘
tŝƚŚŽƵƌŝŶŝƚŝĂůϭϬƉĂƚŝĞŶƚƐǁĞĂƌĞĂďůĞƚŽƌĞƉŽƌƚƚŚĂƚŝŶĂůůϭϬƉĂƚŝĞŶƚƐƚŚĞŝŵĂŐĞƐǁĞƌĞ
ƐƵĐĐĞƐƐĨƵůůǇƌĞƋƵŝƌĞĚ͘tĞƚŚĞŶƉĞƌĨŽƌŵĞĚĂŶĂŶĂůǇƐŝƐŽĨƚŚĞϮϬƚŽƚĂůĐĞƌĞďƌĂůŚĞŵŝƐƉŚĞƌĞƐ
;ƌŝŐŚƚĂŶĚůĞĨƚͿ͘EŝŶĞƚĞĞŶŽĨϮϬŚĞŵŝƐƉŚĞƌĞƐĚĞŵŽŶƐƚƌĂƚĞĚĂƐŝŐŶŝĨŝĐĂŶƚĐŚĂŶŐĞŝŶ&ƉĞƌĨƵƐŝŽŶ
ŝŶƌĞƐƉŽŶƐĞƚŽŝĂŵŽǆ;ƉфϬ͘ϬϱͿ͘^ŝǆŚĞŵŝƐƉŚĞƌĞƐĚĞŵŽŶƐƚƌĂƚĞĚĂϯϬйĐŚĂŶŐĞŝŶ&ĂŶĚϭϮ
ŚĂĚĂϭϱйĐŚĂŶŐĞ͘/ŶϵŚĞŵŝƐƉŚĞƌĞƐƚŚĞƌĞǁĂƐƚŚĞĞǆƉĞĐƚĞĚŝŶĐƌĞĂƐĞŝŶ&ŝŶƌĞƐƉŽŶƐĞƚŽ
ŝĂŵŽǆ͘/ŶϭϬŚĞŵŝƐƉŚĞƌĞƐƚŚĞƌĞǁĂƐĂĚĞĐƌĞĂƐĞŝŶ&͘dŚĞƌĞǁĂƐŶŽƐƚĂƚŝƐƚŝĐĂůĚŝĨĨĞƌĞŶĐĞŝŶ
ƚŚĞƉĞƌĐĞŶƚĐŚĂŶŐĞďĞƚǁĞĞŶůĞĨƚĂŶĚƌŝŐŚƚŚĞŵŝƐƉŚĞƌĞƐǁŚŝĐŚǁŽƵůĚĐŽƌƌĞůĂƚĞǁŝƚŚƚŚĞŐůŽďĂů
ǀĂƐŽĚŝůĂƚŽƌǇĞĨĨĞĐƚƐŽĨŝĂŵŽǆ͘^ǇŵƉƚŽŵĂƚŝĐǀĂƐŽƐƉĂƐŵƚŚĞŶŽŶůǇĚĞǀĞůŽƉĞĚŝŶϮŽĨŽƵƌ
ƉĂƚŝĞŶƚƐ͘/ŶŽŶĞŽĨƚŚĞƐĞƉĂƚŝĞŶƚƐƚŚĞƌĞǁĂƐĂƉĂƚŚŽůŽŐŝĐĂůĚĞĐƌĞĂƐĞŝŶ&ŝŶƌĞƐƉŽŶƐĞƚŽ
ŝĂŵŽǆǁŚŝůĞƚŚĞŽƚŚĞƌŚĂĚĂŶĂƉƉƌŽƉƌŝĂƚĞŝŶĐƌĞĂƐĞŝŶ&͘dŚĞŐŽĂůŽĨƚŚĞĂŶĂůǇƐŝƐŝŶƚŚŝƐ
ĞǆƚĞŶƐŝŽŶŽĨƚŚĞƐƚƵĚǇŝƐƚŽďĞƚƚĞƌƵŶĚĞƌƐƚĂŶĚƚŚĞĐŚĂŶŐĞƐŝŶ&ŝŶƉĂƚŝĞŶƚƐƚŚĂƚŐŽŽŶƚŽ
ĚĞǀĞůŽƉƐǇŵƉƚŽŵĂƚŝĐŽƌĐůŝŶŝĐĂůǀĂƐŽƐƉĂƐŵďĂƐĞĚŽŶĂĐŚĂŶŐĞŝŶŶĞƵƌŽůŽŐŝĐĂůĞǆĂŵ͘
hŶĨŽƌƚƵŶĂƚĞůǇ͕ŝŶŽƵƌĨŝƌƐƚƉŚĂƐĞŽĨƚŚĞƉŝůŽƚƐƚƵĚǇŽŶůǇϮƉĂƚŝĞŶƚƐĚĞǀĞůŽƉĞĚƐǇŵƉƚŽŵĂƚŝĐ
ǀĂƐŽƐƉĂƐŵ͘dŚĞƌĞĂƐŽŶǁĞĂƌĞƌĞƋƵĞƐƚŝŶŐĂŶĞǆƚĞŶƐŝŽŶƚŽϯϬƉĂƚŝĞŶƚƐŝƐƐŽǁĞĐĂŶĐĂƉƚƵƌĞĂ


ůĂƌŐĞƌŶƵŵďĞƌŽĨƉĂƚŝĞŶƚƐǁŝƚŚƐǇŵƉƚŽŵĂƚŝĐǀĂƐŽƐƉĂƐŵ͘dŚĞŶǁĞĐĂŶĂƐƐĞƐƐŽƵƌƐƚĂƚŝƐƚŝĐĂů
ĂŶĂůǇƐŝƐƚŽƐĞĞŝĨƚŚĞǁĞĐĂŶĐŽŶƐŝƐƚĞŶƚůǇƐĞĞĂƐŝŐŶŝĨŝĐĂŶƚůĂĐŬŽĨƌĞƐƉŽŶƐĞ;ĞŝƚŚĞƌфϯϬйŝŶĐƌĞĂƐĞ
ŝŶ&ŽƌĂĚĞĐƌĞĂƐĞŝŶ&ͿƚŽŝĂŵŽǆ͘tŝƚŚŽŶůǇϮƉĂƚŝĞŶƚƐŝŶŽƵƌŝŶŝƚŝĂůĐŽŚŽƌƚĚĞǀĞůŽƉŝŶŐ
ƐǇŵƉƚŽŵĂƚŝĐǀĂƐŽƐƉĂƐŵŝƚŝƐŝŵƉŽƐƐŝďůĞƚŽŵĂŬĞĂŵŽƌĞƌŽďƵƐƚƐƚĂƚŝƐƚŝĐĂůƉƌŽƉŽƐĂůĂŶĚƚŚĂƚŝƐ
ǁŚǇǁĞĂƌĞƐƵďŵŝƚƚŝŶŐĂƌĞƋƵĞƐƚƚŽƐƚƵĚǇŵŽƌĞĐĂƐĞƐ͘
ƐĚŝƐĐƵƐƐĞĚďĞĨŽƌĞ͕ŝŶƚŚŝƐƐƚƵĚǇĚĞƐŝŐŶƚŚĞƌĞŝƐŶŽŶĞĞĚĨŽƌĂĐŽŶƚƌŽůŐƌŽƵƉ͘tĞĂƌĞĐŽŵƉĂƌŝŶŐ
ŽƵƌdŝŶĨŽƌŵĂƚŝŽŶƚŽƚŚĞĐŽŶǀĞŶƚŝŽŶĂůŵĞƚŚŽĚǁŚŝĐŚŝƐƚŚĞĐůŝŶŝĐĂůŶĞƵƌŽůŽŐŝĐĂůĞǆĂŵ
ĐŚĂŶŐĞǁŚŝĐŚŝŶĚŝĐĂƚĞƐĐůŝŶŝĐĂůŽƌƐǇŵƉƚŽŵĂƚŝĐǀĂƐŽƐƉĂƐŵ͘dŚĞĚĂƚĂƚŚĂƚǁŝůůďĞƐƚĂƚŝƐƚŝĐĂůůǇ
ĐŽŵƉĂƌĞĚŝƐƚŚĞƉƌĞͲĚŝĂŵŽǆƉĞƌĨƵƐŝŽŶŝŶĐŽŵƉĂƌŝƐŽŶƚŽƚŚĞƉŽƐƚͲĚŝĂŵŽǆƉĞƌĨƵƐŝŽŶ͘
ƐƚĂƚŝƐƚŝĐĂůůǇƐŝŐŶŝĨŝĐĂŶƚĐŚĂŶŐĞŝŶĐƌĞĂƐĞŝŶ&ƌĞƉƌĞƐĞŶƚƐĂŶĂƉƉƌŽƉƌŝĂƚĞƌĞƐƉŽŶƐĞƚŽŝĂŵŽǆ͘
>ĂĐŬŽĨĐŚĂŶŐĞŝŶ&ŽƌĚĞĐƌĞĂƐĞŝŶ&ĐŽƵůĚďĞƐƵŐŐĞƐƚŝǀĞŽĨƉŽƚĞŶƚŝĂůĨŽƌĚĞǀĞůŽƉŝŶŐ
ǀĂƐŽƐƉĂƐŵ͘DŽƌĞĚĂƚĂǁŝƚŚƉĂƚŝĞŶƚƐǁŚŽĚĞǀĞůŽƉĐůŝŶŝĐĂůǀĂƐŽƐƉĂƐŵŝƐŶĞĞĚĞĚŝŶŽƌĚĞƌƚŽ
ĐŽƌƌĞůĂƚĞƚŚĞƐĞĐŚĂŶŐĞƐǁŝƚŚƚŚŝƐƐƵďƐĞƚŽĨƉĂƚŝĞŶƚƐ͘
dŚĞƐƚĂƚŝƐƚŝĐƐƚŚĂƚǁŝůůďĞƉĞƌĨŽƌŵĞĚŽŶƚŚĞĚĂƚĂŵĂƉƐĂƌĞŽƵƚůŝŶĞĚŝŶƚŚĞŝŵĂŐĞƐďĞůŽǁ͘
hƐŝŶŐƚŚĞƉĞƌĨƵƐŝŽŶŵĂƉǀĂůƵĞƐ͕ǁĞǁŝůůĐĂůĐƵůĂƚĞƌĞůĂƚŝǀĞƉĞƌĐĞŶƚĐŚĂŶŐĞŽƌŝŵƉƌŽǀĞŵĞŶƚ
ĨĂĐƚŽƌǁŚŝĐŚŝƐĚĞƚĂŝůĞĚŝŶƚŚĞƐůŝĚĞƐďĞůŽǁ͘tŚĞŶǁĞƐĂǇƚŚĞƌĞƐƵůƚƐǁĞƌĞƌĞƉƌŽĚƵĐŝďůĞŝƚ
ŵĞĂŶƐƚŚĂƚǁĞǁĞƌĞĂďůĞƚŽĚĞƚĞĐƚĂĐŚĂŶŐĞŝŶƉĞƌĨƵƐŝŽŶŝŶƌĞƐƉŽŶƐĞƚŽŝĂŵŽǆĂŶĚƚŚĂƚƚŚĞ
ŵĂƉƐǁĞƌĞŽĨŐŽŽĚĞŶŽƵŐŚƋƵĂůŝƚǇƚŽďĞĚŝĂŐŶŽƐƚŝĐ͘/ŚĂǀĞŝŶĐůƵĚĞĚĞǆĂŵƉůĞƐďĞůŽǁ͘
dŚĞƐƚĂƚŝƐƚŝĐĂůĂŶĂůǇƐŝƐŽŶƚŚĞƌĞůĂƚŝǀĞƉĞƌĐĞŶƚĐŚĂŶŐĞŝŶ&ǁĂƐĂƐƚĂŶĚĂƌĚďĂƐŝĐƉĂŝƌĞĚ
ƚͲƚĞƐƚ͘dŚŝƐƚĞƐƚǁĂƐƉĞƌĨŽƌŵĞĚŝŶĂŶŝĚĞŶƚŝĐĂůŵĂŶŶĞƌĨŽƌĞĂĐŚŚĞŵŝƐƉŚĞƌĞĨŽƌĞĂĐŚƉĞƌĨƵƐŝŽŶ
ƉĂƌĂŵĞƚĞƌŵĂƉ͘&ŽƌĂŐŝǀĞŶŚĞŵŝƐƉŚĞƌĞĂŶĚŵĂƉƚĞƐƚŚĞƌĞǁĞƌĞϰϬƐůŝĐĞƐŽĨƚŚĞŝŵĂŐĞĂďŽǀĞ
ƚŚĞŽƌďŝƚĂůůŝŶĞ͕ĂŵĞĂŶŵĞĂƐƵƌĞŵĞŶƚǁĂƐŵĂĚĞĨŽƌĞĂĐŚƐůŝĐĞůŽĐĂƚŝŽŶŽĨƚŚĞŚĞŵŝƐƉŚĞƌĞ͘
dŚƵƐ͕ĨŽƌƉƌĞĂŶĚƉŽƐƚŝĂŵŽǆǁĞŽďƚĂŝŶĞĚϰϬƉĂŝƌĞĚƐĂŵƉůĞƐ͘&ƌŽŵƚŚĞƐĞƉĂŝƌĞĚƐĂŵƉůĞƐ
;ƉĂŝƌĞĚŵĞĂŶŝŶŐƚŚĞǇƐŚĂƌĞĚƚŚĞƐĂŵĞƐůŝĐĞůŽĐĂƚŝŽŶƉƌĞĂŶĚƉŽƐƚŝĂŵŽǆͿƚŚĞƉĂŝƌĞĚͲƚĞƐƚǁĂƐ
ƉĞƌĨŽƌŵĞĚďǇƚĂŬŝŶŐƚŚĞĚŝĨĨĞƌĞŶĐĞďĞƚǁĞĞŶĂůůŽĨƚŚĞƉƌĞĂŶĚƉŽƐƚƉĂŝƌĞĚƐĂŵƉůĞƐƚŽŽďƚĂŝŶĂ
ƐĞƚŽĨϰϬĚŝĨĨĞƌĞŶĐĞƐ͘&ƌŽŵƚŚĞƐĞϰϬĚŝĨĨĞƌĞŶĐĞǀĂůƵĞƐŽŶĞĐĂŶŐĞƚĂŵĞĂŶĂŶĚƐƚĂŶĚĂƌĚ
ĚĞǀŝĂƚŝŽŶƚŽŽďƚĂŝŶƚŚĞdƐƚĂƚŝƐƚŝĐǁŚĞƌĞĂĐŽƌƌĞƐƉŽŶĚŝŶŐƉͲǀĂůƵĞĐĂŶƚŚĞŶďĞĐĂůĐƵůĂƚĞĚ͘&Žƌ
ŽƵƌĚĂƚĂƐĞƚ͕ǁĞĂƌĞƐĞůĞĐƚŝŶŐƉͲǀĂůƵĞŽĨфϬ͘ϬϱĂƐƐŝŐŶŝĨŝĐĂŶƚ͘tĞĚŽŶŽƚƉůĂŶƚŽƵƐĞƚŚŝƐĚĂƚĂĨŽƌ
ĂƉŽǁĞƌĂŶĂůǇƐŝƐ͘ZĞƉƌŽĚƵĐŝďŝůŝƚǇŚĂƐďĞĞŶĞƐƚĂďůŝƐŚĞĚ͕ďƵƚǁĞĂƌĞŶŽǁĂŝŵŝŶŐƚŽĚƌĂǁ
ĐŽƌƌĞůĂƚŝŽŶƐďĞƚǁĞĞŶƉĂƚŝĞŶƚƐǁŝƚŚǀĂƐŽƐƉĂƐŵĂŶĚƚŚĞŝƌ&ƌĞƐƉŽŶƐĞƚŽŝĂŵŽǆĂŶĚƚŚĂƚŝƐ
ƚŚĞŵĂŝŶĂŝŵŽĨƚŚŝƐĞǆƉĂŶĚĞĚƉŽƌƚŝŽŶŽĨƚŚĞƐƚƵĚǇ͘
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References 
ϭ͘ 
^ŚŝŶŽĚĂ:͕<ŝŵƵƌĂd͕&ƵŶĂŬŽƐŚŝd͕ƌĂŬŝz͕/ŵĂŽz͘ĐĞƚĂǌŽůĂŵŝĚĞƌĞĂĐƚŝǀŝƚǇŽŶ
ĐĞƌĞďƌĂůďůŽŽĚĨůŽǁŝŶƉĂƚŝĞŶƚƐǁŝƚŚƐƵďĂƌĂĐŚŶŽŝĚŚĂĞŵŽƌƌŚĂŐĞ͘Acta Neurochir 
(Wien)͘ϭϵϵϭ͖ϭϬϵ;ϯͲϰͿ͗ϭϬϮͲϭϬϴ͘ĚŽŝ͗ϭϬ͘ϭϬϬϳͬ&ϬϭϰϬϯϬϬϯ͘
Ϯ͘ 
dĂŶĂŬĂ͕zŽƐŚŝŶĂŐĂ^͕EĂŬĂǇĂŵĂz͕dŽŵŽŶĂŐĂD͘ĞƌĞďƌĂůďůŽŽĚĨůŽǁĂŶĚƚŚĞ
ƌĞƐƉŽŶƐĞƚŽĂĐĞƚĂǌŽůĂŵŝĚĞĚƵƌŝŶŐƚŚĞĂĐƵƚĞ͕ƐƵďĂĐƵƚĞ͕ĂŶĚĐŚƌŽŶŝĐƐƚĂŐĞƐŽĨ
ĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞ͘Neurol Med Chir (Tokyo)͘ϭϵϵϴ͖ϯϴ;ϭϬͿ͗ϲϮϮͲ
ϲϮϯ͘
ϯ͘ 
>ĞĞ͕<͕͘ĞƚĂů͘͚͞dƌŝƉůĞͲ,͛dŚĞƌĂƉǇĨŽƌĞƌĞďƌĂůsĂƐŽƐƉĂƐŵ&ŽůůŽǁŝŶŐ^ƵďĂƌĂĐŚŶŽŝĚ
,ĞŵŽƌƌŚĂŐĞ͘͟Neurocritical Care͕ǀŽů͘ϰ͕ŶŽ͘ϭ͕ϮϬϬϲ͕ƉƉ͘ϲϴʹϳϲ͘
ϰ͘ 
ZŽĚƌşŐƵĞǌZ͕^ĄŶĐŚĞǌzW͘ZĞďůĞĞĚŝŶŐŝŶŶĞƵƌǇƐŵĂů^ƵďĂƌĂĐŚŶŽŝĚ,ĂĞŵŽƌƌŚĂŐĞ͗
ƉŝĚĞŵŝŽůŽŐǇ͕ZŝƐŬ&ĂĐƚŽƌƐ͕WĂƚŚŽƉŚǇƐŝŽůŽŐǇ͕ŝĂŐŶŽƐŝƐĂŶĚWƌĞǀĞŶƚŝǀĞdƌĞĂƚŵĞŶƚ͘
Austin Neurosurg Open Access Austin Neurosurg Open Access͘ϮϬϭϱ͖Ϯ;ϮͿ͗ϭϬϮϵͲϮ͘
ϱ͘ 
ZŽŐĞƌs>͕'ŽĂ͘^͕>ůŽǇĚͲ:ŽŶĞƐD͕ĞƚĂů͘,ĞĂƌƚŝƐĞĂƐĞĂŶĚ^ƚƌŽŬĞ^ƚĂƚŝƐƚŝĐƐͲͲϮϬϭϮ
hƉĚĂƚĞ͗ZĞƉŽƌƚ&ƌŽŵƚŚĞŵĞƌŝĐĂŶ,ĞĂƌƚƐƐŽĐŝĂƚŝŽŶ͘Circulation͘ϮϬϭϮ͖ϭϮϱ;ϭͿ͗ĞϮͲ
ĞϮϮϬ͘ĚŽŝ͗ϭϬ͘ϭϭϲϭͬ/Z͘ϬďϬϭϯĞϯϭϴϮϯĂĐϬϰϲ͘
ϲ͘ 
^ĂŶĚǀĞŝD^͕DĂƚŚŝĞƐĞŶ͕sĂƚƚĞŶ>:͕ĞƚĂů͘/ŶĐŝĚĞŶĐĞĂŶĚŵŽƌƚĂůŝƚǇŽĨĂŶĞƵƌǇƐŵĂů
ƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞŝŶƚǁŽEŽƌǁĞŐŝĂŶĐŽŚŽƌƚƐ͕ϭϵϴϰͲϮϬϬϳ͘Neurology͘
ϮϬϭϭ͖ϳϳ;ϮϬͿ͗ϭϴϯϯͲϭϴϯϵ͘ĚŽŝ͗ϭϬ͘ϭϮϭϮͬtE>͘ϬďϬϭϯĞϯϭϴϮϯϳϳĚĞϯ͘
ϳ͘ 
ŚĂůŽƵŚŝE͕dũŽƵŵĂŬĂƌŝƐ^͕dŚĂŬŬĂƌs͕ĞƚĂů͘ŶĚŽǀĂƐĐƵůĂƌŵĂŶĂŐĞŵĞŶƚŽĨĐĞƌĞďƌĂů
ǀĂƐŽƐƉĂƐŵĨŽůůŽǁŝŶŐĂŶĞƵƌǇƐŵƌƵƉƚƵƌĞ͗ŽƵƚĐŽŵĞƐĂŶĚƉƌĞĚŝĐƚŽƌƐŝŶϭϭϲƉĂƚŝĞŶƚƐ͘
Clin Neurol Neurosurg͘ϮϬϭϰ͖ϭϭϴ͗ϮϲͲϯϭ͘ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĐůŝŶĞƵƌŽ͘ϮϬϭϯ͘ϭϮ͘ϬϭϮ͘
ϴ͘ 
>ĂŐĂƌĞƐ͕ŝĐƵĞŶĚĞǌD͕ZĂŵŽƐ͕ĞƚĂů͘ĐƵƚĞƉĞƌĨƵƐŝŽŶĐŚĂŶŐĞƐĂĨƚĞƌƐƉŽŶƚĂŶĞŽƵƐ
^,͗ƉĞƌĨƵƐŝŽŶdƐƚƵĚǇ͘Acta Neurochir (Wien)͘ϮϬϭϮ͖ϭϱϰ;ϯͿ͗ϰϬϱͲϰϭϭ͘
ĚŽŝ͗ϭϬ͘ϭϬϬϳͬƐϬϬϳϬϭͲϬϭϭͲϭϮϲϳͲǌ͘
ϵ͘ 
WŽƐŶĞƌ:͕WůƵŵ&͘dŚĞƚŽǆŝĐĞĨĨĞĐƚƐŽĨĐĂƌďŽŶĚŝŽǆŝĚĞĂŶĚĂĐĞƚĂŽůĂŵŝĚĞŝŶŚĞƉĂƚŝĐ
ĞŶĐĞƉŚĂůŽƉĂƚŚǇ͘J Clin Invest͘ϭϵϲϬ͖ϯϵ͗ϭϮϰϲͲϭϮϱϴ͘
ϭϬ͘ 
^ƵůůŝǀĂŶ,'͕<ŝŶŐƐďƵƌǇd͕DŽƌŐĂŶD͕ĞƚĂů͘dŚĞƌ&ƌĞƐƉŽŶƐĞƚŽŝĂŵŽǆŝŶŶŽƌŵĂů
ƐƵďũĞĐƚƐĂŶĚĐĞƌĞďƌŽǀĂƐĐƵůĂƌĚŝƐĞĂƐĞƉĂƚŝĞŶƚƐ͘J Neurosurg͘ϭϵϴϳ͖ϲϳ;ϰͿ͗ϱϮϱͲϱϯϰ͘
ĚŽŝ͗ϭϬ͘ϯϭϳϭͬũŶƐ͘ϭϵϴϳ͘ϲϳ͘ϰ͘ϬϱϮϱ͘
ϭϭ͘ 
,ŝŶƐŽŶ:^͕ŚŵĂŶŶDZ͕&ŝŶĞD͕ĞƚĂů͘ZŝƐŬŽĨĐƵƚĞ<ŝĚŶĞǇ/ŶũƵƌǇĨƚĞƌ/ŶƚƌĂǀĞŶŽƵƐ
ŽŶƚƌĂƐƚDĞĚŝĂĚŵŝŶŝƐƚƌĂƚŝŽŶ͘Ann Emerg Med͘ϮϬϭϳ͖ϲϵ;ϱͿ͗ϱϳϳͲϱϴϲ͘
ĚŽŝ͗ϭϬ͘ϭϬϭϲͬũ͘ĂŶŶĞŵĞƌŐŵĞĚ͘ϮϬϭϲ͘ϭϭ͘ϬϮϭ͘
ϭϮ͘ 
WŝĞƉŐƌĂƐĂ͕͘^ĐŚŵŝĞĚĞŬW͕>ĞŝŶƐŝŶŐĞƌ'͕,ĂďĞƌůZ>͕<ŝƌƐĐŚD͕ŝŶŚĂƵƉů<D͘ƐŝŵƉůĞ
ƚĞƐƚƚŽĂƐƐĞƐƐĐĞƌĞďƌŽǀĂƐĐƵůĂƌƌĞƐĞƌǀĞĐĂƉĂĐŝƚǇƵƐŝŶŐƚƌĂŶƐĐƌĂŶŝĂůŽƉƉůĞƌ
ƐŽŶŽŐƌĂƉŚǇĂŶĚĂĐĞƚĂǌŽůĂŵŝĚĞ͘Stroke͘ϭϵϵϬ͖Ϯϭ;ϵͿ͗ϭϯϬϲͲϭϯϭϭ͘
ĚŽŝ͗ϭϬ͘ϭϭϲϭͬϬϭ͘^dZ͘Ϯϭ͘ϵ͘ϭϯϬϲ͘
ϭϯ͘ 
,ĂƵŐĞ͕EŝĐŽůĂǇƐĞŶ'͕dŚŽƌĞƐĞŶD͘ĐƵƚĞĞĨĨĞĐƚƐŽĨĂĐĞƚĂǌŽůĂŵŝĚĞŽŶĐĞƌĞďƌĂů
ďůŽŽĚĨůŽǁŝŶŵĂŶ͘Acta Physiol Scand͘ϭϵϴϯ͖ϭϭϳ;ϮͿ͗ϮϯϯͲϮϯϵ͘
ϭϰ͘ 
dƌĂŶŝŶŚzZ͕>Žƚ'͕ĞŶƌĂďĂŚZ͕ĂƌŽƵĚǇK͕ŽƉŚŝŐŶŽŶ:͕^ĞǇůĂǌ:͘ďŶŽƌŵĂůĐĞƌĞďƌĂů
ǀĂƐŽĚŝůĂƚŝŽŶŝŶĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĞŵŽƌƌŚĂŐĞ͗ƵƐĞŽĨƐĞƌŝĂůϭϯϯyĞĐĞƌĞďƌĂů
ďůŽŽĚĨůŽǁŵĞĂƐƵƌĞŵĞŶƚƉůƵƐĂĐĞƚĂǌŽůĂŵŝĚĞƚŽĂƐƐĞƐƐĐĞƌĞďƌĂůǀĂƐŽƐƉĂƐŵ͘J 
Neurosurg͘ϭϵϵϯ͖ϳϵ;ϰͿ͗ϰϵϬͲϰϵϯ͘ĚŽŝ͗ϭϬ͘ϯϭϳϭͬũŶƐ͘ϭϵϵϯ͘ϳϵ͘ϰ͘ϬϰϵϬ͘


ϭϱ͘ 
<ŝŵƵƌĂd͕^ŚŝŶŽĚĂ:͕&ƵŶĂŬŽƐŚŝd͘WƌĞĚŝĐƚŝŽŶŽĨĐĞƌĞďƌĂůŝŶĨĂƌĐƚŝŽŶĚƵĞƚŽǀĂƐŽƐƉĂƐŵ
ĨŽůůŽǁŝŶŐĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚŚĂĞŵŽƌƌŚĂŐĞƵƐŝŶŐĂĐĞƚĂǌŽůĂŵŝĚĞͲĂĐƚŝǀĂƚĞĚ
ϭϮϯ/Ͳ/DW^Wd͘Acta Neurochir͘ϭϵϵϯ͖ϭϮϯ;ϯͲϰͿ͗ϭϮϱͲϭϮϴ͘
ϭϲ͘ 
,Žůů<͕,ĞŝƐƐůĞƌ,͕EĞŵĂƚŝE͕'ĂĂďDZ͕,ĂƵďŝƚǌ͕ĞĐŬĞƌ,͘΀dŚĞĞĨĨĞĐƚŽĨ
ĂĐĞƚĂǌŽůĂŵŝĚĞͲŝŶĚƵĐĞĚ͕ĞŶĚŽŐĞŶŽƵƐǀŽůƵŵĞƐƚƌĞƐƐŽĨƚŚĞĐĞƌĞďƌŽƐƉŝŶĂůƐǇƐƚĞŵŽŶ
ŝŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞ͘ŝĂŵŽǆͲͲĞĨĨĞĐƚŽŶŝŶƚƌĂĐƌĂŶŝĂůƉƌĞƐƐƵƌĞ΁͘Neurochirurgia 
(Stuttg)͘ϭϵϵϬ͖ϯϯ;ϮͿ͗ϮϵͲϯϲ͘ĚŽŝ͗ϭϬ͘ϭϬϱϱͬƐͲϮϬϬϴͲϭϬϱϯϱϱϬ͘
ϭϳ͘ 
ŚƌĞŶƌĞŝĐŚ͕ƵƌŶƐZ͕ůŵĂŶZ͕&ĂǌĞŬĂƐ:͘/ŶĨůƵĞŶĐĞŽĨĂĐĞƚĂǌŽůĂŵŝĚĞŽŶĐĞƌĞďƌĂů
ďůŽŽĚĨůŽǁ͘Arch Neurol͘ϭϵϲϭ͖ϱ͗ϮϮϳͲϮϯϮ͘
ϭϴ͘ 
zĂƐƵĚĂZ͕ZŽǇĂůƚǇ<͕WƵůĨĞƌ<͕ŽŶƐŝŐŶǇ͕^ƚƌŽƚŚĞƌD͘ͲĂƌŵdŵĞĂƐƵƌĞŵĞŶƚŽĨ
ĐĞƌĞďƌĂůďůŽŽĚǀŽůƵŵĞƵƐŝŶŐŝŶƚƌĂͲĂƌƚĞƌŝĂůŝŶũĞĐƚŝŽŶŽĨĐŽŶƚƌĂƐƚŵĞĚŝƵŵ͗Ŷ
ĞǆƉĞƌŝŵĞŶƚĂůƐƚƵĚǇŝŶĐĂŶŝŶĞƐ͘Am J Neuroradiol͘ϮϬϭϮ͖ϯϯ;ϵͿ͗ϭϲϵϲͲϭϳϬϭ͘
ĚŽŝ͗ϭϬ͘ϯϭϳϰͬĂũŶƌ͘ϯϬϳϳ͘
ϭϵ͘ 
ŚŵĞĚ^͕ĞůůĞƌŚŽĨĨD͕^ƚƌŽƚŚĞƌD͕ĞƚĂů͘ͲĂƌŵdŵĞĂƐƵƌĞŵĞŶƚŽĨĐĞƌĞďƌĂůďůŽŽĚ
ǀŽůƵŵĞ͗ŶĞǆƉĞƌŝŵĞŶƚĂůƐƚƵĚǇŝŶĐĂŶŝŶĞƐ͘Am J Neuroradiol͘ϮϬϬϵ͖ϯϬ;ϱͿ͗ϵϭϳͲϵϮϮ͘
ĚŽŝ͗ϭϬ͘ϯϭϳϰͬĂũŶƌ͘ϭϱϭϯ͘
ϮϬ͘ 
<ĂŵƌĂŶD͕ǇƌŶĞ:s͘ͲĂƌŵĨůĂƚĚĞƚĞĐƚŽƌĐŽŵƉƵƚĞĚƚŽŵŽŐƌĂƉŚǇƉĂƌĞŶĐŚǇŵĂůďůŽŽĚ
ǀŽůƵŵĞŝŵĂŐŝŶŐ͗ƚŚĞŶĂƚƵƌĞŽĨƉĂƌĞŶĐŚǇŵĂůďůŽŽĚǀŽůƵŵĞƉĂƌĂŵĞƚĞƌĂŶĚƚŚĞ
ĨĞĂƐŝďŝůŝƚǇŽĨƉĂƌĞŶĐŚǇŵĂůďůŽŽĚǀŽůƵŵĞŝŵĂŐŝŶŐŝŶĂŶĞƵƌǇƐŵĂůƐƵďĂƌĂĐŚŶŽŝĚ
ŚĂĞŵŽƌƌŚĂŐĞƉĂƚŝĞŶƚƐ͘Neuroradiology͘ϮϬϭϱ͖ϱϳ;ϵͿ͗ϵϯϳͲϵϰϵ͘ĚŽŝ͗ϭϬ͘ϭϬϬϳͬƐϬϬϮϯϰͲ
ϬϭϱͲϭϱϰϱͲϭ͘
Ϯϭ͘ 
ƌƵĐĞZ͕Ğƚ͘Ăů͘ĂĐŬŐƌŽƵŶĚ&ůƵĐƚƵĂƚŝŽŶƐŽĨ<ŝĚŶĞǇ&ƵŶĐƚŝŽŶsĞƌƐƵƐŽŶƚƌĂƐƚ/ŶĚƵĐĞĚ
EĞƉŚƌŽƚŽǆŝĐŝƚǇ͘:EZϮϬϬϵ͖ϭϵϮ͗ϳϭϭͲϳϭϴ͘
ϮϮ͘ 
:ŽƐĞƉŚƐŽŶ^͘:Ğƚ͘Ăů͘/ŶĐŝĚĞŶĐĞŽĨĐŽŶƚƌĂƐƚŶĞƉŚƌŽƉĂƚŚǇĨƌŽŵĐĞƌĞďƌĂůdĂŶŐŝŽŐƌĂƉŚǇ
ĂŶĚƚƉĞƌĨƵƐŝŽŶŝŵĂŐŝŶŐ͘EĞƵƌŽůŽŐǇϮϬϬϱ͖ϲϰ͗ϭϴϬϱͲϭϴϬϲ͘
Ϯϯ͘ 
DĂƌĞŶd,͕ZŽďŝŶƐŽŶ͘WŚĂƌŵĂĐŽůŽŐǇŽĨĂĐĞƚĂǌŽůĂŵŝĚĞŝŶŵĂŶ͕ǁŝƚŚƉĂƌƚŝĐƵůĂƌ
ƌĞĨĞƌĞŶĐĞƚŽƚŚĞĐĞƌĞďƌŽƐƉŝŶĂůĨůƵŝĚ͘Am J Med͘ϭϵϱϵ͖Ϯϳ;ϮͿ͗ϯϭϳ͘
 
 
 
 
 
 
 
 


Appendix A: 
 
 
Appendix B: 
 
,ƵŶƚĂŶĚ,ĞƐƐ'ƌĂĚŝŶŐ^ĐĂůĞ
 
Appendix C: 
 
ŚƚƚƉƐ͗ͬͬƵĐŽŶŶĞĐƚ͘ǁŝƐĐ͘ĞĚƵͬƉŽůŝĐŝĞƐͬĐůŝŶŝĐĂůͬƵǁŚĐͲĐůŝŶŝĐĂůͬƵǁŚĐͲǁŝĚĞͬůĞŐĂůͲĂĨĨĂŝƌƐͬϰϭϳ͘ƉŽůŝĐǇ
 
Appendix D:  Consent Form Questions 
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ŽǇŽƵŚĂǀĞƚŽƉĂƌƚŝĐŝƉĂƚĞŝŶƚŚŝƐƐƚƵĚǇ͍
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tŚĂƚǁŽƵůĚǇŽƵĚŽŝĨǇŽƵĚĞĐŝĚĞĚƚŚĂƚǇŽƵŶŽůŽŶŐĞƌǁĂŶƚĞĚƚŽƉĂƌƚŝĐŝƉĂƚĞ͍
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tŚĂƚĂƌĞƚŚĞƌŝƐŬƐƚŽǇŽƵŝĨǇŽƵƉĂƌƚŝĐŝƉĂƚĞ͍


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ŽǇŽƵǁĂŶƚƚŽƉĂƌƚŝĐŝƉĂƚĞŝŶƚŚĞƌĞƐĞĂƌĐŚƐƚƵĚǇƚŚĂƚŚĂƐũƵƐƚďĞĞŶĚĞƐĐƌŝďĞĚƚŽǇŽƵ͍
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