Clinical trial NCT01589263
Conditions: Benign Prostatic Hyperplasia Lower Urinary Track Symptoms
Keywords: Benign Prostatic Hyperplasia Lower Urinary Track Symptoms BPH LUTS
Sponsor: VA Office of Research and Development
Start date: 2012-06-01; Completion date: 2019-09-30
Enrollment: 63 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Benign prostatic hyperplasia (BPH) and its related symptoms are a common condition that affects nearly half of men over age 50 and 90% of men over 80. Lower urinary tract symptoms (LUTS) caused by BPH can be very troublesome, affect an individual's quality of life significantly, and are costly.

his Phase 2 clinical research trial is a double-blind, randomized, placebo-controlled, parallel-group study to compare the treatment effects of onaBoNT-A 200 U versus 0.4 mg per day of oral tamsulosin in male Veterans diagnosed with moderate to severe LUTS \[American Urologic Association Symptom Score (AUASS) equal to or greater than 8\] associated with BPH. A total of 74 volunteers will be recruited to participate in this clinical trial. Volunteers will include only males who are greater than 50 years of age and diagnosed with LUTS associated with BPH. They are Veterans who visit the Michael E. DeBakey Veterans Affairs Medical Center - Houston (MEDVAMC). There are no eligibility restrictions as to race or ethnicity.

Detailed description:
This proposed intervention is the first randomized clinical trial comparing the effects of onaBoNT-A prostate injection versus alpha adrenergic antagonist medication for LUTS associated with BPH. Up to this point, clinical studies using onaBoNT-A in the prostate has been limited to patient's refractory to -1 adrenoceptor blocker therapy. The study will directly compare onaBoNT-A against -1 adrenoceptor blockers as frontline therapy in a male Veteran cohort suffering from moderate to severe LUTS. Besides its obvious efficacy in patients' refractory to -1 adrenoceptor blocker therapy, onaBoNTA injection has several potential advantages over oral agents. Focal prostate injection has been shown to be safe and obviates the systemic side effects observed with -1 adrenoceptor blockers (i.e. orthostatic hypotension, sexual dysfunction). In addition, most clinical studies demonstrate a durable response to onaBoNT-A treatment exceeding 12 months. Although this study is of modest length (i.e. total 4 years), significant results could drive paradigm shifts in how LUTS associated with BPH is treated, even with regards to frontline therapy.

Although sophisticated molecular techniques (i.e. LCM with Microarray Analysis) have been used by other investigators to characterize gene profile changes with BPH and LUTS, this will be the first study examining gene profile changes in drug na ve BPH View Protocol Record patients following treatment with the -1 adrenoceptor blocker Tamsulosin or onaBoNT-A. This study is important because scant knowledge exists on the true mechanisms by which -1 adrenoceptor blockers like Tamsulosin or onaBoNT-A improve patient urinary tract symptoms and quality of life. It is clear, however, that nerves not only regulate prostate growth and function but also account for LUTS that drive patients to seek therapy. This investigation will utilize onaBoNT-A as a biological tool to identify potential novel mechanistic pathways for future investigation that will push the development of targeted therapy to benefit those patients refractory to all pharmacologic treatment. Potential inflammatory pathways or neural sensory signaling alterations induced by BPH, which are modified by onaBoNT-A or Tamsulosin to improve symptoms via gene profile changes, can be explored by expert laboratories in the Texas Medical Center. This is a highly collaborative project utilizing expertise across departments that will foster translational work from the laboratory to the patient. Although not the primary goal of this study, the investigators will also search for possible biological markers with prognostic value that could be confirmed in a future multi-center trial.

The primary objective of this Phase 2 clinical research study is to compare the efficacy of 200 U onaBoNT-A injected into the prostate versus oral tamsulosin for the treatment of lower urinary tract symptoms caused by BPH in male Veteran volunteers at the MEDVAMC. The secondary objective is to determine the impact of tamsulosin and onaBoNT-A on the pathologic parameters and RNA profiles of epithelium and stroma in BPH tissues.

Volunteers will be randomized into two groups with one receiving ona-BoNT-A injection into the prostate and an oral placebo pill taken once daily and the other group will receive a placebo injection and an oral tamsulosin pill once daily.

Volunteers will make five clinic visits and be contacted by telephone twice.

Arms: arm 1: onaBoNT-A 200 U prostate injection and placebo oral capsule daily arm 2: Placebo prostate injection (saline) and tamsulosin 0.4 mg capsule daily.
Interventions: intervention 1: onaBoNT-A + placebo intervention 2: Tamsulosin + placebo
Intervention descriptions: intervention 1: 200 U prostate injection once

Arms: ARM 1: onaBoNT-A + placebo intervention 2: 0.4 mg capsule daily for 3 months Arms: ARM 2: Saline + Tamsulosin

Protocol documents:
Prot_SAP_000.pdf: 
A Double-Blind, Randomized Study of the Efficacy of OnabotulinumtoxinA (onaBoNT-A) 
versus Oral Tamsulosin in Men with BPH and LUTS (Protocol # 02-10-10-05) 
 
 
 
Version: August 15, 2018 
 
 
 
 
 
PRINCIPAL INVESTIGATOR: 
Christopher P. Smith, MD 
Associate Professor 
Scott Department of Urology 
Baylor College of Medicine 
Houston, TX 77030 
 
 
CO-INVESTIGATORS:  
Gustavo Ayala, M.D. 
Professor 
Vice Chair for Outreach 
Distinguished Chair in Pathology and Laboratory Medicine  
University of Texas Health Science Center Medical School  
Houston, Texas 
 
 
 
 
 
 
 
 
KEYWORDS: 
OnabotulinumtoxinA, BPH, LUTS     
 
 
 
IND/IDE #  
115,132 
 
 
BCM IRB# 
H-27457 
 
 
 
 
 
 
 
 
 
 
 
This clinical research protocol will be conducted in accordance with FDA, ICH and IRB 
regulations and guidelines.  The Scott Department of Urology complies fully with the HIPAA 
guidelines. 


 
CPS BTX + Tam 
Page 2 of 32 
8/15/18 
TABLE OF CONTENTS 
 
 
I. 
BACKGROUND -------------------------------------------------------------------------------------------- 3 
II 
PRELIMINARY STUDIES ------------------------------------------------------------------------------- 8 
III 
SIGNIFICANCE AND RATIONALE ----------------------------------------------------------------- 12 
IV 
OBJECTIVES--------------------------------------------------------------------------------------------- 13 
V. 
DRUG INFORMATON---------------------------------------------------------------------------------- 13 
VI 
PHASE OF STUDY ------------------------------------------------------------------------------------- 15 
VII 
ELIGIBILITY CRITERIA -------------------------------------------------------------------------------- 15 
VIII 
DESIGN---------------------------------------------------------------------------------------------------- 16 
IX 
BIOLOGICAL SPECIMENS --------------------------------------------------------------------------- 21 
X 
STATISTICAL ANALYSIS ----------------------------------------------------------------------------- 23 
XI 
SAMPLE SIZE-------------------------------------------------------------------------------------------- 24 
XII 
RETENTION AND DROPOUT/WITHDRAWAL -------------------------------------------------- 24 
XIII 
CRITERIA FOR DISCONTINUING THE STUDY ------------------------------------------------ 24 
XIV 
DATA ANALYSIS ---------------------------------------------------------------------------------------- 25 
XV 
RISKS AND DISCOMFORTS ------------------------------------------------------------------------ 25 
XVI 
BENEFITS ------------------------------------------------------------------------------------------------ 27 
XVII 
ALTERNATIVES ----------------------------------------------------------------------------------------- 28 
XVIII 
COSTS TO SUBJECTS-------------------------------------------------------------------------------- 28 
XIX 
PAYMENT TO SUBJECTS---------------------------------------------------------------------------- 28 
XX 
ADVERSE EVENT REPORTING -------------------------------------------------------------------- 28 
XXI 
DATA HANDLING AND RECORD KEEPING----------------------------------------------------- 28 
XXII 
ETHICS AND GOOD CLINICAL PRACTICE------------------------------------------------------ 29 
XXIII 
REFERENCES ------------------------------------------------------------------------------------------- 30 
XXIV 
APPENDICES -------------------------------------------------------------------------------------------- 32 
 
 
 


 
CPS BTX + Tam 
Page 3 of 32 
8/15/18 
I. 
BACKGROUND 
 
BPH and LUTS:  Benign prostatic hyperplasia (BPH) with its related symptoms is a common 
condition that affects nearly half of men over age 50 and 90% of men over 80.1  Lower urinary 
tract symptoms (LUTS) caused by BPH which include nocturia, frequency, urgency, hesitancy, 
intermittency and incomplete emptying, can be very bothersome, affect an individual’s lifestyle 
significantly, and are costly.2  The anatomical location of the human prostate and the urethra 
lend itself to the development of LUTS, including both obstructive and irritative symptoms.  The 
initial evaluation of BPH/LUTS includes administration of the seven-item American Urological 
Association Symptom Index (AUASI) which evaluates the presence and severity of the main 
components of LUTS. The importance of symptoms in the pathophysiology of BPH is 
underscored by the fact that symptom measurements comprised 78% of all endpoints from the 
recent Medical Treatment of Prostate Symptoms (MTOPS) trial, compared to 22% of endpoints 
for objective measures such as urinary retention and urinary tract infection.3  BPH, in large part, 
is a neural phenomenon given that sensory symptoms such as frequency, urgency, and nocturia 
are the key factors that push patients to seek treatment.  Increasing basic and clinical evidence 
suggests that neural pathways within the prostate modulate bladder storage function and may 
play a significant role in LUTS. 
 
Prostate Innervation:  The prostate is dually innervated by the sympathetic and parasympathetic 
nervous systems.4 Sympathetic fibers arise from the thoraco-lumbar cord (T10-L2) and course 
within the hypogastric nerve as either presynaptic neurons to terminate on short post-ganglionic 
adrenergic fibers near the prostate or as post-ganglionic neurons via the sympathetic chain to 
terminate directly on prostatic smooth muscle.  The majority of norepinephrine containing 
nerves occurs in the thick stromal smooth muscle layer around the prostatic ducts and acini.  
Parasympathetic fibers arise from the lumbo-sacral cord (L5-S1) and course within the pelvic 
nerve to synapse on post-ganglionic fibers within peri-prostatic ganglion.  Parasympathetic, 
cholinergic fibers localize to the prostatic epithelium, where their main function is thought to 
involve regulation of prostatic secretions.  Recent data demonstrate a robust cholinergic 
innervation within the human prostate with muscarinic receptor densities exceeding those of 
alpha-adrenergic receptors.5    In addition, the sensory nociceptor TRPV1 has been localized in 
abundance within prostatic urethral mucosa and prostatic acini.  Taken into context, there 
should be no doubt that prostate innervation plays a key role in the development and 
pathophysiology of LUTS. 
 
Alpha-adrenergic Receptor Antagonists for BPH: While surgery remains the gold standard for 
relieving obstruction and symptoms, more recent attention has been focused on 
pharmacotherapy as an alternative approach.  The American Urological Association 
recommends alpha-adrenergic receptor blockers as first-line pharmacologic therapy for male 
patients suffering from LUTS/BPH.  Alpha-adrenergic receptor blockers antagonize adrenergic 
receptors, blocking the effects of norepinephrine released from sympathetic nerve terminals.  
The end result is reduced smooth muscle tone.  Of the three known α-adrenergic receptors 
(α1A, α1B, and α1D), α1A is the most abundant within the prostate, the α1B subtype is 
predominant within peripheral blood vessels, and the α1D receptor subtype is localized to the 
bladder and spinal cord.  Numerous studies have documented a beneficial effect of alpha-
adrenergic receptor blockers for improving LUTS and urinary flowrates.6  However, use of 
alpha-adrenergic receptor blockers can be associated with serious cardiovascular and sexual 
side effects that contribute to the fact that one-third of men discontinue drug use despite 
bothersome LUTS.7  In addition, alpha-adrenergic receptor blockers directly target sympathetic 


 
CPS BTX + Tam 
Page 4 of 32 
8/15/18 
pathways and ignore the contributory effect of parasympathetic innervation on prostate growth 
and LUTS. 
 
Effects of Surgical Denervation:  McVary and colleagues demonstrated that surgical denervation 
of the rat prostate induces significant changes in the size of the rat ventral prostatic lobe.8  
Removal of sympathetic innervation caused a marked atrophy of the ipsilateral ventral lobe.  In 
contrast, physical denervation of parasympathetic input had no effect on the ipsilateral lobe but 
promoted marked hyperplasia of the contralateral non-denervated lobe.  The investigators 
hypothesized that growth factors secreted as a result of parasympathetic denervation may have 
contributed to enlargement of the contralateral ventral lobe.  The effect of altered neural input on 
prostate growth was evaluated in a population of partial and complete spinal cord injured men.9  
The study found no difference in prostate volume with increased age, a finding that contradicts 
observations from longitudinal studies in neurally intact males demonstrating that prostate size 
positively correlates with age.  Given that no abnormalities in pituitary-gonadal axis were 
observed, it appears likely that loss of neural input resulting from SCI stunts prostate growth.  
These basic and clinical studies support further research evaluating the effect of targeted 
prostate denervation on male LUTS associated with BPH. 
 
 
OnabotulinumtoxinA (onaBoNT-A) Mechanism of Action: In the search for more effective non-
invasive therapies to treat BPH, the role of somatic and visceral neuromuscular activity in the 
manifestation of LUTS has been studied.10  OnaBoNT-A (BOTOX, Allergan, Inc., Irvine, CA) 
was first introduced as a therapeutic agent in the late 1970’s for strabismus; thereafter, 
onabotulinumtoxinA has been safely used in the treatment of numerous other disorders 
characterized by excessive or inappropriate muscle contraction.11  The drug is administered for 
a wide variety of medical conditions including muscular dystonia and axillary hyperhidrosis, and 
in a number of urological conditions including voiding dysfunction.  OnaBoNT-A injections have 
already been successfully carried out to treat BPH12, 13 and other urologic disorders such as 
detrusor-sphincter dyssynergia, neurogenic detrusor over activity, chronic retention, chronic 
pelvic pain and motor and sensory urinary urge incontinence.14  These studies demonstrate that 
the use of onaBoNT-A in genitourinary disorders does not have significant side effects.  
OnaBoNT’s primary function is to inhibit the exocytosis of acetylcholine from the presynaptic 
nerve terminal.  After binding to the nerve cell membrane at a specific acceptor/receptor site 
and internalizing into the cell, onaBoNT cleaves one or more specific SNARE proteins that lead 
to reduced neurotransmitter release. At greater doses, it can also block the release of other 
neurotransmitters including norepinephrine, substance P, calcitonin-gene related peptide and 
glutamate.15   
 
Chemical Denervation of Prostate with onaBoNT-A:  When injected into rat prostates, onaBoNT-
A produces: (1) a generalized atrophy of the prostatic gland with no evidence of inflammatory 
infiltrate; (2) an increase in apoptosis with DNA fragmentation and formation of apoptotic bodies 
on Tunnel stain and decrease in proliferation; (3) a reduction in the proliferation of epithelial 
cells and; (4) a reduction in α1A adrenergic receptor but not androgen receptor expression.16, 17  
Silva and associates found that onaBoNT-A induced prostate atrophy in rats could be prevented 
with daily injection of the adrenergic agonist phenylephrine but not from daily administration of 
the cholinergic agonist bethanecol.18  Their investigations suggest that the predominant 
mechanism by which onaBoNT-A induces prostate atrophy and apoptosis in the rat is by 
inhibiting sympathetic neural transmission.  Atrophy and apoptosis has also been observed in 
prostate tissue of dogs and humans following onaBoNT-A injection although the selective effect 


 
CPS BTX + Tam 
Page 5 of 32 
8/15/18 
of onaBoNT-A on parasympathetic or sympathetic pathways has not been evaluated in 
humans.19 
 
OnaBoNT-A: Effective Treatment for Male LUTS Refractory to Medical Therapy:  The effect of 
onaBoNT-A on LUTS associated with BPH has been evaluated in several studies in men that 
have failed standard therapy with an alpha-adrenergic antagonist + 5α-reductase inhibitor.  The 
first off-label use of onaBoNT-A to treat BPH in humans was reported by Maria et al in 2003.13 
In a randomized, placebo-controlled study, 30 men with symptomatic BPH were randomized to 
receive either saline or 200 units of onaBoNT-A.  One hundred units of onaBoNT-A in 2 cc of 
saline or saline alone were injected into each lobe of the prostate through the perineum via a 
22-gauge spinal needle with transrectal ultrasound guidance.  Clinical improvement was evident 
within 1 month of treatment in the onaBoNT-A group.  By 2 months, 13 patients in the treatment 
group (87%) versus 3 patients in the control group (10%) reported subjective BPH symptom 
relief (p = 0.00001).  At 12 months, the International Prostate Symptom Score (IPSS) decreased 
by 62%, max urinary flowrate (Qmax) increased by 85%, post void residual (PVR) urine 
decreased by 85%, and prostate size (determined ultrasonographically) decreased by 61%.  
The PSA values were also reduced by 38%.  This degree of improvement was remarkable 
considering the fact that most patients had severe baseline symptoms (average IPSS = 23) and 
the mean prostate size was large (i.e. 52 cc) prior to injection.  No urinary incontinence or 
systemic side effects were reported over the 19.6 month follow-up period.      
 
Several case series have looked at specific BPH patient subpopulations to determine the 
effectiveness of onaBoNT-A treatment.  Kuo et al. treated 10 patients who were either in frank 
urinary retention or carried a large PVR.  These patients had already failed combination medical 
therapy (5α-reductase inhibitor and alpha-blocker) were not surgical candidates due to 
comorbid medical conditions.20  Two hundred units of BoNT-A was diluted in 10 cc of saline and 
was injected via a cystoscope into 10 sites in the prostate (4 sites on each lateral lobe, 2 sites at 
the median bar, 20 units per site).  After onaBoNT-A injection, 7 of 10 patients (70%) could void 
spontaneously while 3 required intermittent self-catheterization for 2 weeks.  The therapeutic 
effects were experienced as early as one week after injection.  By 3 and 6 months, significant 
improvements in Qmax, PVR, and prostate volumes were noted (53%, 85%, and 24%, 
respectively).  Eight of ten patients continued to use combination medical therapy after BoNT-A 
injection to maintain good symptomatic relief.   
 
Chuang et al. stratified patients who had failed medical treatment based on the prostate size: 
those with <30 cc were treated with 100 units onaBoNT-A while those with >30 cc were treated 
with 200 units (perineal injection).12, 21  At 12 months, the percent improvements in IPSS, Qmax, 
and PVR were very similar to those of Maria et al, except that the percent shrinkage of prostate 
size was substantially smaller (13-19% versus 61%).  In 12 of 41 men (29%) there was no 
change in prostate volume, yet 7 of these 12 men (58%) still had a > 30% improvement in IPSS, 
Qmax, and PVR, suggesting that onaBoNT-A may relieve BPH symptoms in ways other than 
reducing the prostate size alone (i.e. effect on sensory nerve pathways).   
 
As the table below indicates, a handful of clinical studies have been conducted to date 
measuring the efficacy of onaBoNT-A prostate injections to treat BPH.  However, only two 
studies provide level one evidence of clinical improvement from onaBoNT-A prostate injection, 
although they strongly disagree on whether onaBoNT-A has any effect on serum PSA level or 
prostate volume.  The remaining open-label studies do not conclusively support the results of 
one randomized trial over the other.  Our study will provide further level one evidence to either 


 
CPS BTX + Tam 
Page 6 of 32 
8/15/18 
support or refute the hypothesis that prostate denervation with onaBoNT-A reduces serum 
prostate levels and induces significant atrophy and prostate shrinkage.   
 
Investigator Study type, N 
Symptom Score 
Decrease 
PSA 
Decrease 
Prostate 
Volume 
Decrease 
Qmax 
Increase 
Durability 
Maria et al 
Randomized 
N=30 
200U 
62% 
51% 
68% 
90% 
12 months 
Brisinda et al. Open Label 
N=77 
200U 
64% 
58% 
55% 
92% 
30 months 
Kuo et al. 
Open Label 
N=10 
200U 
NA 
NA 
30% 
53% 
6 months 
Chuang et al. Open Label 
N=16 
100U 
61% 
NA 
16% 
73% 
6 months 
Chuang et al. Open Label 
N=21 
100U 
62% 
NA 
19% 
70% 
12 months 
Chuang et al. Open Label 
N=20 
200U 
73% 
NA 
17% 
70% 
12 months 
Silva et al. 
Open Label 
N=21 
200U 
Indwelling Cath 
24% 
40% 
Indwelling 
Cath 
12-18  
months 
Crawford et 
al. 
Randomized 
N=125 
100U, 300U 
38%, 46% 
0% 
0% 
25%, 27% 12 months 
 
 
No Effective Clinical Marker to Explain LUTS:  The improvement in LUTS following onaBoNT-A 
injection appears unrelated to baseline prostate size or to change in prostate size following 
treatment.  This observation is consistent with prior studies demonstrating a weak correlation 
between the symptoms of LUTS and prostate size, whether in men diagnosed with BPH or men 
in the general community over the age of 50 years.22-24 While 5-α-reductase inhibitors (i.e. 
which reduce prostate volume) have virtually no benefit at relieving LUTS25, drugs that do not 
impact prostate volume (i.e. alpha blockers, phosphodiesterase inhibitors, and anticholinergics) 
are often more effective in relieving LUTS.26-28  Thus, prostate size does not equate with LUTS.  
Because LUTS includes a complex assortment of symptoms affecting urine storage, voiding and 
micturition, Bladder Outlet Obstruction (BOO) was linked with LUTS.  Urological dogma 
reinforced the theory that BOO was linked with LUTS because of the observation that urinary 
flow decreases and LUTS increases with age.26  Moreover, BOO can be present irrespective of 
prostate size.  However, epidemiologic studies reveal a weak correlation between the severity of 
BOO and LUTS.22-24  In addition, changes in urinary flow rate and changes in LUTS following 
alpha blocker therapy and TURP do not strongly correlate providing further evidence that the 
mechanism for symptom improvement following these treatments is not related to simply 
relieving BOO.29, 30  Finally, phosphodiesterase inhibitors improve LUTS without having any 


 
CPS BTX + Tam 
Page 7 of 32 
8/15/18 
effect on flow rate giving further credence to the notion that neither the pathophysiology of BPH 
nor symptom improvement is dependent on relief of BOO.27  The lack of correlation between 
clinical and subjective measures of LUTS/BPH demands the exploration of novel biological 
markers and molecular targets that not only are associated with moderate to severe LUTS but 
which respond appropriately to treatment and symptom resolution. 
 
Gene Profile Changes with BPH:  Gene expression patterns in BPH are distinct from those 
found in normal and cancerous prostate tissue.31  Investigators have categorized BPH tissue 
based on clinical symptoms in an effort to identify genes that may be associated with a higher 
risk of symptomatic BPH.  Changes in gene expression with symptomatic BPH have been 
segregated into 5 main categories:  1. Growth regulatory genes; 2. Immunologic/Inflammatory 
genes; 3. Transcription Factors/ Cell Signalling genes; 4. Stromal Component Genes; and 5. 
Hormone genes.   
 
Bauman and colleagues reported on transcript profiling of proteins associated with androgen 
signaling in epithelial and stromal culture models from normal and BPH prostates.32   While no 
significant differences in androgen signaling were noted between BPH and normal epithelial 
cells, dramatic differences suggesting an increased androgen response were noted in BPH 
compared to normal stroma cells.32  The investigators noted an almost tripling of the AR:ERβ 
ratio in BPH stroma as well as significant increases in RL-HSD and a decrease in the ratio of 
AKR1C1:AKR1C2.  These factors all point to the heightened production of DHT as well as the 
decreased metabolism of DHT to the proaptotic ligand 3-β diol. 
 
Significant changes in genes that encode immunological regulation have also been described in 
men with BPH and LUTS including B-cell homing chemokine (i.e. 36 fold increase from normal), 
and MHC class II DP beta-1 (i.e. 5.5 fold increase compare to normal).33  Increases in 
expression of cytokines such as IL-1-alpha, -2, -4, -8, -15, -17 as well as decreases in the level 
of the macrophage inhibitory cytokine-1 gene (MIC-1), pre-B-cell colony enhancing factor, and 
interferon-stimulated gene have been reported as well.33-35  More recently, investigators have 
evaluated the molecular mechanisms of BPH in a rat model of phenylephrine induced 
histomorphologic BPH.  The study demonstrated a significant involvement of inflammatory 
pathways, in particular those involving activation of the TGF-beta signaling cascade.36   
 
Growth regulatory genes are thought to play an important role in the pathogenesis of BPH, 
particularly in epithelial cell growth and regulation.  Investigators have found a number of these 
genes to be upregulated in BPH:  1. Neural epidermal growth factor-like 2 (nel-like 2) (i.e. 6-
fold); 2. Early growth response 1 (i.e. 6-fold); 3. Insulin-like growth factor binding protein 10 (i.e. 
5-fold); as well as significant increases in stromal expression of Insulin Growth Factors (IGF-2), 
Insulin Growth Factor Receptors (IGF-I-R), and Fibroblast Growth Factors (FGF-2).33, 37  Finally, 
cell signaling genes noted to be more expressed in the prostates of symptomatic BPH patients 
include an increase in v-fos FBJ murine osteosarcoma viral oncogene homolog (i.e. 13 fold), an 
increase in mitogenic  activated protein kinases (i.e. ERK, p-38), an increase in bcl-2 (anti-
apoptotic factor), and an increase in the cell senescence marker SA-β-gal (epithelial).33, 38, 39  
 
Although the relative significance of each of these changes in gene expression remains to be 
determined, we hypothesize that Gene expression profiling will allow us to assess the impact of 
Tamsulosin or onaBoNT-A on prostate cells.  Systematic studies of gene expression in prostate 
tissues after treatment with onaBoNT-A or targeted blockade of adrenergic pathways with 
Tamsulosin should help us understand how these agents ameliorate BPH induced symptoms 
and identify better molecular targets to treat LUTS.  Ultimately, the translational goal would be to 


 
CPS BTX + Tam 
Page 8 of 32 
8/15/18 
provide symptom relief beyond simplistically targeting a reduction in prostate size or relieving 
BOO since the mechanisms responsible for either treatment response remains to be 
determined. 
 
 
II. 
PRELIMINARY STUDIES 
 
Clinical:  Our site was one of 7 centers involved in a 12-week Phase II trial of 100 and 300 units 
of onaBoNT-A for the management of BPH (Table 1).40  A total of 134 men were enrolled and 
treated (68 at dose 100 U and 66 at dose 300 U).  One hundred twenty five men provided 
complete primary outcome data (63 at dose 100 U and 62 at dose 300 U).  A positive effect of 
onaBoNT-A was characterized as a ≥ 30% change from baseline in AUA Symptom Score 
(AUASS) and/or Qmax.  Both arms passed the efficacy criteria:  73% passed at the 100 U dose 
and 81% passed at the 300 U dose (Table 1; yellow shading = pass efficacy criteria).  
Interestingly, no significant changes in Total Prostate Volume (TPV) or Transition Zone Volume 
(TZV) in the combined data of 100 U and 300 U (i.e. TPV increased slightly from 49.7 cc to 50.1 
cc and TZV increased 
slightly from 24 cc to 
24.4 cc) were observed.  
In addition, PSA values 
did not change 
significantly as a result 
of onaBoNT-A 
treatment (i.e. 
increased non-
significantly from 2.4-
2.7 at 12 weeks follow-
up).   
 
Our results are consistent with other clinical studies of onaBoNT-A in BPH although the 3-month 
improvements in AUASS (39.1% for 100 U dose; 42.6% for 300 U dose) and Qmax (25.6% and 
28.5%, respectively) demonstrated in our study were smaller than those described in prior 
studies (i.e. AUASS decrease 61-73% and Qmax increase 53-92%).12, 13, 20, 21   
 
A decrease in prostate size that is known to occur following physical or chemical (i.e. onaBoNT-
A) denervation in rats was not observed within this study.8, 16  These results suggest that the 
mechanism of action of onaBoNT-A to improve LUTS in men with BPH is multi-factorial and not 
solely related to its effects on altering parasympathetic or sympathetic neural input.  Thus, 
additional directed investigation into the mechanism of action for onaBoNT-A in prostate tissues 
is appropriate, particularly in view of clinical evidence in human bladders that onaBoNT-A 
injection can modulate both the expression of sensory nerve receptors and the release of 
sensory neurotransmitters and nerve growth factor.41-43 
 
Basic: The following experiments were conducted in a rat model to examine the effects of 
chemical denervation (i.e. onaBoNT-A injection) or surgical denervation (i.e. Major Pelvic 
Ganglion (MPG) dissection) on gene expression profiles of different compartments of the 
prostate in a prostate cancer model.  These results are proof of principle that validate our ability 
to measure changes in gene expression of prostatic epithelial and stromal cells following 
chemical denervation with onaBoNT-A.  We will use the same methods in human prostate 
tissue to identify genetic changes occurring with BPH/LUTS development and after successful 
treatment of LUTS with either Tamsulosin or onaBoNT-A. 
Table 1:  Results of 12-week Phase II clinical trial 
 
100 Units 
300 Units 
 
Qmax  fail Qmax pass Qmax fail Qmax pass 
AUA SS 
fail 
17 (27%) 
10 (16%) 
12 (19%) 
8 (13%) 
AUA SS 
pass 
20 (32%) 
16 (25%) 
27 (44%) 
15 (24%) 


 
CPS BTX + Tam 
Page 9 of 32 
8/15/18 
 
Reduction of tumor size by prostatic denervation: To determine the functional significance of 
innervation within the prostate and in PCa, we used an orthotopic rat animal model. Transgenic 
mice do not survive the complications caused by prostatic denervation (i.e. neurogenic bladder 
and rectum). The experiments have been performed as a component of the Tumor 
Microenvironment Network. Athymic NIH-RNU rats were denervated mechanically through 
removal of the male pelvic ganglion (MPG). This technique has been widely used in rats 49. Rat 
prostates were also denervated chemically through the use of BOTOX®. VCaP cells were 
injected orthotopically into the prostates one week after the denervation procedures. Control 
animals were injected at the same time. Animals were followed for 7 weeks. Of the 8 animals 
per group, we only lost one rat from the pelvic ganglion denervation arm. Animals were 
sacrificed and full autopsies performed. The prostates were halved and one section was 
formalin-fixed and paraffin-embedded, while the other was frozen. Hematoxylin and eosin-
stained sections were obtained from both halves. These were imaged and the tumors mapped 
and quantified using J Image. The results suggest that nerves are functionally required for tumor 
growth in this orthotopic rat model. While large tumors were present in 50% of the control arm, 
only 1/8 were identified in the BOTOX® group and 2 in the pelvic ganglion denervation group. 
The tumors were much smaller in the denervated group (Fig. 1). To evaluate gene expression 
changes in normal epithelial, stromal, and PCa tissues after denervation, we laser-captured 
each cell type and performed RNA expression array analysis. Cluster analysis showed that 
BOTOX® chemical and physical denervation had similar gene profile effects on all 
compartments studied (Fig. 2). Our results demonstrate that denervation of the prostate has 
profound effects on both the stromal and epithelial compartments of the prostate.  
 
 
 
 
 
 
Figure 1: The size of tumors in rats with 
mechanical MPG and Botox denervation 
is smaller than sham operation controls. 
Figure 2: Unsupervised clustering of gene 
expression of normal epithelial and stromal, 
and PCa tissue in denervated and control mice. 


 
CPS BTX + Tam 
Page 10 of 32 
8/15/18 
Denervation Effects on Non-Neoplastic [Rat Prostate] Epithelium: To determine the effects of 
denervation on the non-neoplastic epithelium we laser captured the viable non-cancer epithelial 
cells away from the tumors in both the treated and control animals. We extracted RNA and 
performed gene array studies. Initial gene ontology studies of genes downregulated in the 
denervated animals showed that major cellular processes were affected. These included 
translation and translation initiation factor activity (signal transducer and activator of 
transcription 3, eukaryotic translation initiation factor 4A1, eukaryotic translation elongation 
factor 1 gamma*, eukaryotic translation initiation factor 3, subunit B, C and F); ribosomes and 
structural constituents of ribosome’s (ribosomal protein L22*, L5, L6, S17 and S6, mitochondrial 
ribosomal protein S14), and metabolic pathways (ST8 alpha-N-acetyl-neuraminide alpha-2,8-
sialyltransferase). Other  genes included proteasome (prosome, macropain) subunit, alpha type 
5, protein tyrosine phosphatase domain containing 1, tyrosine kinase with immunoglobulin-like 
and EGF-like domains*, heat shock protein 1-like, cAMP responsive element binding protein 1, 
Forkhead box K2 and RING1 and YY1 binding protein*.  
 
We validated successfully 12 out of 16 genes, marked previously with a “*”. Validation was done 
on a second laser capture microdissection, as material from the first was utilized for array 
studies. The histologic translation of these findings is generalized atrophy, as seen in figure 3. 
There is significant reduction in cell height and secretions into the lumens, as previously 
demonstrated.16  However, the phenotype was variable, and other patterns were noted. The 
second most seen pattern was apoptotic epithelial cells and collagenous nodules attempting to 
close down damaged acini (Figure 4). The latter phenotype can be explained by the upregulated 
gene profile pattern of these cells.   
 
Figure 3: Effects of Saline or onaBoNT-A injection on rat 
prostate morphology.  Note flattening of epithelium in onaBoNT-
A treated tissues (denervated). 


 
CPS BTX + Tam 
Page 11 of 32 
8/15/18 
 
 
 
 
We identified that the epithelial cells gene profile indicated an expected acute phase response, 
driven most likely by serum response factor, as this seems to be the most common motif that 
regulates this set of genes (SRF:Serum response factor (c-fos serum response element-binding 
transcription factor)). Endothelin* and endothelin receptors types A and B were among the most 
upregulated genes. Insulin I* and II* and insulin-like growth factor 1 and insulin-like growth 
factor binding protein 4 were also significantly upregulated. Numerous other growth factors were 
also upregulated including c-fos induced growth factor, connective tissue growth factor as well 
as epidermal growth factor receptor. Fas ligand (TNF superfamily, member 6) and tumor 
necrosis factor receptor superfamily, member 1b were also upregulated.  
 
The epithelial cells acquired a more mesenchymal phenotype with production of multiple 
collagens (collagen, type XVI, alpha 1, collagen, type XIV, alpha 1, collagen, type III, alpha 1, 
collagen, type I, alpha 1), probably responsible for the collagenous nodules. Genes usually 
identified with stemness properties were also upregulated (noggin, secreted frizzled-related 
protein 4, wingless-related MMTV integration site 11, dickkopf homolog 4).  
 
Denervation effects on Non-Neoplastic Human Prostate Epithelium:  As an initial clinical 
translation and proof-of-concept study, we next evaluated tissues from three patients with 
prostate cancer enrolled in a Phase I clinical trial examining the effects of onaBoNT-A injections 
on prostate epithelial biology.  Patients received unilateral injection with onaBoNT-A (100 units 
in 1.0 ml) into one transition lobe and a vehicle control injection (i.e. saline) into the contralateral 
lobe.  Examination of tissue from radical prostatectomies performed 4 weeks after injection 
Figure 4: In the second most common histologic pattern observed, 
ona-BoNT-A treated prostate tissues demonstrated apoptotic 
epithelial cells and excessive collagenous deposits within acini. 


 
CPS BTX + Tam 
Page 12 of 32 
8/15/18 
revealed a significant or trend increase in the apoptotic ratio by TUNEL studies in two out of 
three patients (Figure 5). No significant changes were observed in the proliferation index, 
measured by Ki-67.    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
In summary, these studies suggest that nerves exert trophic effects on normal epithelial cells 
through the regulation of basic cellular processes such as gene expression, protein translation, 
and metabolism. The loss of nerve function induces a pattern of gene expression associated 
survival and wound repair as well as a general atrophic phenotype in all experimental 
denervation conditions.  These studies provide proof of principle that nerves have the ability to 
affect cell growth directly. 
 
Our ability to measure meaningful changes in gene expression profiles in an orthotopic rat 
animal model and in a small group of human patients following chemical denervation with 
onaBoNT-A substantiate the need to apply these same methods to a greater extent in human 
prostate tissue following injection with onaBoNT-A.  Such studies would allow for the 
identification of potential molecular targets highlighted by the onaBoNT-A effect for future 
investigation. 
 
 
III. 
SIGNIFICANCE AND RATIONALE  
 
Our proposed intervention is the first randomized clinical trial comparing the effects of 
onaBoNT-A prostate injection versus alpha adrenergic antagonist medication for LUTS 
Non Neoplastic Epithelium
Figure 5. Effect of onaBoNT-A on human prostate 
epithelial tissue by TUNEL studies. 
Non Neoplastic Epithelium
Figure 5. Effect of onaBoNT-A on human prostate 
epithelial tissue by TUNEL studies. 


 
CPS BTX + Tam 
Page 13 of 32 
8/15/18 
associated with BPH.  Up to this point, clinical studies using onaBoNT-A in the prostate has 
been limited to patient’s refractory to α-1 adrenoceptor blocker therapy.  Our study will directly 
compare onaBoNT-A against α-1 adrenoceptor blockers as frontline therapy in a male veteran 
cohort suffering from moderate to severe LUTS.  Besides its obvious efficacy in patients’ 
refractory to α-1 adrenoceptor blocker therapy, onaBoNT-A injection has several potential 
advantages over oral agents.  Focal prostate injection has been shown to be safe and obviates 
the systemic side effects observed with α-1 adrenoceptor blockers (i.e. orthostatic hypotension, 
sexual dysfunction).  In addition, most clinical studies demonstrate a durable response to 
onaBoNT-A treatment exceeding 12 months.  Although this study is of modest length (i.e. total 4 
years), significant results could drive paradigm shifts in how LUTS associated with BPH is 
treated, even with regards to frontline therapy. 
 
Secondly, although sophisticated molecular techniques (i.e. LCM with Microarray Analysis) have 
been used by other investigators to characterize gene profile changes with BPH and LUTS, this 
will be the first study examining gene profile changes in BPH patients following treatment with 
the α-1 adrenoceptor blocker Tamsulosin or onaBoNT-A.  This study is important because scant 
knowledge exists on the true mechanisms by which α-1 adrenoceptor blockers like Tamsulosin 
or onaBoNT-A improve patient urinary tract symptoms and quality of life.  It is clear, however, 
that nerves not only regulate prostate growth and function but also account for LUTS that drive 
patients to seek therapy.  This investigation will utilize onaBoNT-A as a biological tool to identify 
potential novel mechanistic pathways for future investigation that will push the development of 
targeted therapy to benefit those patients refractory to all pharmacologic treatment.  Potential 
inflammatory pathways or neural sensory signaling alterations induced by BPH, which are 
modified by onaBoNT-A or Tamsulosin to improve symptoms via gene profile changes, can be 
explored by expert laboratories in the Texas Medical Center.  This is a highly collaborative 
project utilizing expertise across departments that will foster translational work from the 
laboratory to the patient.  Although not the primary goal of this study, we will also search for 
possible biological markers with prognostic value that could be confirmed in a future multi-center 
trial.    
 
IV. OBJECTIVES 
 
A 
Primary objective:   
 
The primary objective of this Phase 2 clinical research study is to compare the 
efficacy of 200 U onaBoNT-A injected into the prostate versus oral tamsulosin for the 
treatment of lower urinary tract symptoms caused by BPH in male veteran volunteers 
at the Michael E. DeBakey Veterans Affairs Medical Center, Houston (MEDVAMC). 
 
B 
Secondary objective: 
 
The secondary objective is to determine the impact of tamsulosin and onaBoNT-A on 
the pathologic parameters and RNA profiles of epithelium and stroma in BPH tissues. 
 
 
V. 
DRUG INFORMATON 
 
A 
Botulinum toxin A is marketed in two pharmaceutical distinct formulations that are not 
equipotent in terms of mouse units. Differences in species sensitivities to different 
botulinum neurotoxin serotypes preclude extrapolation of animal-dose activity 
relationships to human dose estimates. For the purposes of this study, patients are 


 
CPS BTX + Tam 
Page 14 of 32 
8/15/18 
treated with the formulation onaBoNT-A which is marketed in the U.S. as BOTOX® 
by Allergan. OnaBoNT-A is a purified neurotoxin complex supplied as a sterile, 
vacuum dried purified botulinum toxin type A, produced from fermentation of 
Clostridium botulinum type A. 
 
One unit of onaBoNT-A corresponds to the calculated median intraperitoneal lethal 
dose (LD 50) in mice. The specific activity of onaBoNT-A is approximately 20 
units/nanogram of neurotoxin protein complex. 
 
BOTOX® is the brand name for onaBoNT-A. For this study’s treatment injections, we 
will be using a total of 200 units of BOTOX® in 4 cc of preservative free normal saline, 
or 4 cc of preservative free normal saline for placebo. 
 
BOTOX® blocks neuromuscular transmission by binding to acceptor sites on motor or 
sympathetic nerve terminals, entering the nerve terminals, and inhibiting the release 
of acetylcholine.  This inhibition occurs as the neurotoxin cleaves SNAP-25, a protein 
integral to the successful docking and release of acetylcholine from vesicles situated 
within nerve endings. When injected intramuscularly at therapeutic doses, BOTOX® 
produces partial chemical denervation of the muscle resulting in a localized reduction 
in muscle activity.  In addition, the muscle may atrophy, axonal sprouting may occur, 
and extra-junctional acetylcholine receptors may develop.  There is evidence that 
reinnervation of the muscle may occur, thus slowly reversing muscle denervation 
produced by BOTOX®.  
 
BOTOX® is not expected to be present in the peripheral blood at measurable levels 
following IM or intradermal injection at the recommended doses.  The recommended 
doses of neurotoxin administered at each treatment session are not expected to 
result in systemic, overt distant clinical effects, i.e., muscle weakness, in patients 
without other neuromuscular dysfunction.  However, some clinical systemic effects 
have been shown by a single fiber electromyography after IM doses of botulinum 
toxins appropriate to produce clinically observable local muscle weakness. 
 
BOTOX® is contraindicated in the presence of infection at the proposed injection 
site(s), and in individuals with known hypersensitivity to any ingredient in the 
formulation. 
 
BOTOX® is supplied in a single-use vial.  Each vial contains 100 units of vacuum-
dried Clostridium botulinum type A neurotoxin components. 
 
Unopened vials of BOTOX® should be stored in a refrigerator (2° to 8° C) for up to 24 
months (or the expiration date on the product label).  Administer BOTOX® within four 
hours of reconstitution and within 30 minutes of drawing into syringe; during this 
period the reconstituted BOTOX® should be stored in a refrigerator (2° to 8° C).   
 
Additional BOTOX® information is available in the BOTOX® Prescribing Information 
package insert. 
 
B 
Tamsulosin, marketed as Flomax®, is an alpha adrenoreceptor-blocker that is used to 
improve symptoms associated with an enlarged prostate (BPH). It works by relaxing 
muscles in the bladder and prostate.  This may improve urine flow rates and decrease 
urinary symptoms such as hesitancy and urgency. 


 
CPS BTX + Tam 
Page 15 of 32 
8/15/18 
 
VI 
PHASE OF STUDY   Phase 2 
 
 
VII 
ELIGIBILITY CRITERIA 
 
A 
Inclusion 
 
1 
Males at least 50 years of age 
2 
AUA Symptom Score greater than 8  
3 
Voided volume greater than125 ml  
4 
Maximum urinary flowrate less than 15 ml/sec.  
5 
Must agree to all procedures and willfully consented 
 
B 
Exclusion 
 
1 
Any prior surgical intervention or use of 5-alpha reductase medical treatment for 
BPH   
2 
Current diagnosis of acute or chronic prostatitis (which may cause LUTS that 
mimic BPH) 
3 
Previous exposure to onabotulinumtoxinA 
4 
Overactive bladder without obstructive symptoms (i.e. decrease in force of 
stream, hesitancy, intermittency, post-void dribbling);  
5 
Active urinary tract disease or biopsy of the prostate within the past 6 weeks; 
6 
Two documented urinary tract infections of any type in the past year (UTI 
defined as greater than 100,000 colonies per ml urine from midstream clean 
catch or catheterized specimen) 
7 
Uncontrolled diabetes 
8 
History of bladder calculi (stones) 
9 
Penile prosthesis or artificial urinary sphincter [placement] 
10 
Documented bacterial or acute prostatitis within the past year 
11 
Episode of unstable angina pectoris, myocardial infarction, transient ischemic 
attack, or cerebrovascular accident (stroke) within the past 6 months 
12 
Known primary neurologic conditions such as multiple sclerosis, myasthenia 
gravis or Parkinson’s disease, or other neurological diseases known to affect 
bladder function 
13 
History or current evidence of carcinoma of the prostate or bladder, pelvic 
radiation or surgery, urethral stricture, or bladder neck obstruction 
14 
Cancer that is not considered cured, except basal cell or squamous cell 
carcinoma of the skin (cured defined as no evidence of cancer within the past 5 
years) 
15 
Any serious medical condition that is likely to impede successful completion of 
the study, such as certain mental disorders, hypersensitivity to 
onabotulinumtoxinA or anesthetics used in the study, syncope 
16 
Daily use of a pad or device for incontinence required  
17 
Interested in future fertility 
18 
PVR greater than 350 ml 
19 
Serum prostate specific antigen level greater than 8 ng/ml (Hybritech).  For 
those with a PSA between 4-8 ng/ml, the PSA elevation must be considered to 


 
CPS BTX + Tam 
Page 16 of 32 
8/15/18 
be from a benign cause in the opinion of the PI.  This decision can be based on 
PSA velocity, previous TRUS biopsy, percent free PSA, or other clinical 
estimations in keeping with sound urologic care 
20 
No alpha-blockers in the past 7 days before biopsy. 
21 
Has taken phenylephrine, pseudoephedrine, imipramine, an anticholinergic, or 
cholinergic medication within the past 2 weeks  
22 
Has taken estrogen, androgen, any drug producing androgen suppression, or 
anabolic steroids within the past 4 months 
23 
Is taking aminoglycosides or any drug that interfere with neuromuscular 
transmission. Eaton-Lambert syndrome, hemophilia, hereditary clotting factors 
deficiency, or bleeding diathesis 
24 
Must be off aspirin, NSAIDS, and Coumadin for 7 or more days prior to 
onabotulinumtoxinA injection 
25 
Enrolled in another treatment trial for any disease within the past 30 days 
 
 
VIII DESIGN 
 
This Phase 2 clinical research trial is a double-blind, randomized, placebo-controlled, 
parallel-group study to compare the treatment effects of onaBoNT-A 200 U versus 0.4 mg 
per day of oral tamsulosin in male veterans diagnosed with moderate to severe LUTS 
(AUASS equal to or greater than 8) associated with BPH.  A total of 74 volunteers will be 
recruited to participate in this clinical trial.  Volunteers will include only males who are 
greater than 50 years of age and diagnosed with LUTS associated with BPH.  They are 
veterans who visit the MEDVAMC.  There are no eligibility restrictions as to race or 
ethnicity.   
 
Transition zone biopsies will be performed at Visit 2, 30 days before treatment, and again 
at 3 months post-treatment.  A total of 6 biopsy cores (i.e. 3 cores from the left and right 
transition zone) will be obtained from each volunteer.  Prostate biopsy cores will be rapidly 
snap frozen in liquid nitrogen in coded and labeled containers and sent to Dr. Gustavo E. 
Ayala's laboratory located at University of Texas Health Science Center - Houston Medical 
School for further processing. 
 
A 
Randomization  
 
Volunteers will be randomized using a blocked randomization approach by the 
MEDVAMC Research Pharmacy to either:  ARM 1: onaBoNT-A 200 U prostate 
injection and placebo oral capsule daily or ARM 2: Placebo prostate injection (saline) 
and tamsulosin 0.4 mg capsule daily.  Subjects will be randomized into one of the two 
treatment arms, using a block size of 4. The order in which the treatments are 
assigned in each block is randomized and this process is repeated for consecutive 
blocks of subjects until all subjects are randomized.  This process ensures that after 
every fourth randomized subject, the number of subjects in each treatment group is 
equal.  The MEDVAMC will prepare both pills (i.e. tamsulosin and placebo pill) and 
injections (i.e. onaBoNT-A and placebo saline injection) so that the study subject, 
investigator and all personnel treating or evaluating the subject will be blinded to 
treatment allocation. 
 
 


 
CPS BTX + Tam 
Page 17 of 32 
8/15/18 
B 
Schedule Of Events During Treatment Protocol  
 
 
C 
Procedures  
 
1 
Visit 1: Screening 
 
• 
Informed consent will be obtained prior to any research-related procedures. 
• 
A physical including a digital rectal exam (DRE) will be performed. 
• 
The subject's medical history and concomitant medications will be 
discussed and documented. 
• 
The subject's vital signs will be taken and documented. 
• 
The subject will complete the following questionnaires: 
• 
The AUA symptom score 
• 
BPH Impact Scale 
Tests/Time 
Visit 1: 
Screening 
Visit 2:  
Biopsy 
Visit 3: 
Injection 
(4 weeks  
Post- 
biopsy ± 3 
days) 
Visit 4:  
Telephone 
Visit  
(Day 3 Post 
Prostate 
Injection) 
Visit 5: 
Telephone Visit   
(1 Week Post- 
Injection   
± 3 days) 
Visit 6:       
(4 Weeks 
Post- 
Injection ± 3 
days) 
Visit 7:   
End of 
Study       
(3 months 
Post 
Injection ± 
3 days) 
Physical with DRE 
X 
 
 
 
 
 
X 
Medical History  
X 
 
 
 
 
 
 
Vital signs 
X 
X 
X 
 
 
X 
X 
Flowrate 
X 
 
 
 
 
X 
X 
PVR 
X 
 
 
 
 
X 
X 
PSA 
X 
 
 
 
 
 
X 
CBC /platelet count 
X 
 
 
 
 
 
 
Urinalysis (dipstick) 
X 
X 
X 
 
 
X 
X 
Biopsy (Transrectal 
Ultrasound Guided - 
TRUS) 
 
X 
 
 
 
 
X 
Prostate Volume 
 
X 
 
 
 
 
X 
Antibiotic 
 
X 
X 
 
 
 
X 
Fleets Enema 
 
X 
X 
 
 
 
 
Anesthesia 
(periprostate block) 
 
X 
X 
 
 
 
 
onaBoNT-A or saline 
injection via TRUS 
 
 
X 
 
 
 
 
Informed Consent 
X 
 
 
 
 
 
 
Antibiotic dispensing 
X 
X 
 
 
 
X 
 
Instructions to stop 
alpha blocker meds 7 
days prior to biopsy 
X 
 
 
 
 
 
 
Drug/Placebo 
dispensing 
 
 
X 
 
 
X 
 
Drug/Placebo 
accountability 
 
 
 
 
 
X 
X 
AUA Symptom score 
X 
 
 
 
 
X 
X 
BPH Impact Scale 
X 
 
 
 
 
X 
X 
Bladder Function 
X 
 
 
 
 
X 
X 
Erectile Function 
X 
 
 
 
 
X 
X 
Ejaculatory Function 
X 
 
 
 
 
X 
X 
Adverse Events 
 
 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 


 
CPS BTX + Tam 
Page 18 of 32 
8/15/18 
• 
Bladder Function 
• 
Erectile Function 
• 
Ejaculatory Function 
• 
The subject will undergo uroflow testing and will provide a post-void 
residual urine measurement. 
• 
Blood (about 10 ccs or 2 teaspoons) will be drawn for CBC with platelets 
and PSA testing. 
• 
A urinalysis (dipstick) will be performed. 
• 
Dispense a Bactrim DS (antibiotic) 160/800mg tablet orally twice a day 
[Cipro (generic is permissible) 500 mg twice a day] with instructions to take 
for 1 day prior to biopsy, day of biopsy, and for 1 day following biopsy (total 
of 3 days). 
• 
Subjects will be instructed to stop taking alpha blocker medications 7 days 
prior to biopsy. 
 
2 
Visit 2: Biopsy 
 
• 
The subject's concomitant medications will be discussed and documented. 
• 
The subject's vital signs will be taken and documented. 
• 
A urinalysis (dipstick) will be performed to ensure that no infection is noted 
or suspected. 
• 
Dispense an antibiotic  
• 
Prostate size is measured via transrectal ultrasound on patients after 
receiving a Fleet’s enema the morning of the examination. 
• 
Transition zone biopsies will be performed. 
 
3 
Visit 3: Injection (4 weeks post-biopsy, ± 3 days) 
 
• 
The subject's concomitant medications will be discussed and documented. 
• 
The subject's vital signs will be taken and documented. 
• 
Any adverse events experienced by the subject will be documented. 
• 
Injection Procedures: onaBoNT-A solution does not contain a preservative, 
it should be administered within 4 hours after reconstitution and within 30 
minutes of drawing into the syringe.  The drug should be stored in a 
refrigerator when not in use during this period. 
− 
Patient Preparation 
a. Patient is examined and submits urine for urinalysis which is 
examined by standard dipstick analysis or microscopic 
examination prior to randomization and preparing onaBoNT-A 
solution to ensure that no infection is noted or suspected. 
b. Prostate size is measured via transrectal ultrasound on patients 
after receiving a Fleet’s enema the morning of the examination.  
The patient is placed in the lateral decubitus position with knees 
tucked against the chest and the transrectal probe introduced.  A 
multi-planar probe that gives a 112° sector image is used to allow 
viewing in both transverse and longitudinal planes without moving 
the probe.  The prostate size is measured initially using the height 
(H), width (W), and length (L) functions available on the ultrasound 
machine.  Scanning of the prostate is carried out in two planes at 


 
CPS BTX + Tam 
Page 19 of 32 
8/15/18 
right angles to each other.  The height and width are identified on 
a transverse image and recorded.  The length is identified and 
recorded in the perpendicular longitudinal plane.  The volume is 
calculated as a machine function using the formula H x W x L x 
π/6 and recorded on hard copy.   
− 
OnabotulinumtoxinA or Saline placebo Injection 
a. Anesthesia is delivered according to the clinical practice of the 
center PI.  Transrectal periprostatic block may be used with a 5 ml 
bolus of 1% lidocaine given just superiolateral to each seminal 
vesicle as visualized using the transrectal sound probe in the 
sagittal plane.  The bolus is given via an appropriately long 22-
gauge needle.  
b. The onabotulinumtoxinA toxin type A solution is given via the 
same approach using a second needle.   
i. 
For men randomized to the 200 unit onaBoNT-A arm, 50 units 
per 1.0 ml volume is given at the following points of the 
transitional zone:  left and right inferior and superior 
transitional zone.   
ii. For men randomized to the placebo arm, 1.0ml of saline is 
given at the following points of the transitional zone:  left and 
right inferior and superior transitional zone.   
c. The needle is passed from posterior to anterior through the 
peripheral zone (PZ) into the base of the prostate at the transition 
zone/central zone junction on the left side.  The needle is 
advanced to superior aspect of the transition zone. 
d. Prior to injection of onabotulinumtoxinA the needle is aspirated to 
insure that there is no blood return.  This is repeated prior to each 
injection. 
e. The initial 1.0 ml of solution is first deposited at the superior 
(bladder base) transition zone (TZ).  The needle is withdrawn to 
the inferior (apex) transition zone/central zone junction and the 
second 1.0 ml of solution is deposited on the same side as the 
needle is withdrawn. 
f. The needle is passed from posterior to anterior through the 
peripheral zone (PZ) on the right side into the base of the prostate 
at the transition zone/central zone junction on the left side.  The 
needle is advanced to superior (bladder base) aspect of the 
transition zone. 
g. The 1.0 ml of solution is first deposited at the inferior (apex) 
transition zone (TZ).  The needle is withdrawn to the inferior 
(apex) transition zone/central zone junction and the second 1.0 ml 
of solution is deposited on the same side as the needle is 
withdrawn. 
h. The needle, syringe, and vial are disposed of in a biohazard 
container according to institutional policy, and a witness signs a 
form. 
i. 
After the injection, the patient remains in the clinic until a 
spontaneous void has occurred. 
• 
Subjects will receive an adequate supply of tamsulosin/placebo with 
instructions on dosing. 


 
CPS BTX + Tam 
Page 20 of 32 
8/15/18 
• 
Because of the theoretical possibility of diffusion of onabotulinumtoxinA into 
seminal fluid, and no evidence to the contrary, those patients who engage 
in sexual intercourse are required to use condoms for 48 hours after the 
injection. 
 
4 
Visits 4 (Day 3 post-injection)  
 
The subjects will be contacted by telephone 3 days after injection to monitor for 
symptoms of infection or bleeding. 
 
5 
Visits 5 (1 Week ± 3 days post-injection) 
 
The subjects will be contacted by telephone 1 week after injection to collect 
medical events, concomitant medication update, and status. 
 
6 
Visit 6: (4 Weeks post-injection ± 3 days) 
 
• 
The subject's concomitant medications will be discussed and documented. 
• 
The subject's vital signs will be taken and documented. 
• 
Any adverse events experienced by the subject will be documented. 
• 
The subject will undergo uroflow testing and will provide a post-void 
residual urine measurement. 
• 
A urinalysis (dipstick) will be performed. 
• 
The subjects returned drug product packaging will be reviewed and 
discussed with him.  A new supply of tamsulosin will be dispensed. 
• 
The subject will complete the following questionnaires: 
• 
The AUA symptom score 
• 
BPH Impact Scale 
• 
Bladder Function 
• 
Erectile Function 
• 
Ejaculatory Function 
• 
Dispense an antibiotic  
 
7 
Visit 7: End of Study (3 months post-injections ± 3 days) 
 
• 
A physical including a digital rectal exam (DRE) will be performed. 
• 
The subject's concomitant medications will be discussed and documented. 
• 
Any adverse events experienced by the subject will be documented. 
• 
The subject's vital signs will be taken and documented. 
• 
The subjects returned drug product packaging will be reviewed and 
discussed with him. 
• 
The subject will complete the following questionnaires: 
• 
The AUA symptom score 
• 
BPH Impact Scale 
• 
Bladder Function 
• 
Erectile Function 
• 
Ejaculatory Function 
• 
The subject will undergo uroflow testing and will provide a post-void 
residual urine measurement. 


 
CPS BTX + Tam 
Page 21 of 32 
8/15/18 
• 
Blood (about 5 ccs or 1 teaspoon) will be drawn for PSA testing. 
• 
A urinalysis (dipstick) will be performed. 
• 
Transition zone biopsies will be performed and the prostate volume will be 
measured. 
 
 
IX 
BIOLOGICAL SPECIMENS 
 
A 
Prostate tissue will be collected at the time biopsy to conduct gene array studies to 
determine the effects of onaBoNT-A and tamsulosin on the genetic profile of human 
normal and BPH tissues.  The specimens will be coded and will not include any 
subject identifying information. Testing on the tissue specimens will be conducted in 
Dr. Ayala's laboratory.  The specimens will be stored until the end of the study at 
which time any unused specimens will be destroyed. These specimens will not be 
released to anyone not listed as an investigator on the protocol, nor will they be sold 
or transferred to any third party. If at any time the subject withdraws from this study, 
he will not be able to get the specimens back.  Upon written request to Dr. Smith, the 
stored samples will be destroyed but the data collected up until that time will not be 
deleted. 
 
The gene expression profiles in epithelial and stromal BPH cells of the prostates 
injected with onaBoNT-A and saline (i.e. Tamsulosin group), respectively, will be 
compared.  Pre and post treatment biopsies will be frozen for laser capture 
microdissection and subsequent RNA extraction. All 6 biopsies will be frozen to 
guarantee adequate representation of both epithelia and stromal compartments of 
BPH.  These sections will be used to orient laser capture microscopy in immediate 
frozen serial sections.  Epithelial and stromal cells of the BPH nodules will be laser 
captured. Laser captured microdissection (LCM) tissues will be processed for gene 
expression profiling using Agilent Oligo Microarrays.  Samples will be hybridized on a 
4x44K slide formatted with the Whole Human Genome Oligo Microarray Kit that 
contains 41,000 unique genes and transcripts. Gene expression profiles will be 
evaluated using BioConductor software that will be used to process and normalize 
data.  Significant differences in mean mRNA levels between groups will be 
determined with two-sided t-tests.  Visualization of data (color maps) will be 
performed using Cluster and Java TreeView software.  We will search for GO 
annotation terms in gene sets and will establish protein interaction networks analysis 
using the Human Protein Reference Database as we have reported previously and 
visualization will use Cytoscape software. Our next step is always to confirm the array 
analyses using qRT-PCR using pre-designed and validated primers when available. 
Otherwise primers will be designed and validated as described previously in 
numerous publications by Dr. Ittmann and our prostate research group. As a result of 
this study we will identify differential gene expression profiles in epithelial and stromal 
cells in the onaBoNT-A versus Tamsulosin treated prostates.  In addition, we will be 
able to assess changes in gene expression profile before and after treatment with 
either agent.  This analysis will permit us to assess whether Tamsulosin and 
onaBoNT-A have similar effects on human tissues as we have identified in rats.  
These results will serve as substantiation for further human clinical trials. 
 
In addition to determining the effects of onaBoNT-A and tamsulosin on the genetic 
profile of human normal and BPH tissues, another goal is to determine the effects of 


 
CPS BTX + Tam 
Page 22 of 32 
8/15/18 
Tamsulosin and onaBoNT-A on the human BPH prostate tissue proliferation, 
apoptosis, innervation, stromal response, and angiogenesis. 
 
1 
Apoptosis: The apoptotic rates of normal and BPH epithelial cells will be 
measured, as onaBoNT-A denervation is known to induce apoptosis. For the 
detection of apoptosis in situ will use the TUNEL technique. Apoptotic bodies will 
be counted under a light microscope (x400).  The area with highest positive 
stain within areas of BPH will be selected for counting. The number of apoptotic 
bodies will be determined in a total of approximately 1000 cells, normalized to 
100 cells and defined as apoptotic index (AI). We expect to see an increase in 
apoptosis with onaBoNT-A compared to tamsulosin treatment.  
 
2 
Proliferation: The proliferation rate of BPH cells in human tissues will be 
determined using the immunoperoxidase method with antibodies against Ki-67. 
The proliferation index (PI) will be defined as the ratio of KI-67 positive BPH 
cells to total prostate  BPH epithelial cells in the highest positive stain fields (at 
least 2000 cells), using a microscopic grid at 400x magnification. We expect to 
see a decrease in proliferation. 
 
3 
Nerves: To measure nerve density in these specimens we will immunostained 
with PGP9.5 antibodies using IHC Detection System as described previously. 
Total area of nerves will be quantified visually and with image analysis. We 
expect to identify a decrease in the density of nerves following onaBoNT-A 
treatment.  It is possible that we will identify a time dependent compensatory 
effect. 
 
4 
Reactive stroma formation: Previous studies suggest that paracrine stromal 
interactions may be important factors in inducing and maintaining BPH. 
Therefore, we will determine if the stroma shows changes induced by 
denervation with onaBoNT-A. Tissue staining will be evaluated following 
procedures we have reported previously for quantitative determination of 
expression indexes for reactive stroma markers.  A decrease in the stromal 
reactive response to BPH is expected.  
 
5 
Angiogenesis: Angiogenesis and neurogenesis are concomitant processes in 
embryologic development and wound response. Therefore we will look at the 
effect of denervation with onaBoNT-A on vessel density using standard vessel 
count methodology. 
 
B 
Blood samples collected during the screening visit are routine for patients with BPH 
and LUTS and will be handled according to standard of practice.  The test results will 
be included in the subject's research and medical charts. 
 
C 
Urine specimens collected for dipstick analysis during the screening visit are routine 
for patients with BPH and LUTS and will be handled according to standard of 
practice.  The test results will be included in the subject's research and medical 
charts. 
 
 
 


 
CPS BTX + Tam 
Page 23 of 32 
8/15/18 
X. 
STATISTICAL ANALYSIS  
 
The primary endpoint, change in AUASS score from baseline to 3 months, between the 
onaBoNT-A and tamsulosin groups will be analyzed using the 2-sided independent t-test.   
 
Baseline measures of the data such as age and ethnicity as well as secondary endpoints 
will be examined using summary statistics to determine if any differences exist between 
the 2 study groups.     
 
Graphical methods will be used to access distributional properties of the secondary 
endpoints (urinary flow rate, serum PSA, prostate volume symptom relief, post-void 
residual, BPH impact score, Bladder Function, Erectile Function and Ejaculatory Function 
questionnaires). If extreme departures from normality are found, use of non-parametric 
analytical methods such as the Wilcoxon rank-sum test or transformation of the data will be 
considered.  Questionnaire scores will be examined for reliability using Cronbach’s alpha.  
The distributions of the scores will be examined to see if they are evenly distributed around 
the mid-point of the scales or are clustered at the top or bottom of the scales (ceiling or 
floor effect).  If strong ceiling or floor effects are found, this could limit the usefulness of 
these measures.  Changes in these secondary endpoints will be assessed using either the 
independent t-test or its non-parametric equivalent, the Wilcoxon rank sum-test.  Statistical 
analysis will be done using SAS, version 9.2 (SAS Institute, Cary NC). 
 
The endpoints apoptotic index, proliferation index, nerve density, stromal reactive indexes, 
and vessel density, will be checked for their distributional properties using the methods 
described for the data collected in Aim 1.  Change from baseline to 3 months will be 
analyzed using either the 2 sided t-test or the Wilcoxon rank sum test. 
 
Statistical analysis of expression data will be performed similar to that of previous studies 
44, using public datasets of pathway-associated genes to identify general pathways 
involved. Our data indicates that epithelial cells are directly targeted by nerves. 
Denervation induces generalized atrophy of the epithelium and a significant decrease in 
protein production that cannot be reversed through supraphysiologic levels of testosterone. 
Mechanistically, denervation induces a translational and metabolic shutdown of the 
epithelial cells, which undergo a non-proliferative and more stem like phenotype with 
epithelial mesenchymal transformation.  Particular emphasis will be given to specific 
markers within categories of genes we hypothesize onaBoNT-A treatment will have a 
greater impact given evidence within the BPH literature and our own experience with 
onaBoNT-A in rat and human prostate tissues:  1. Immune/Inflammation: IL-8, B cell 
homing chemokine, SRF:Serum response factor (c-fos serum response element-binding 
transcription factor), and MIC-1; 2. translation and translation initiation factor activity (signal 
transducer and activator of transcription 3, eukaryotic translation initiation factor 4A1, 
eukaryotic translation elongation factor 1 gamma*, eukaryotic translation initiation factor 3, 
subunit B, C and F); 3. Metabolic pathways (ST8 alpha-N-acetyl-neuraminide alpha-2,8-
sialyltransferase);] 4. Growth Factors: IGF-2, FGF-2, IGF-I-R; and 5. Androgen Regulation: 
AR, ERβ, RLS-HD, AKR1C1, AKR1C2, AR:ERβ ratio, AKR1C1:AKR1C2 ratio.  
Corroborative studies will be performed with qPCR, immunofluorescence, and 
immunohistochemistry experiments.     
 
 
 
 


 
CPS BTX + Tam 
Page 24 of 32 
8/15/18 
XI. SAMPLE SIZE  
 
Mean AUA score reduction in the alpha blocker group is expected to be at most 9.6 with a 
standard deviation of 6.3 based on published results of a randomized trial comparing 
tamsulosin versus placebo.29  However, that same study showed a strong pill placebo 
effect with a mean reduction of 5.5, resulting in a treated reduction of 4.1 above the 
placebo group. Another study13, comparing botulinum toxin to placebo, showed a mean 
score reduction in the botulinum group of 15.2 and no placebo change.  For our study, we 
will assume a mean reduction of 15.2 in the onaBoNT-A group which is 9.7 more than the 
pill placebo effect, a mean reduction of 9.6 in the alpha blocker group and a standard 
deviation of 6.3 for both groups. Based on these assumptions, a sample size of 29 
subjects per group will achieve 90% power to detect a difference of 5.6 with an alpha level 
of 0.05 using the 2-sided independent t-test. Sample size calculations were done using 
PASS 2008 software (Hintze, J.  (2008). NCSS, LLC.  Kaysville, Utah.  www.ncss.com). 
  
The drop-out rate in the alpha-blocker study was as large as 20% and our own experience 
with onabotulinumtoxinA (onaBoNT-A) in the MIST-2 trial has demonstrated a dropout rate 
of 14%.  So adjusting our sample size for an expected dropout rate of 20%, we will enroll 
37 patients into the onaBoNT-A and tamsulosin groups for a total of 74 patients.  To 
address some of the problems with possible attrition bias, we will use intent to treat 
analysis and patients will be kept in the study as long as possible even if they are no 
longer on treatment.  We will also compare results between the intent to treat groups and 
the subjects who completed treatment to determine if differences exist. 
 
 
XII. RETENTION AND DROPOUT/WITHDRAWAL 
 
Minimal dropout or loss to follow-up is expected in this cohort, especially given the short 
follow-up.  However, if a patient drops out before 4 weeks, he will be replaced so that the 
required sample size is realized. For purposes of tracking the feasibility of conducting a 
trial of treatment with onaBoNT-A, reasons for dropout or withdrawal will be documented. 
 
 
XIII. CRITERIA FOR DISCONTINUING THE STUDY 
 
A 
Subjects unable to tolerate [tamsulosin or] onaBoNT-A due to side effects. 
B 
Subjects can request removal from the study for any reason at any time. 
C 
Subjects may be withdrawn at any time at the discretion of the investigator for safety, 
compliance, or other reasons. 
 
A discontinuation occurs when an enrolled subject ceases participation in the study, 
regardless of the circumstances, prior to completing the protocol.  
 
The reasons for a subject discontinuing from the study will be recorded in the Case Report 
Form. 
 


 
CPS BTX + Tam 
Page 25 of 32 
8/15/18 
XIV. DATA ANALYSIS 
 
Analysis will begin with descriptive statistics. Implausible and missing values will be 
identified and double-checked for accuracy. Parametric methodology will be used unless 
measurements have tested positive for violation of normality assumption. The differences 
between the study subjects groups will be evaluated using the paired-samples t-tests. The 
clinical outcomes will be compared using Fisher’s test. The criterion for significance (alpha) 
has been set at 0.05.  All tests are 2-tailed, which means that an effect in either direction 
will be interpreted. Analysis will be conducted using SPSS 17.0. (“SPSS Statistics 17.0”, 
SPSS Inc., Chicago, IL, 2008). 
 
 
XV. RISKS AND DISCOMFORTS  
 
A 
BOTOX®:  It is expected that some participants may have some or all of the following 
side effects when given BOTOX®. Other side effects may occur which were not seen 
before. Side effects are usually temporary and manageable. However, it is possible 
they could cause serious disease or death. The study may include risks that are 
unknown at this time. 
 
There have been rare reports of serious and/or immediate or even deadly abnormally 
sensitive reactions after treatment with BOTOX. These reactions include allergic 
reaction, skin rash, itching, swelling, and difficulty in breathing. 
 
It is a rare possibility that the injection of BOTOX® could lead to botulism. The classic 
symptoms of botulism include double vision, blurred vision, drooping eyelids, slurred 
speech, difficulty swallowing, dry mouth, and muscle weakness. The doctor's 
examination may reveal that the gag reflex and the deep tendon reflexes like the 
knee jerk are decreased or absent. 
 
There have been rare reports of sudden death, sometimes associated with difficulty in 
swallowing or pneumonia. There have also been rare reports of heart problems 
(including irregular heart beats and heart attack, some resulting in death). Some of 
these patients were already at risk for heart disease. It is not known if BOTOX 
actually caused these problems. 
 
It should not be used when infection is present at the injection site or in people known 
to be abnormally sensitive to BOTOX. 
 
The following events have been observed since it has been marketed: skin rash, 
itching, and allergic reaction. In general, these side effects occur within the first week 
following injection and, while usually temporary, they may last several months. Pain, 
tenderness, or bruising around the injection site may also occur. Local weakness of 
the injected muscle(s) is expected. Weakness of nearby muscles may also occur due 
to spread of BOTOX. 
 
There are also possible risks of urinary retention, fecal incontinence and infection as 
a result of intraprostatic onabotulinumtoxinA injection. 
 


 
CPS BTX + Tam 
Page 26 of 32 
8/15/18 
BOTOX contains albumin, which comes from human blood. Although the blood is 
rigorously tested, there is an extremely remote risk for the transmission of viruses and 
similar infectious agents. 
 
B 
Flomax®: Possible side effects of FLOMAX may include: 
 
Flomax capsules may cause a sudden drop in blood pressure upon standing, 
especially after the first dose or when changing doses.  Symptoms may include 
fainting, dizziness, and lightheadedness.  
 
Allergic reactions may include rash, itching, and hives. Rare and more serious allergic 
reactions may also include swelling of face, tongue, or throat, and difficulty breathing.  
 
Priapism (a painful erection that will not go away) may occur.  
 
During cataract surgery, a condition called intra-operative floppy iris syndrome (IFIS) 
can happen if FLOMAX is being taken or has been taken in the past.  
 
Common side effects of FLOMAX capsules may include runny nose, dizziness, and 
decreased semen. 
 
Adverse experiences with Lidocaine® are, in general, dose-related and may result 
form high plasma levels caused by excessive dosage, rapid absorption or inadvertent 
intravascular injection, or may result from a hypersensitivity, idiosyncrasy or 
diminished tolerance on the part of the patient.   
 
Central nervous system symptoms that may be experienced are lightheadedness, 
nervernousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, 
blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, 
tremors, convulsions, unconsciousness, respiratory depression and arrest.   
 
Cardiovascular manifestations are usually depressant and are characterized by 
bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac 
arrest. 
 
Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or 
anaphylactoid reactions.  These reactions to Lidocaine are extremely rare. 
 
C 
Lidocaine® 
 
Adverse experiences with Lidocaine® are, in general, dose-related and may result 
form high plasma levels caused by excessive dosage, rapid absorption or inadvertent 
intravascular injection, or may result from a hypersensitivity, idiosyncrasy or 
diminished tolerance on the part of the patient.   
 
Central nervous system symptoms that may be experienced are lightheadedness, 
nervernousness, apprehension, euphoria, confusion, dizziness, drowsiness, tinnitus, 
blurred or double vision, vomiting, sensations of heat, cold or numbness, twitching, 
tremors, convulsions, unconsciousness, respiratory depression and arrest.   
 


 
CPS BTX + Tam 
Page 27 of 32 
8/15/18 
Cardiovascular manifestations are usually depressant and are characterized by 
bradycardia, hypotension, and cardiovascular collapse, which may lead to cardiac 
arrest. 
 
Allergic reactions are characterized by cutaneous lesions, urticaria, edema, or 
anaphylactoid reactions.  These reactions to Lidocaine are extremely rare. 
 
D 
Antibiotic 
1 
Bactrim DS may cause allergic reactions: hives, difficult breathing, and swelling 
of face, lips, tongue, or throat.  It may also cause diarrhea, pale skin, rapid heart 
rate, trouble concentrating, sudden weakness, fever, chills, new or worsening 
cough, vomiting, headache, jaundice, skin rash. 
2 
Cipro may cause hypoglycemia and mental health issues, such as, disturbances 
in attention, disorientation, agitation, nervousness, memory impairment, and 
delirium.  Other side effects may be pounding heart or very fast pulse, dizziness, 
pale skin, feeling shaky, sweating, unusual hunger, trembling, headaches, 
irritability, unusual anxiety, tendinitis, and changes in sensation and nerve 
damage. 
 
E 
Transrectal Ultrasound (TRUS): The ultrasound rarely results in physical discomfort 
but some anxiety before and during the procedure may be experienced. 
 
F 
Blood Draw: Inserting needles into veins for collecting blood may be uncomfortable.  
Risks include slight bruising at the injection site, fainting, the formation of a small 
blood clot or swelling of the vein and surrounding tissue, bleeding from the site, and 
the remote possibility of infection at the site of the needle puncture.  Fainting is 
usually harmless, of short duration, and typically produces feelings of weakness, 
sweating, slowing of the heart rate and an abnormal decrease in blood pressure. 
Care will be taken to avoid these complications. 
 
G 
Questionnaires:  Completing the questionnaires may cause the subject to have or to 
experience some level of emotional discomfort due to the personal nature of the 
questions.  The study doctor and staff will maintain a professional and caring attitude 
while administering the questionnaires. 
 
H 
Loss of Confidentiality: The loss of confidentiality regarding research information is a 
possibility; although, the risk is very small. 
 
I 
Birth Control:  Because of the theoretical possibility of diffusion of onabotulinumtoxinA 
into seminal fluid, and no evidence to the contrary, those patients who engage in 
sexual intercourse are required to use condoms for 48 hours after the injection. 
 
 
XVI.  BENEFITS 
 
A 
Subject: Patients with LUTS should see a benefit to onaBoNT-A injection within one 
week after injection.  This may be manifested by a decrease in AUA symptom scores 
and an increase in urinary flowrate. 
 
B 
Society: A secondary benefit of this study is to society because we will gain insight 
into the molecular changes in BPH and bladder tissues induced by onaBoNT-A 


 
CPS BTX + Tam 
Page 28 of 32 
8/15/18 
injection.  The results of this study could potentially lead to novel treatments for BPH 
and LUTS. 
 
C 
Risk to Benefit Ratio: The risks of the injection are minimal (i.e. bleeding, infection) 
and are mitigated in this protocol (i.e. no blood thinner medications, peri-injection 
antibiotics).  The benefit of offering novel, minimally invasive treatments for BPH and 
LUTS far exceed the risk of prostate injection. 
 
XVII.  ALTERNATIVES 
 
The alternative to participating in this research study is watchful waiting, medical therapy 
with approved drugs, or surgical treatment.   
 
 
XVIII. COSTS TO SUBJECTS 
 
Other than the study investigative products and anesthesia, all events and procedures are 
considered standard of care for this patient population. 
 
 
XIX. PAYMENT TO SUBJECTS 
 
Subjects will not receive payment for participating in this study. 
 
 
XX. ADVERSE EVENT REPORTING  
 
Adverse Events will be reported in accordance to all applicable FDA, ICH, and IRB rules, 
regulations, and guidelines.  
 
 
XXI. DATA HANDLING AND RECORD KEEPING 
 
A 
Case Report Forms 
 
B 
Protocol-specific data will be collected on Case Report Forms (CRFs). The completed 
dataset should not be made available in any form to third parties, except for 
authorized representatives of appropriate Health/Regulatory Authorities, without 
written permission from BCM. 
 
C 
Record Retention 
 
D 
To enable evaluations and/or audits from Health Authorities/BCM, the investigator 
agrees to keep records, including the identity of all participating patients (sufficient 
information to link records; e.g., hospital records), all original signed informed consent 
forms, copies of all CRF’s, and detailed records of drug disposition.  To comply with 
international regulations, the records should be retained by the investigator in 
compliance with regulations. 
 
 


 
CPS BTX + Tam 
Page 29 of 32 
8/15/18 
XXII. ETHICS AND GOOD CLINICAL PRACTICE 
 
This study must be carried out in compliance with the protocol and the principles of 
Good Clinical Practice (GCP) in accordance with International Conference on 
Harmonisation (ICH) Tripartite Guidelines for Good Clinical Practice and the US 21 Code 
of Federal Regulations dealing with clinical studies. 
 
The investigator agrees to adhere to the instructions and procedures described in it and 
thereby to adhere to the principles of GCP that it conforms to. 
 
A 
Institutional Review Board (IRB) and Other Institutional Review Committees 
 
Before implementing this study, the protocol, the proposed informed consent form 
and other information to subjects, must be reviewed by a properly constituted and 
other institutional review committees, as required. A signed and dated statement that 
the protocol and informed consent document(s) have been approved by the IRB and 
committees will be provided to the FDA in a general correspondence submission. 
 
B 
Informed Consent Process 
 
Subjects will be identified from those visiting in the Urology clinic at MEDVAMC. The 
investigator or his designated personnel must explain to each subject (or legally 
authorized representative) the nature of the study, its purpose, the procedures 
involved, the expected duration, the potential risks and benefits involved and any 
discomfort it may entail. Each subject must be informed that participation in the study 
is voluntary and that he/she may withdraw from the study at any time and that 
withdrawal of consent will not affect his/her subsequent medical treatment or 
relationship with the treating physician. Informed consent will be obtained in every 
patient prior to performing a biopsy or any protocol-related procedures or tests.  
 
This informed consent should be given by means of a standard written statement, 
written in non-technical language. The subject should read and consider the 
statement before signing and dating it, and should be given a copy of the signed 
document. If the subject cannot read or sign the documents, oral presentation may be 
made or signature given by the subject’s legally appointed representative, if 
witnessed by a person not involved in the study, mentioning that the patient could not 
read or sign the documents. No patient can enter the study before his informed 
consent has been obtained. The original signed informed consent form will be kept 
with the research study documents and a signed copy will be given to the subject. 
 
C 
Confidentiality 
 
Each subject will be assigned a unique, consecutive three-digit identification number 
(i.e., 001, 002, …). The study number will be utilized for identification of the subject 
throughout the study. The clinical study coordinator of the trial will maintain the code 
that links the name of the participant to their study identification number. The study 
coordinator will maintain the code in a secured cabinet and the code will be kept 
confidential. Only the clinical study coordinator and principal investigator can access 
and view the codes. 
 


 
CPS BTX + Tam 
Page 30 of 32 
8/15/18 
Data for all participant enrolled at MEDVAMC will be managed under the privacy 
guidelines as determined by MEDVAMC. 
 
D 
Regulatory Documents  
 
All regulatory documents will be managed by Research Administration of the Scott 
Department of Urology located at Main Baylor in rooms 502 and 506D in the Jewish 
Wing.  The offices have keyed entries. All computers are password protected. 
 
The Scott Department of Urology complies fully with the HIPAA Privacy Rule. 
E   Protocol Changes  
 
If it is necessary for the study protocol to be amended, the amendment will be 
submitted to the BCM IRB for approval.  Amended procedures will not be in effect 
until after IRB approval has been given.  The principal investigator is responsible for 
the distribution of the approved documents to the staff.   
 
Revisions to questionnaires or CRFs will not require IRB; therefore, these revisions 
will not be reported.  
 
 
XXIII. REFERENCES 
 
1. 
McVary, K. T.: BPH: epidemiology and comorbidities. Am J Manag Care, 12: S122, 2006 
2. 
Wei, J. T., Calhoun, E., Jacobsen, S. J.: Urologic diseases in America project: benign 
prostatic hyperplasia. J Urol, 173: 1256, 2005 
3. 
Gormley, G. J., Stoner, E., Bruskewitz, R. C. et al.: The effect of finasteride in men with 
benign prostatic hyperplasia. 1992. J Urol, 167: 1102, 2002 
4. 
McVary, K. T., McKenna, K. E., Lee, C.: Prostate innervation. Prostate Suppl, 8: 2, 1998 
5. 
Witte, L. P., Chapple, C. R., de la Rosette, J. J. et al.: Cholinergic innervation and 
muscarinic receptors in the human prostate. Eur Urol, 54: 326, 2008 
6. 
Nickel, J. C., Sander, S., Moon, T. D.: A meta-analysis of the vascular-related safety 
profile and efficacy of alpha-adrenergic blockers for symptoms related to benign 
prostatic hyperplasia. Int J Clin Pract, 62: 1547, 2008 
7. 
Verhamme, K. M., Dieleman, J. P., Bleumink, G. S. et al.: Treatment strategies, patterns 
of drug use and treatment discontinuation in men with LUTS suggestive of benign 
prostatic hyperplasia: the Triumph project. Eur Urol, 44: 539, 2003 
8. 
McVary, K. T., Razzaq, A., Lee, C. et al.: Growth of the rat prostate gland is facilitated by 
the autonomic nervous system. Biol Reprod, 51: 99, 1994 
9. 
Benaim, E. A., Montoya, J. D., Saboorian, M. H. et al.: Characterization of prostate size, 
PSA and endocrine profiles in patients with spinal cord injuries. Prostate Cancer 
Prostatic Dis, 1: 250, 1998 
10. 
Lepor, H., Baumann, M., Shapiro, E.: Identification and characterization of alpha 1 
adrenergic receptors in the canine prostate using [125I]-Heat. J Urol, 138: 1336, 1987 
11. 
Jankovic, J., Brin, M. F.: Therapeutic uses of botulinum toxin. N Engl J Med, 324: 1186, 
1991 
12. 
Chuang, Y. C., Chiang, P. H., Yoshimura, N. et al.: Sustained beneficial effects of 
intraprostatic botulinum toxin type A on lower urinary tract symptoms and quality of life in 
men with benign prostatic hyperplasia. BJU Int, 98: 1033, 2006 


 
CPS BTX + Tam 
Page 31 of 32 
8/15/18 
13. 
Maria, G., Brisinda, G., Civello, I. M. et al.: Relief by botulinum toxin of voiding 
dysfunction due to benign prostatic hyperplasia: results of a randomized, placebo-
controlled study. Urology, 62: 259, 2003 
14. 
Smith, C. P.: Botulinum toxin in the treatment of OAB, BPH, and IC. Toxicon, 54: 639, 
2009 
15. 
Chancellor, M. B., Fowler, C. J., Apostolidis, A. et al.: Drug Insight: biological effects of 
botulinum toxin A in the lower urinary tract. Nat Clin Pract Urol, 5: 319, 2008 
16. 
Doggweiler, R., Zermann, D. H., Ishigooka, M. et al.: Botox-induced prostatic involution. 
Prostate, 37: 44, 1998 
17. 
Chuang, Y. C., Huang, C. C., Kang, H. Y. et al.: Novel action of botulinum toxin on the 
stromal and epithelial components of the prostate gland. J Urol, 175: 1158, 2006 
18. 
Silva, J., Pinto, R., Carvallho, T. et al.: Mechanisms of prostate atrophy after glandular 
botulinum neurotoxin type a injection: an experimental study in the rat. Eur Urol, 56: 134, 
2009 
19. 
Chuang, Y. C., Tu, C. H., Huang, C. C. et al.: Intraprostatic injection of botulinum toxin 
type-A relieves bladder outlet obstruction in human and induces prostate apoptosis in 
dogs. BMC Urol, 6: 12, 2006 
20. 
Kuo, H. C.: Prostate botulinum A toxin injection--an alternative treatment for benign 
prostatic obstruction in poor surgical candidates. Urology, 65: 670, 2005 
21. 
Chuang, Y. C., Chiang, P. H., Huang, C. C. et al.: Botulinum toxin type A improves 
benign prostatic hyperplasia symptoms in patients with small prostates. Urology, 66: 
775, 2005 
22. 
Barry, M. J., Cockett, A. T., Holtgrewe, H. L. et al.: Relationship of symptoms of 
prostatism to commonly used physiological and anatomical measures of the severity of 
benign prostatic hyperplasia. J Urol, 150: 351, 1993 
23. 
Chute, C. G., Panser, L. A., Girman, C. J. et al.: The prevalence of prostatism: a 
population-based survey of urinary symptoms. J Urol, 150: 85, 1993 
24. 
Eckhardt, M. D., van Venrooij, G. E., Boon, T. A.: Symptoms and quality of life versus 
age, prostate volume, and urodynamic parameters in 565 strictly selected men with 
lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Urology, 57: 
695, 2001 
25. 
Lepor, H., Williford, W. O., Barry, M. J. et al.: The efficacy of terazosin, finasteride, or 
both in benign prostatic hyperplasia. Veterans Affairs Cooperative Studies Benign 
Prostatic Hyperplasia Study Group. N Engl J Med, 335: 533, 1996 
26. 
Lepor, H.: Prostatic diseases, 1st ed. Philadelphia: W.B. Saunders Co., pp. xvii, 586 p., 
2000 
27. 
Kaplan, S. A., Gonzalez, R. R.: Phosphodiesterase type 5 inhibitors for the treatment of 
male lower urinary tract symptoms. Rev Urol, 9: 73, 2007 
28. 
Kaplan, S. A., Roehrborn, C. G., Rovner, E. S. et al.: Tolterodine and tamsulosin for 
treatment of men with lower urinary tract symptoms and overactive bladder: a 
randomized controlled trial. JAMA, 296: 2319, 2006 
29. 
Lepor, H.: Phase III multicenter placebo-controlled study of tamsulosin in benign 
prostatic hyperplasia. Tamsulosin Investigator Group. Urology, 51: 892, 1998 
30. 
Lepor, H., Rigaud, G.: The efficacy of transurethral resection of the prostate in men with 
moderate symptoms of prostatism. J Urol, 143: 533, 1990 
31. 
Stamey, T. A., Caldwell, M. C., Fan, Z. et al.: Genetic profiling of Gleason grade 4/5 
prostate cancer: which is the best prostatic control tissue? J Urol, 170: 2263, 2003 
32. 
Bauman, D. R., Steckelbroeck, S., Peehl, D. M. et al.: Transcript profiling of the 
androgen signal in normal prostate, benign prostatic hyperplasia, and prostate cancer. 
Endocrinology, 147: 5806, 2006 


 
CPS BTX + Tam 
Page 32 of 32 
8/15/18 
33. 
Shah, U. S., Getzenberg, R. H.: Fingerprinting the diseased prostate: associations 
between BPH and prostate cancer. J Cell Biochem, 91: 161, 2004 
34. 
Lee, K. L., Peehl, D. M.: Molecular and cellular pathogenesis of benign prostatic 
hyperplasia. J Urol, 172: 1784, 2004 
35. 
Taoka, R., Tsukuda, F., Ishikawa, M. et al.: Association of prostatic inflammation with 
down-regulation of macrophage inhibitory cytokine-1 gene in symptomatic benign 
prostatic hyperplasia. J Urol, 171: 2330, 2004 
36. 
Kim, J., Yanagihara, Y., Kikugawa, T. et al.: A signaling network in phenylephrine-
induced benign prostatic hyperplasia. Endocrinology, 150: 3576, 2009 
37. 
Dong, G., Rajah, R., Vu, T. et al.: Decreased expression of Wilms' tumor gene WT-1 and 
elevated expression of insulin growth factor-II (IGF-II) and type 1 IGF receptor genes in 
prostatic stromal cells from patients with benign prostatic hyperplasia. J Clin Endocrinol 
Metab, 82: 2198, 1997 
38. 
Royuela, M., Arenas, M. I., Bethencourt, F. R. et al.: Regulation of proliferation/apoptosis 
equilibrium by mitogen-activated protein kinases in normal, hyperplastic, and 
carcinomatous human prostate. Hum Pathol, 33: 299, 2002 
39. 
Castro, P., Giri, D., Lamb, D. et al.: Cellular senescence in the pathogenesis of benign 
prostatic hyperplasia. Prostate, 55: 30, 2003 
40. 
Crawford, E. D., Hirst, K., Kusek, J. W. et al.: Effects of 100 and 300 Units of 
Onabotulinum Toxin A on Lower Urinary Tract Symptoms of Benign Prostatic 
Hyperplasia: A Phase II Randomized Clinical Trial. J Urol, 186: 965, 2011 
41. 
Apostolidis, A., Jacques, T. S., Freeman, A. et al.: Histological changes in the urothelium 
and suburothelium of human overactive bladder following intradetrusor injections of 
botulinum neurotoxin type A for the treatment of neurogenic or idiopathic detrusor 
overactivity. Eur Urol, 53: 1245, 2008 
42. 
Giannantoni, A., Di Stasi, S. M., Nardicchi, V. et al.: Botulinum-A toxin injections into the 
detrusor muscle decrease nerve growth factor bladder tissue levels in patients with 
neurogenic detrusor overactivity. J Urol, 175: 2341, 2006 
43. 
Liu, H. T., Chancellor, M. B., Kuo, H. C.: Urinary nerve growth factor levels are elevated 
in patients with detrusor overactivity and decreased in responders to detrusor botulinum 
toxin-A injection. Eur Urol, 56: 700, 2009 
44. 
Dakhova, O., Ozen, M., Creighton, C. J. et al.: Global gene expression analysis of 
reactive stroma in prostate cancer. Clin Cancer Res, 15: 3979, 2009 
 
 
XXIV. APPENDICES 
 
 A. Questionnaires 
 
1 
AUA Symptom Score 
2 
BPH Impact Scale 
3 
Bladder Function Questionnaire 
4 
Erectile Function Questionnaire 
5 
Ejaculation Function Questionnaire 
 
 
 B. SDU QA/QC protocol 
 
 
 

ICF_001.pdf: 

	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
#$ "%&"#'()
#
*!"'
$%&'%
()*+,-,&.
/0($)(1-+&-

&+
-
.*22*%
.*%3&,&*%
,/-,
-44$.,+
%$-)10
/-14
*4
2$%
*5$)
-'$
"
-%3
6"7
*4
2$%
*5$)
8"9
*:$)
;)&%-)0
,)-.,
+02(,*2+

.-;+$3
<0

:/&./
2-0
&%.1;3$
$=.$++&5$
;)&%-,&%'
-,
%&'/,
;)&%-,&%'
*4,$%
/-5&%'
,*
/;))0
,*
;)&%-,$
%*,
<$&%'
-<1$
,*
+,-),
,/$
;)&%$
+,)$-2

+,-)&%'
-%3
+,*((&%'
*4
,/$
;)&%$
+,)$-2
-%3
%*,
4;110
$2(,0&%'
0*;)
<1-33$)9
/$+$
+02(,*2+
.-%
<$
5$)0
<*,/$)+*2$
.-%
+&'%&4&.-%,10
-44$.,
0*;)
1&4$+,01$
-%3
-)$
.*+,109
;)
+&,$
:-+
*%$
*4

.$%,$)+
&%5*15$3
&%
-
#:$$>
/-+$


+,;30
*4
#""
-%3
?""
;%&,+
*4
*%-* 

4*)
,/$
2-%-'$2$%,
*4
9


,*,-1
*4
#?
2$%
:$)$
$%)*11$3
-%3
,)$-,$3
-%3
#
.*2(1$,$3
,/$
+,;309


(*+&,&5$
$44$.,
*4
*%-*
:-+
./-)-.,$)&@$3
-+
-
?"7
*)
<$,,$)
./-%'$
&%
,/$&)
+02(,*2+9
/&+
+,;30
&+
-
.1&%&.-1
)$+$-)./
+,;30
,/-,
&+
.*%3;.,$3
;%3$)
,/$

**3
-%3
);'
32&%&+,)-,&*%9

/$
*%-*
/-+
<$$%
-(()*5$3
4*)
;+$
&%
/;2-%+
4*)
*,/$)
()*<1$2+
<;,
%*,
4*)
()*+,-,$
()*<1$2+9

-2+;1*+&%
1*2-=
/-+
<$$%
-(()*5$3
<0
,/$

4*)
,/$
,)$-,2$%,
*4
0*;)
+02(,*2+9
*;
-)$
<$&%'
-+>$3
,*
(-),&.&(-,$
&%
,/&+
.1&%&.-1
)$+$-)./
+,;30
<$.-;+$
0*;
/-5$


-%3
*)
 9
1$-+$
)$-3
,/&+
4*)2
.-)$4;1109

->$
,&2$
,*
-+>
,/$
3*.,*)
*)
+,;30
+,-44
-+
2-%0
A;$+,&*%+
-<*;,
,/$
+,;30
-+
0*;
:*;13
1&>$9

4
,/$)$
-)$
-%0
:*)3+
*)
&%4*)2-,&*%
,/-,
0*;
3*
%*,
;%3$)+,-%3
,/$
3*.,*)
*)
+,;30
+,-44
:&11
$=(1-&%
,/$2
,*
0*;9

$-3&%'
,/&+
4*)2
-%3
,-1>&%'
,*
,/$
3*.,*)
*)
+,;30
+,-44
2-0
/$1(
0*;
3$.&3$
:/$,/$)
,*
(-),&.&(-,$
*)
%*,9

4
0*;
3$.&3$
,*
,->$
(-),
&%
,/$
+,;30
0*;
2;+,
+&'%
-%3
3-,$
,/$
+,-,$2$%,
*4
.*%+$%,
-%3
-;,/*)&@-,&*%
*%
,/$
1-+,
(-'$
*4
,/&+
4*)29
"
/$
2-&%
(;)(*+$
*4
,/$
+,;30
&+
,*
.*2(-)$
,/$
$44$.,&5$%$++
*4
""

*%-*
&%B$.,$3
&%,*
,/$
()*+,-,$
5$)+;+

,-2+;1*+&%
4*)
,/$
,)$-,2$%,
*4
1*:$)
;)&%-)0
,)-.,
+02(,*2+
.-;+$3
<0
9
/-%'$+
&%
,/$
()*+,-,$
,&++;$
,/-,
&+
)$2*5$3
3;)&%'
,/$
()*+,-,$
<&*(+&$+
:&11
-1+*
<$
.*2(-)$39
"
'
/$
)$+$-)./
:&11
<$
.*%3;.,$3
-,
,/$
4*11*:&%'
1*.-,&*%+C

-01*)
*11$'$
*4
$3&.&%$
&./-$1
	9
$->$0
$,$)-%+
44-&)+
$3&.-1
$%,$)
-%3
C
$-1,/
.&$%.$
$%,$)

*;+,*%9


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
/$
+,;30
2$3&.-,&*%+
4*)
,/&+
+,;30
-)$
*%-*
&%B$.,&*%
(1-.$<*
&%B$.,&*%
*)-1
<0
2*;,/
,-2+;1*+&%
1*2-=
-%3
(1-.$<*
*)-1
3);'9

*)
,/&+
+,;30
,/$
(1-.$<*
&%B$.,&*%
&+
+-1&%$
+-1,
:-,$)
-%3
,/$
*)-1
3);'
&+
-
1**>-1&>$
.-(+;1$
,/-,
.*%,-&%+
%*
2$3&.&%$9


*;
:&11
<$
&%

#
*%-*
&%B$.,&*%
-%3
(1-.$<*
.-(+;1$
,/-,
&+
,->$%
$5$)0
3-0
<0
2*;,/
*)


(1-.$<*
+-1,
:-,$)
&%B$.,&*%
-%3
-
,-2+;1*+&%
"9
2'
.-(+;1$
,->$%
$5$)0
3-0
<0
2*;,/9
*;
:&11
/-5$

.1&%&.
5&+&,+
-%3

,$1$(/*%$
5&+&,+
3;)&%'
,/&+
+,;309

*;)
(-),&.&(-,&*%
&%
,/$
+,;30
:&11
<$
-<*;,

,*

2*%,/+9

#C
.)$$%&%'C
/$+$
()*.$3;)$+
-%3
$5$%,+
:&11
<$
3*%$
,*
+$$
&4
0*;
-)$
-11*:$3
,*
,->$
(-),
&%
,/$
+,;309

/$0
:&11
<$
3*%$
-4,$)
0*;
/-5$
)$5&$:$3
,/&+
4*)2
-%3
,/$
+,;30
3*.,*)
*)
-
2$2<$)
*4
,/$
+,;30
/-+
-%+:$)$3
-11
*4
0*;)
A;$+,&*%+
-%3
0*;
/-5$
+&'%$3
,/&+
&%4*)2$3
.*%+$%,
4*)29

*;)
&%4*)2-,&*%
,/-,
&+
.*11$.,$3
4*)
,/$
+,;30
-)$
,/$
0*;)
&%&,&-1+
3-,$
*4
<&),/
'$%3$)
-%3
-.$E	,/%&.&,09

/$
	
)$A;&)$+
,/-,
0*;)
*.&-1
$.;)&,0
;2<$)
&+
-33$3
,*
,/&+
.*%+$%,
4*)29

/&+
&%4*)2-,&*%
:&11
%*,
<$
'&5$%
,*
-%0*%$
*;,+&3$
*4
,/$
	
+0+,$2
;%1$++
)$A;&)$3
,*
3*
+*
<0
1-:9

*;
:&11
<$
'&5$%
-
;%&A;$
+,;30
&3$%,&40&%'
%;2<$)9

/&+
%;2<$)
:&11
<$
$%,$)$3
*%
-11
+,;30
3*.;2$%,+
-%3
;+$3
,/)*;'/*;,
,/$
+,;309




11
()*+,-,$
+($.&2$%+
.*11$.,$3
-+
(-),
*4
,/$
)$+$-)./
()*.$3;)$+
4*)
,/&+
+,;30
:&11
<$
.*3$3
+*
,/-,
,/$
)$+;1,+
*4
,/$
,$+,+
.-%
%*,
<$
3&)$.,10
1&%>$3
,*
0*;9
#9

*;
:&11
/-5$
-
(/0+&.-1
$=-2&%-,&*%
&%.1;3&%'
-
3&'&,-1
)$.,-1
$=-2&%-,&*%
	9

/$
3*.,*)
:&11
&%+$),
/&+
'1*5$3
4&%'$)
&%,*
0*;)
)$.,;2
,*
4$$1
,/$
()*+,-,$
&%
*)3$)
,*
$+,&2-,$
,/$
()*+,-,$F+
+&@$
+/-($
-%3
.*%+&+,$%.09
9

*;)
5&,-1
+&'%+
(;1+$
<)$-,/&%'
)-,$
,$2($)-,;)$
-%3
<1**3
()$++;)$
:&11
<$
,->$%
-%3
)$.*)3$39

?9

*;
:&11
<$
-+>$3
A;$+,&*%+
-<*;,
0*;)
2$3&.-1
/&+,*)0
-%3
-<*;,
-%0
2$3&.-,&*%+
0*;
-)$
%*:
,->&%'9
9

*;
:&11
.*2(1$,$
,/$
4*11*:&%'

A;$+,&*%%-&)$+C


/$

2$)&.-%
)*1*'&.-1
++*.&-,&*%
+02(,*2
+.*)$

-+>+
A;$+,&*%+
-<*;,
0*;)
;)&%-,&%'
+02(,*2+



2(-.,
.-1$

-+>+
A;$+,&*%+
-<*;,
/*:
0*;)
;)&%-)0
()*<1$2+
$44$.,
0*;)
3-&10
1&4$9


1-33$)
;%.,&*%

-+>+
2*)$
3$,-&1$3
A;$+,&*%+
-<*;,
0*;)
;)&%-)0
/-<&,+


	)$.,&1$
;%.,&*%

-+>+
A;$+,&*%+
&%
*)3$)
,*
3$,$)2&%$
/*:
0*;)
;)&%-)0
+02(,*2+
-)$
$44$.,&%'
0*;)
$)$.,&*%+


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$

*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""


	B-.;1-,*)0
;%.,&*%

-+>+
A;$+,&*%+
-<*;,
0*;)
$B-.;1-,&*%+
:/$%
/-5&%'
+$=;-1
-.,&5&,0
*;)
)$+(*%+$+
,*
,/$+$
A;$+,&*%%-&)$+
:&11
'&5$
,/$
+,;30
3*.,*)
-
<$,,$)
;%3$)+,-%3&%'
*4
0*;)
;)&%-)0
+02(,*2+
-%3
/*:
,/$0
-)$
$44$.,&%'
0*;)
1&4$9
9

*;)
;)&%$
41*:
:&11
<$
,$+,$3
:/&1$
+,-%3&%'
-%3
;)&%-,&%'
&%,*
-
1-)'$
(1-+,&.
4;%%$1
,/-,
/-+
-
+$%+*)
&%
,/$
<*,,*2
:/&./
2$-+;)$+
,/$
4*).$
*4
,/$
;)&%$
+,)$-29

/$
-2*;%,
*4
;)&%$
1$4,
&%
,/$
<1-33$)
:&11
<$
2$-+;)$3
;+&%'
-
<1-33$)
+.-%%$)9


/$
+.-%%$)
&+
(1-.$3
3&)$.,10
*%
,*(
*4
,/$
+>&%
*5$)
0*;)
<1-33$)
:/&./
/-+
-
'$1
-((1&$3
,*
,/$
+;)4-.$9

G9

*;
:&11
/-5$
-<*;,

,$-+(**%+
*4
<1**3
3)-:
,*
,$+,
0*;)

()*+,-,$+($.&4&.
-%,&'$%
-%3
0*;)
.*2(1$,$
<1**3
.*;%,
9

/$

&+
-
,$+,
,/-,
+.)$$%+
4*)
.-%.$)
*4
,/$
()*+,-,$9

/$

,$+,+
,*
+$$
&4
0*;
/-5$
-%0
&11%$++
*)
&%4$.,&*%9
9

*;
:&11
()*5&3$
-
;)&%$
+-2(1$
,/-,
:&11
<$
,$+,$3
,*
+$$
&4
0*;
/-5$
-
;)&%-)0
,)-.,
&%4$.,&*%
*)
-%0
*,/$)
()*<1$2+9
89

*;
:&11
<$
'&5$%
3*+$+
*4
-%
-%,&<&*,&.
2$3&.&%$
:&,/
&%+,);.,&*%+
,*
,->$
,/$2
#
3-0
<$4*)$
,/$
<&*(+0
*%
,/$
3-0
*4
,/$
<&*(+0
-%3
*%
,/$
3-0
-4,$)
,/$
<&*(+09
69
*;
:&11
<$
&%+,);.,$3
,*
+,*(
,->&%'
0*;)
-1(/-
<1*.>$)
2$3&.-,&*%+

3-0+
()&*)
,*
,/$
<&*(+09
#"9

*;
:&11
<$
+./$3;1$3
4*)
&+&,
9

C
&*(+0
#9

*;
:&11
<$
-+>$3
-<*;,
0*;)
.;))$%,
2$3&.-,&*%+
-%3
&4
0*;)
/$-1,/
/-+
./-%'$3
*)
&4
0*;
/-5$
/-3
-%0
()*<1$2+
+&%.$
0*;)
1-+,
5&+&,9

*;
5&,-1+
+&'%+
:&11
<$
,->$%
-%3
0*;
:&11
()*5&3$
-
;)&%$
+-2(1$
4*)
,$+,&%'9
9

*;
:&11
<$
-+>$3
&4
0*;
,**>
,/$
3*+$
*4
-%,&<&*,&.
,/$
3-0
<$4*)$
,/$
<&*(+0
-%3
*%
,/$
3-0
*4
,/$
<&*(+09

*;
:&11
<$
)$2&%3$3
,*
,->$
-%*,/$)
3*+$
,/$
3-0
-4,$)
,/$
<&*(+09
?9

*;
:&11
)$.$&5$
-
1$$,
$%$2-9

1$$,
	%$2-
&+
-
+-1&%$
+-1,
:-,$)
1-=-,&5$9
-1&%$
1-=-,&5$+
:*)>
<0
3)-:&%'
:-,$)
&%,*
,/$
.*1*%
:/&./
/$1(+
()*3;.$
-
<*:$1
2*5$2$%,9
/&+
()*5&3$+
-
+*4,
+,**1
2-++
-%3
&%.)$-+$3
<*:$1
-.,&*%9

<*:$1
2*5$2$%,
+/*;13
<$
+,&2;1-,$3
&%
#
,*

2&%;,$+
:&,/*;,
(-&%
*)
+(-+29


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
?
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
9

*;
:&11
;%3$)'*
-
)-%+)$.,-1
1,)-+*;%3
C
%
,/&+
,$+,
-
+2-11
()*<$
&+
(1-.$3
&%
,/$
)$.,;2
%$-)
,/$
()*+,-,$
&%
-
(*+&,&*%
+&2&1-)
,*
,/$
3&'&,-1
)$.,-1
$=-2&%-,&*%
($)4*)2$3
<0
,/$
3*.,*)9
/$
()*<$
;+$+
;1,)-+*;%3
:-5$+
:/&./
-)$
%*,
/-)24;1
,*
()*3;.$
-%
&2-'$
*4
,/$
()*+,-,$9
/$
()*.$3;)$
;+;-110
1-+,
-(()*=&2-,$10
"
2&%;,$+
4)*2
+,-),
,*
4&%&+/9
9


<&*(+0
:&11
<$
.*%3;.,$3
<0
&%+$),&%'
-
,&%0
%$$31$
-1*%'+&3$
,/$

()*<$
,*
)$2*5$
-
+2-11
+-2(1$
*4
()*+,-,$
,&++;$9
G9

*;
:&11
<$
'&5$%
3*+$+
*4
-%
-%,&<&*,&.
2$3&.&%$
:&,/
&%+,);.,&*%+
,*
,->$
,/$2
#
3-0
<$4*)$
,/$
&%B$.,&*%
*%
,/$
3-0
*4
,/$
&%B$.,&*%
-%3
*%
,/$
3-0
-4,$)
,/$
&%,$)B$.,&*%9
9

*;
:&11
<$
+./$3;1$3
4*)
&+&,
?9

?C

*;)
:$$>+
(1;+
*)
2&%;+
?
3-0+
-4,$)

9
/&+
&+
,/$
)-%3*2&@-,&*%
-%3
&%B$.,&*%
5&+&,9

#9

*;
:&11
<$
-+>$3
-<*;,
0*;)
.;))$%,
2$3&.-,&*%+
-%3
&4
0*;)
/$-1,/
/-+
./-%'$3
*)
&4
0*;
/-5$
/-3
-%0
()*<1$2+
+&%.$
0*;)
1-+,
5&+&,9
9

*;
:&11
/-5$
-
(/0+&.-1
$=-2&%-,&*%
&%.1;3&%'
-
	
-%3
0*;)
5&,-1
+&'%+
:&11
<$
,->$%9
?9

*;
:&11
()*5&3$
-
;)&%$
+-2(1$
,/-,
:&11
<$
,$+,$3
,*
+$$
&4
0*;
/-5$
-
;)&%-)0
,)-.,
&%4$.,&*%
*)
-%0
*,/$)
()*<1$2+9
9

*;
:&11
<$
-+>$3
&4
0*;
,**>
,/$
3*+$
*4
-%,&<&*,&.
,/$
3-0
<$4*)$
,/$
<&*(+0
-%3
*%
,/$
3-0
*4
,/$
<&*(+09

*;
:&11
<$
)$2&%3$3
,*
,->$
-%*,/$)
3*+$
,/$
3-0
-4,$)
,/$
<&*(+09
9

*;
:&11
/-5$
-%
$%$2-
B;+,
1&>$
0*;
3&3
3;)&%'
&+&,
9
G9

*;
:&11
/-5$
-

B;+,
-+
0*;
3&3
&%
&+&,
9
9

*;
:&11
<$
'&5$%
-
1*.-1
-%$+,/$,&.
,*
<1*.>
,/$
(-&%
4)*2
,/$
()*+,-,$
&%B$.,&*%9
89

*;
:&11
<$
)-%3*2&@$3
,*
$&,/$)
C


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$

*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""



#C
*%-*
&%B$.,&*%
-%3
(1-.$<*
.-(+;1$
,/-,
&+
,->$%
$5$)0
3-0
<0
2*;,/




C
(1-.$<*
+-1,
:-,$)
&%B$.,&*%
-%3
-
,-2+;1*+&%
"9
2'
.-(+;1$
,->$%
$5$)0
3-0
<0
2*;,/9
-%3*2&@-,&*%
&+
,/$
-++&'%&%'
*4
:/&./
,)$-,2$%,
')*;(
0*;
:&11
<$
&%9

,
&+
3*%$
<0
./-%.$
+&2&1-)
,*
,*++&%'
-
.*&%9

/&+
&+
-
3*;<1$
<1&%3
+,;30
:/&./
2$-%+
0*;
%*)
,/$
+,;30
3*.,*)
:&11
>%*:
:/&./
+,;30
3);'+
0*;
-)$
)$.$&5&%'9

%
.-+$
*4
$2$)'$%.0
,/$

(/-)2-.&+,
:&11
<$
-<1$
,*
,$11
,/$
3*.,*)
:/&./
3);'+
0*;
:$)$
'&5$%9
69


/$
+,;30
3*.,*)
:&11
($)4*)2
,/$
()*+,-,$
&%B$.,&*%
()*.$3;)$9
#"9

*;
:&11
)$2-&%
&%
,/$
.1&%&.
;%,&1
0*;
-)$
-<1$
,*
;)&%-,$9
##9

*;
:&11
<$
'&5$%
,/$
*)-1
+,;30
3);'
,*
,->$
/*2$
:&,/
0*;9
/$
+,;30
.**)3&%-,*)
:&11
()*5&3$
0*;
:&,/
3$,-&1$3
&%+,);.,&*%+
-%3
-
.-(+;1$
3&-)0
+*
0*;
.-%
)$.*)3
,/$
3-0
-%3
,&2$
,/-,
0*;
,->$
0*;)
+,;30
2$3&.-,&*%9
#9

*;
:&11
<$
)$A;&)$3
,*
;+$
.*%3*2+
:/$%
0*;
$%'-'$
&%
+$=;-1
-.,&5&,&$+
4*)
8
/*;)+
-4,$)
,/$
&%B$.,&*%
()*.$3;)$9

C
-0
?
-4,$)
,/$
&%B$.,&*%
()*.$3;)$
*;
:&11
<$
.*%,-.,$3
<0
,$1$(/*%$
?
3-0+
-4,$)
&%B$.,&*%
,*
-+>
0*;
&4
0*;
-)$
$=($)&$%.&%'
-%0
+02(,*2+
*4
&%4$.,&*%
*)
&4
<1$$3&%'
/-+
*..;))$39

C
#
 $$>
(1;+
*)
2&%;+
?
3-0+
-4,$)
,/$
&%B$.,&*%
()*.$3;)$
*;
:&11
<$
.*%,-.,$3
<0
,$1$(/*%$
-<*;,
#
:$$>
-4,$)
&%B$.,&*%
,*
-+>
-<*;,
-%0
2$3&.-1
()*<1$2+
0*;
2-0
/-5$
:/-,
.;))$%,
2$3&.-,&*%+
0*;
-)$
,->&%'
-%3
/*:
0*;
-)$
4$$1&%'9

GC

 $$>+
(1;+
*)
2&%;+
?
3-0+
-4,$)
,/$
&%B$.,&*%
()*.$3;)$
#9

*;
:&11
<$
-+>$3
-<*;,
0*;)
.;))$%,
2$3&.-,&*%+
-%3
&4
0*;)
/$-1,/
/-+
./-%'$3
*)
&4
0*;
/-5$
/-3


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$

*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
-%0
()*<1$2+
+&%.$
0*;)
1-+,
5&+&,9
9

*;)
5&,-1
+&'%+
:&11
<$
,->$%9
?9

*;
:&11
()*5&3$
-
;)&%$
+-2(1$
4*)
,$+,&%'9
9

*;
:&11
.*2(1$,$
,/$
4*11*:&%'

A;$+,&*%%-&)$+
-+
0*;
3&3
-,

#9
9

*;)
;)&%$
41*:
:&11
<$
,$+,$3
:/&1$
+,-%3&%'
-%3
;)&%-,&%'
&%,*
-
1-)'$
(1-+,&.
4;%%$1
,/-,
/-+
-
+$%+*)
&%
,/$
<*,,*2
:/&./
2$-+;)$+
,/$
4*).$
*4
,/$
;)&%$
+,)$-29
/$
-2*;%,
*4
;)&%$
1$4,
&%
,/$
<1-33$)
:&11
<$
2$-+;)$3
;+&%'
-
<1-33$)
+.-%%$)9
/$
+.-%%$)
&+
(1-.$3
3&)$.,10
*%
,*(
*4
,/$
+>&%
*5$)
0*;)
<1-33$)
:/&./
/-+
-
'$1
-((1&$3
,*
,/$
+;)4-.$9
G9

*;
:&11
)$,;)%
,/$
+,;30
3);'
<*,,1$
-%3
0*;)
3);'
3&-)0
:&11
<$
)$5&$:$3
-%3
3&+.;++$3
:&,/
0*; 9
9

*;
:&11
<$
'&5$%
%$:
+;((10
*4
+,;30
3);'9
89

*;
:&11
<$
+./$3;1$3
4*)
0*;)
%$=,
+,;30
5&+&,9
69


*;
:&11
<$
'&5$%
3*+$+
*4
-%
-%,&<&*,&.
2$3&.&%$
:&,/
&%+,);.,&*%+
,*
,->$
,/$2
#
3-0
<$4*)$
,/$
<&*(+0
*%
,/$
3-0
*4
,/$
<&*(+0
-%3
*%
,/$
3-0
-4,$)
,/$
<&*(+09



	
*4
C
?
*%,/+
(1;+
*)
2&%;+
?
3-0+
-4,$)
,/$
&%B$.,&*%
()*.$3;)$
#99*;
:&11
/-5$
-
(/0+&.-1
$=-2&%-,&*%
&%.1;3&%'
-
3&'&,-1
)$.,-1
$=-2&%-,&*%
	
9

*;)
5&,-1
+&'%+
:&11
<$
,->$%9
?9

*;
:&11
<$
-+>$3
-<*;,
0*;)
.;))$%,
2$3&.-,&*%+
-%3
&4
0*;)
/$-1,/
/-+
./-%'$3
*)
&4
0*;
/-5$
/-3
-%0
()*<1$2+
+&%.$
0*;)
1-+,
5&+&,9
9

*;
:&11
)$,;)%
0*;
+,;30
3);'
()*3;.,
(-.>-'&%'
-%3
0*;)
+,;30
3);'
3&-)0
:&11
<$
)$5&$:$3
-%3
3&+.;++$3
:&,/
0*;9

9

*;)
;)&%$
41*:
:&11
<$
,$+,$3
:/&1$
+,-%3&%'
-%3
;)&%-,&%'
&%,*
-
1-)'$
(1-+,&.
4;%%$1
,/-,
/-+
-
+$%+*)
&%
,/$
<*,,*2
:/&./
2$-+;)$+
,/$
4*).$
*4
,/$
;)&%$
+,)$-29
/$
-2*;%,
*4
;)&%$
1$4,
&%
,/$
<1-33$)
:&11
<$
2$-+;)$3
;+&%'
-
<1-33$)
+.-%%$)9
/$
+.-%%$)
&+
(1-.$3
3&)$.,10
*%
,*(
*4
,/$
+>&%
*5$)
0*;)


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
G
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
<1-33$)
:/&./
/-+
-
'$1
-((1&$3
,*
,/$
+;)4-.$9
G9

*;
:&11
.*2(1$,$
,/$
4*11*:&%'

A;$+,&*%%-&)$+
-+
0*;
3&3
-,
5&+&,+
#
-%3
G9
9

*;
:&11
/-5$
-<*;,
#
,$-+(**%
*4
<1**3
3)-:
,*
,$+,
0*;)

()*+,-,$+($.&4&.
-%,&'$%
89

*;
:&11
()*5&3$
-
;)&%$
+-2(1$
,/-,
:&11
<$
,$+,$3
,*
+$$
&4
0*;
/-5$
-
;)&%-)0
,)-.,
&%4$.,&*%
*)
-%0
*,/$)
()*<1$2+9
69

*;
:&11
;%3$)'*
-
)-%+)$.,-1
1,)-+*;%3
C
%
,/&+
,$+,
-
+2-11
()*<$
&+
(1-.$3
&%
,/$
)$.,;2
%$-)
,/$
()*+,-,$
&%
-
(*+&,&*%
+&2&1-)
,*
,/$
3&'&,-1
)$.,-1
$=-2&%-,&*%
($)4*)2$3
<0
,/$
3*.,*)9
/$
()*<$
;+$+
;1,)-+*;%3
:-5$+
:/&./
-)$
%*,
/-)24;1
,*
()*3;.$
-%
&2-'$
*4
,/$
()*+,-,$9
/$
()*.$3;)$
;+;-110
1-+,
-(()*=&2-,$10
"
2&%;,$+
4)*2
+,-),
,*
4&%&+/9
#"9


<&*(+0
:&11
<$
.*%3;.,$3
<0
&%+$),&%'
-
,&%0
%$$31$
-1*%'+&3$
,/$

()*<$
,*
)$2*5$
-
+2-11
+-2(1$
*4
()*+,-,$
,&++;$9
/&+
:&11
$%3
0*;)
(-),&.&(-,&*%
&%
,/&+
)$+$-)./
+,;309
($.&2$%+E&++;$+C
/$
<1**3
-%3
;)&%$
+($.&2$%+
.*11$.,$3
3;)&%'
,/$
+.)$$%&%'
5&+&,
-)$
)*;,&%$
4*)
(-,&$%,+
:&,/
0*;)
+02(,*2+
-%3
:&11
<$
/-%31$3
-..*)3&%'
,*
+,-%3-)3
*4
()-.,&.$9
/$
,$+,
)$+;1,+
:&11
<$
&%.1;3$3
&%
0*;)
)$+$-)./
-%3
2$3&.-1
./-),+9
*;
:&11
/-5$
-<*;,
?
,$-+(**%+
*4
<1**3
3)-:%
3;)&%'
0*;)
(-),&.&(-,&*%
&%
,/&+
+,;309
*;)
()*+,-,$
,&++;$
,/-,
&+
.*11$.,$3
3;)&%'
,/&+
+,;30
:&11
<$
.*3$3
<$4*)$
<$&%'
+$%,
,*
) 9
H;+,-5*
0-1-F+
1-<*)-,*)0
1*.-,$3
-,
,/$
%&5$)+&,0
*4
$=-+
$3&.-1
./**1

*;+,*%
4*)
,$+,&%'
,*
+$$
-<*;,
,/$
./-%'$+
.-;+$3
<0
,/$

&%B$.,&*%9
/$
,&++;$
&+
.*3$3
:&,/
0*;)
;<B$.,

%;2<$)
+*
,/-,
,/$
1-<*)-,*)0
($)+*%%$1
:&11
%*,
>%*:
&,
<$1*%'+
,*
0*;9
/$
+,;30
3*.,*)
:&11
/-5$
,/$
*%10
1*'
,/-,
1&%>+
0*;)
%-2$
,*
0*;)
;<B$.,

%;2<$)9
4
-%0
*4
0*;)
,&++;$+
)$2-&%
-,
,/$
$%3
*4
,/$
+,;30
,/$0
:&11
<$
3$+,)*0$39

/$
,&++;$+
:&11
%*,
<$
)$1$-+$3
,*
-%0*%$
%*,
1&+,$3
-+
-%
&%5$+,&'-,*)
*%
,/$
()*,*.*1
%*)
:&11
,/$0
<$
+*13
*)
,)-%+4$))$3
,*
-%0
,/&)3
(-),09
*;
:&11
%*,
<$
-<1$
,*
'$,
,/$
,&++;$+
<-.>9
(*%
0*;)
:)&,,$%
)$A;$+,
,*
)9
2&,/
-01*)
*11$'$
*4
$3&.&%$
.*,,
$(-),2$%,
*4
)*1*'0
#"6
)03$%
;&,$
#G""
-&1
,*(


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$

*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
?8"
*;+,*%

"?"
,/$
,&++;$+
:&11
<$
3$+,)*0$3
<;,
,/$
3-,-
.*11$.,$3
;(
;%,&1
,/-,
,&2$
:&11
%*,
<$
3$1$,$39
/$
+,;30F+
3-,-
:&11
<$
-%-10@$3
<0
,/$
+,;30F+
3*.,*)+
:/*
-)$
-44&1&-,$3
:&,/
,/$

-%3
-01*)
*11$'$
*4
$3&.&%$9

%4*)2-,&*%
()*5&3$3
,*
,/$
3*.,*)+
:&11
<$
.*3$3
+*
,/$0
:&11
%*,
<$
-<1$
,*
1&%>
0*;)
%-2$
:&,/
,/$
3-,-9
"&'6
/$
/$-1,/
&%4*)2-,&*%
,/-,
:$
2-0
;+$
*)
3&+.1*+$
)$1$-+$
4*)
,/&+
)$+$-)./
&%.1;3$+C





I

%4*)2-,&*%
4)*2
/$-1,/
)$.*)3+
+;./
-+
3&-'%*+$+
()*')$++
%*,$+
2$3&.-,&*%+
1-<
*)
)-3&*1*'0
4&%3&%'+
$,.9





I

$2*')-(/&.
&%4*)2-,&*%
%-2$
999
-'$
'$%3$)
)-.$
$,.9





I

;11
*.&-1
$.;)&,0
!





I

-),&-1
*.&-1
$.;)&,0
!
-+,
4*;)
3&'&,+
+$
*)
&+.1*+;)$
$A;&)$3
<0
-:
*;)
/$-1,/
&%4*)2-,&*%
:&11
<$
;+$3
*)
3&+.1*+$3
:/$%
)$A;&)$3
<0
1-:9
*;)
/$-1,/
&%4*)2-,&*%
2-0
<$
+/-)$3
:&,/
-
(;<1&.
/$-1,/
-;,/*)&,0
,/-,
&+
-;,/*)&@$3
<0
1-:
,*
.*11$.,
*)
)$.$&5$
+;./
&%4*)2-,&*%
4*)
,/$
(;)(*+$
*4
()$5$%,&%'
*)
.*%,)*11&%'
3&+$-+$
&%B;)0
*)
3&+-<&1&,0
-%3
.*%3;.,&%'
(;<1&.
/$-1,/
+;)5$&11-%.$
&%5$+,&'-,&*%+
*)
&%,$)5$%,&*%+9
*
(;<1&.-,&*%
*)
(;<1&.
()$+$%,-,&*%
-<*;,
,/$
)$+$-)./
3$+.)&<$3
-<*5$
:&11
)$5$-1
0*;)
&3$%,&,0
:&,/*;,
-%*,/$)
-;,/*)&@-,&*%
4)*2
0*;9
"*'
"&"
J
*%-*C

,
&+
$=($.,$3
,/-,
+*2$
(-),&.&(-%,+
2-0
/-5$
+*2$
*)
-11
*4
,/$
4*11*:&%'
+&3$
$44$.,+
:/$%
'&5$%
J9
,/$)
+&3$
$44$.,+
2-0
*..;)
:/&./
:$)$
%*,
+$$%
<$4*)$9
&3$
$44$.,+
-)$
;+;-110
,$2(*)-)0
-%3
2-%-'$-<1$9
*:$5$)
&,
&+
(*++&<1$
,/$0
.*;13
.-;+$
+$)&*;+
3&+$-+$
*)
3$-,/9
/$
+,;30
2-0
&%.1;3$
)&+>+
,/-,
-)$
;%>%*:%
-,
,/&+
,&2$9
/$)$
/-5$
<$$%
)-)$
)$(*),+
*4
+$)&*;+
-%3E*)
&22$3&-,$
*)
$5$%
3$-310
-<%*)2-110
+$%+&,&5$
)$-.,&*%+
-4,$)
,)$-,2$%,
:&,/
J9
/$+$
)$-.,&*%+
&%.1;3$
-11$)'&.
)$-.,&*%
+>&%
)-+/
&,./&%'
+:$11&%'
-%3
3&44&.;1,0
&%
<)$-,/&%'9
,
&+
-
)-)$
(*++&<&1&,0
,/-,
,/$
&%B$.,&*%
*4
J
.*;13
1$-3
,*
<*,;1&+29
/$
.1-++&.
+02(,*2+
*4


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
8
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
<*,;1&+2
&%.1;3$
3*;<1$
5&+&*%
<1;))$3
5&+&*%
3)**(&%'
$0$1&3+
+1;))$3
+($$./
3&44&.;1,0
+:-11*:&%'
3)0
2*;,/
-%3
2;+.1$
:$->%$++9
/$
3*.,*)F+
$=-2&%-,&*%
2-0
)$5$-1
,/-,
,/$
'-'
)$41$=
-%3
,/$
3$$(
,$%3*%
)$41$=$+
1&>$
,/$
>%$$
B$)>
-)$
3$.)$-+$3
*)
-<+$%,9
/$)$
/-5$
<$$%
)-)$
)$(*),+
*4
+;33$%
3$-,/
+*2$,&2$+
-++*.&-,$3
:&,/
3&44&.;1,0
&%
+:-11*:&%'
*)
(%$;2*%&-9
/$)$
/-5$
-1+*
<$$%
)-)$
)$(*),+
*4
/$-),
()*<1$2+
&%.1;3&%'
&))$';1-)
/$-),
<$-,+
-%3
/$-),
-,,-.>
+*2$
)$+;1,&%'
&%
3$-,/9

,
&+
%*,
>%*:%
&4
J
-.,;-110
.-;+$3
,/$+$
()*<1$2+9
,
+/*;13
%*,
<$
;+$3
:/$%
&%4$.,&*%
&+
()$+$%,
-,
,/$
&%B$.,&*%
+&,$
*)
&%
($*(1$
>%*:%
,*
<$
+$%+&,&5$
,*
J9
/$
4*11*:&%'
$5$%,+
/-5$
<$$%
*<+$)5$3
+&%.$
&,
/-+
<$$%
2-)>$,$3C
+>&%
)-+/
&,./&%'
-%3
-11$)'&.
)$-.,&*%9
%
'$%$)-1
,/$+$
+&3$
$44$.,+
*..;)
:&,/&%
,/$
4&)+,
:$$>
4*11*:&%'
&%B$.,&*%
-%3
:/&1$
;+;-110
,$2(*)-)0
,/$0
2-0
1-+,
+$5$)-1
2*%,/+9
-&%
,$%3$)%$++
*)
<);&+&%'
-)*;%3
,/$
&%B$.,&*%
+&,$
2-0
-1+*
*..;)9
*.-1
:$->%$++
*4
,/$
&%B$.,$3
2;+.1$+
&+
$=($.,$39
 $->%$++
*4
%$-)<0
2;+.1$+
2-0
-1+*
*..;)
3;$
,*
+()$-3
*4
J9
/$)$
-)$
-1+*
(*++&<1$
)&+>+
*4
%*,
<$&%'
-<1$
,*
$2(,0
,/$
<1-33$)
3&-))/$-
-%3
&%4$.,&*%
-+
-
)$+;1,
*4
,/$
J
&%B$.,&*%9
J
.*%,-&%+
-1<;2&%
:/&./
.*2$+
4)*2
/;2-%
<1**39
1,/*;'/
,/$
<1**3
&+
)&'*)*;+10
,$+,$3
,/$)$
&+
-%
$=,)$2$10
)$2*,$
)&+>
4*)
,/$
,)-%+2&++&*%
*4
5&);+$+
-%3
+&2&1-)
&%4$.,&*;+
-'$%,+9
$.$%,10
<1-33$)
+,*%$+
/-5$
<$$%
)$(*),$3
&%
2*%>$0+
)$.$&5&%'
2;1,&(1$

J
&%B$.,&*%+
&%,*
,/$
()*+,-,$9
/$
+&'%&4&.-%.$
*4
,/&+
4&%3&%'
&+
%*,
.;))$%,10
>%*:%9
,
&+
&2(*),-%,
,/-,
0*;
,*
&%4*)2
0*;)
+,;30
+,-44
-<*;,
0*;)
*,/$)
2$3&.-1
.*%3&,&*%+9
%
(-),&.;1-)
-%0
%$)5$2;+.1$
3&+*)3$)+
<$.-;+$
(-,&$%,+
:&,/
.$),-&%
3&+$-+$+
2-0
<$
-,
&%.)$-+$3
)&+>
*4
.1&%&.-110
+&'%&4&.-%,
*)
$5$%
4-,-1
$44$.,+9

1*2-=C

-2+;1*+&%
.-(+;1$+
2-0
.-;+$
-
+;33$%
3)*(
&%
<1**3
()$++;)$
;(*%
+,-%3&%'
$+($.&-110
-4,$)
,/$
4&)+,
3*+$
*)
:/$%
./-%'&%'
3*+$+9

02(,*2+
2-0
&%.1;3$
4-&%,&%'
3&@@&%$++
-%3
1&'/,/$-3$3%$++9
11$)'&.
)$-.,&*%+
2-0
&%.1;3$
)-+/
&,./&%'
-%3
/&5$+9
-)$
-%3
2*)$
+$)&*;+
-11$)'&.
)$-.,&*%+
2-0
-1+*
&%.1;3$
+:$11&%'
*4
4-.$
,*%';$
*)
,/)*-,
-%3
3&44&.;1,0
<)$-,/&%'9
)&-(&+2
-
(-&%4;1
$)$.,&*%
,/-,
:&11
%*,
'*
-:-0
2-0
*..;)9


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
6
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
;)&%'
.-,-)-.,
+;)'$)0
-
.*%3&,&*%
.-11$3
&%,)-*($)-,&5$
41*((0
&)&+
+0%3)*2$

.-%
/-(($%
&4
,-2+;1*+&%
&+
<$&%'
,->$%
*)
/-+
<$$%
,->$%
&%
,/$
(-+,9
*22*%
+&3$
$44$.,+
*4
,-2+;1*+&%
.-(+;1$+
2-0
&%.1;3$
);%%0
%*+$
3&@@&%$++
-%3
3$.)$-+$3
+$2$%9
	J
'&5$%
,*
3$-3$%
,/$
-)$-
-)*;%3
,/$
&%B$.,&*%
+&,$C

/$
-2*;%,
*4
&3*.-&%$
,/-,
0*;
:&11
)$.$&5$
;+;-110
3*$+
%*,
.-;+$
-%0
+&3$
$44$.,+9
-)$10
,/$
4*11*:&%'
+&3$
$44$.,+
2-0
<$
$=($)&$%.$3C

1&'/,/$-3$3%$++

%$)5*;+%$++

-%=&*;+
*)
+.-)$3

4$$1&%'
*4
:$11<$&%'
-%3
')$-,
/-((&%$++

.*%4;+&*%

3&@@&%$++

3)*:+&%$++

)&%'&%'
*)
<;@@&%'
&%
,/$
$-)

<1;))$3
*)
3*;<1$
5&+&*%

5*2&,&%'

+$%+-,&*%+
*4
/$-,
.*13
*)
%;2<%$++

+1&'/,
B$)>&%'
2*,&*%+

+/->&%'

.*%5;1+&*%+
*)
+$&@;)$+

1*++
*4
-:-)$%$++
*4
+;))*;%3&%'+

3&44&.;1,0
<)$-,/&%'
*)
%*,
<)$-,/&%'
-,
-11

+1*:
/$-),
<$-,

1*:
<1**3
()$++;)$

+,*((&%'
*4
,/$
/$-),
	=,)$2$10
)-)$
+&3$
$44$.,+
&%.1;3$
/&5$+
+:$11&%'
-%3
+/*.>9
	
		C


*2$
($*(1$
&%
,/$
+,;30
:&11
'$,
(1-.$<*
&%B$.,&*%
&%+,$-3
*4
J
+*1;,&*%9

->&%'
(1-.$<*
&+
,/$
+-2$
-+
%*,
)$.$&5&%'
-%0,/&%'
4*)
0*;)

+02(,*2+9

4
0*;
,->$
(1-.$<*
3;)&%'
,/$
+,;30
&,
&+
(*++&<1$
,/-,
0*;)

+02(,*2+
2-0
'$,
:*)+$9



D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#"
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
*2$
($*(1$
&%
,/$
+,;30
:&11
'$,
(1-.$<*
.-(+;1$
&%+,$-3
*4
-2+;1*+&%
.-(+;1$9

->&%'
(1-.$<*
&+
,/$
+-2$
-+
%*,
)$.$&5&%'
-%0,/&%'
4*)
0*;)

+02(,*2+9

4
0*;
,->$
(1-.$<*
3;)&%'
,/$
+,;30
&,
&+
(*++&<1$
,/-,
0*;)

+02(,*2+
2-0
'$,
:*)+$9
1$-+$
-+>
,/$
+,;30
3*.,*)
*)
+,;30
+,-44
&4
0*;
/-5$
-%0
A;$+,&*%+
-<*;,
(1-.$<*9
C
%
-%,&<&*,&.
2-0
.-;+$
;(+$,
+,*2-./
3&-))/$-
5*2&,&%'
+>&%
)-+/
&,./&%'
/&5$+
3&44&.;1,0
<)$-,/&%'
*)
+:-11*:&%'
:/$$@&%'
;%;+;-1
<1$$3&%'
*)
<);&+&%'
+*)$
,/)*-,
(-&%4;1
2*;,/
*)
,/)*-,
+*)$+
5-'&%-1
&%4$.,&*%9

,
2-0
-1+*
.-;+$
.*%4;+&*%
3&@@&%$++
4$$1&%'
+/->0
;%;+;-1
/;%'$)
/$-3-./$+
&))&,-<&1&,0
(*;%3&%'
/$-),
*)
5$)0
4-+,
(;1+$
(-1$
+>&%
+:$-,&%'
,)$2<1&%'
:$->%$++
;%;+;-1
-%=&$,0
-%3
.*2-9
*2-
&+
-
+,-,$
*4
;%.*%+.&*;+%$++
&%
:/&./
-
($)+*%
.-%%*,
<$
-:->$%$3K
4-&1+
,*
)$+(*%3
%*)2-110
,*
(-&%4;1
+,&2;1&
1&'/,
*)
+*;%3K
1-.>+
-
%*)2-1
:->$+1$$(
.0.1$K
-%3
3*$+
%*,
&%&,&-,$
5*1;%,-)0
-.,&*%+
*;
+/*;13
,$11
-
2$2<$)
*4
,/$
+,;30
,$-2
&4
0*;
-)$
,->&%'
-
3&-<$,$+
2$3&.&%$
:/$%
0*;)
+,;30
3*.,*)
&+
.*%+&3$)&%'
()$+.)&<&%'
-%
-%,&<&*,&.
-%3
-1+*
&4
0*;
/-5$
1*:
<1**3
+;'-)
*)
+02(,*2+
*4
&,
:/&1$
,->&%'
-
,/$
-%,&<&*,&.9
*)
(-,&$%,+
:&,/
3&-<$,$+
0*;)
+,;30
3*.,*)
2-0
-+>
0*;
,*
./$.>
0*;)
<1**3
+;'-)
2*)$
*4,$%
:/&1$
,->&%'
,/$
-%,&<&*,&.9
	

C
/$
;1,)-+*;%3
)-)$10
)$+;1,+
&%
(/0+&.-1
3&+.*24*),
<;,
0*;
2-0
$=($)&$%.$
+*2$
-%=&$,0
<$4*)$
-%3
3;)&%'
,/$
()*.$3;)$9

 C
%+$),&%'
%$$31$+
&%,*
5$&%+
4*)
.*11$.,&%'
<1**3
2-0
<$
;%.*24*),-<1$9

&+>+
&%.1;3$
+1&'/,
<);&+&%'
-,
,/$
(;%.,;)$
+&,$
4-&%,&%'
,/$
4*)2-,&*%
*4
-
+2-11
<1**3
.1*,
*)
+:$11&%'
*4
,/$
5$&%
-%3
+;))*;%3&%'
,&++;$
<1$$3&%'
4)*2
,/$
+&,$
-%3
,/$
)$2*,$
(*++&<&1&,0
*4
&%4$.,&*%
-,
,/$
+&,$
*4
,/$
%$$31$
(;%.,;)$9

-&%,&%'
&+
;+;-110
/-)21$++
*4
+/*),
3;)-,&*%
-%3
,0(&.-110
()*3;.$+
4$$1&%'+
*4
:$->%$++
+:$-,&%'
+1*:&%'
*4
,/$
/$-),
)-,$
-%3
-%
-<%*)2-1
3$.)$-+$
&%
<1**3
()$++;)$9
-)$
:&11
<$
,->$%
,*
-5*&3
,/$+$
.*2(1&.-,&*%+9
L		C

*2(1$,&%'
,/$
A;$+,&*%%-&)$+
2-0
.-;+$
0*;
,*
/-5$
*)
,*
$=($)&$%.$
+*2$
1$5$1
*4
$2*,&*%-1
3&+.*24*),
3;$
,*
,/$
($)+*%-1
%-,;)$
*4
,/$
A;$+,&*%+9

/$
+,;30
3*.,*)
-%3
+,-44
:&11
2-&%,-&%
-
()*4$++&*%-1
-%3
.-)&%'
-,,&,;3$
:/&1$
-32&%&+,$)&%'
,/$
A;$+,&*%%-&)$+9


	C
/$
1*++
*4
.*%4&3$%,&-1&,0
)$'-)3&%'
)$+$-)./
&%4*)2-,&*%
&+
-
(*++&<&1&,0K
-1,/*;'/
,/$
)&+>
&+
5$)0
+2-119

*;)
()*+,-,$
,&++;$
+($.&2$%+
:&11
1-<$1$3
:&,/
0*;)
+;<B$.,
.*3$
<$4*)$
<$&%'
+$%,
,*
)9
0-1-F+
1-<*)-,*)09
/$
1-<*)-,*)0
($)+*%%$1
:&11
%*,
<$
-<1$
,*
>%*:
,/-,
,/$+$
+($.&2$%+
-)$
0*;)+9

,;30
3*.;2$%,+
2-0
&%.1;3$
0*;)
&%&,&-1+
-%3
+;<B$.,
.*3$
<;,
%*
*,/$)
&3$%,&40&%'
&%4*)2-,&*%9


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
##
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""

C

$.-;+$
*4
,/$
(*++&<&1&,0
*4
3&44;+&*%
*4
J
&%,*
+$2&%-1
41;&3
-%3
%*
$5&3$%.$
,*
,/$
.*%,)-)0

0*;

;+$
.*%3*2+
&4
0*;
$%'-'$3
&%
+$=;-1
&%,$).*;)+$
3;)&%'
,/$
8
/*;)+
-4,$)
,/$
&%B$.,&*%9
/$)$
2-0
<$
;%>%*:%
)&+>+
*)
3&+.*24*),+
&%5*15$39
,;30
+,-44
:&11
;(3-,$
0*;
&%
-
,&2$10
:-0
*%
-%0
%$:
&%4*)2-,&*%
,/-,
2-0
-44$.,
0*;)
3$.&+&*%
,*
+,-0
&%
,/$
+,;309

/$)$
&+
-
+2-11
)&+>
4*)
,/$
1*++
*4
.*%4&3$%,&-1&,09
*:$5$)
,/$
+,;30
($)+*%%$1
:&11
2->$
$5$)0
$44*),
,*
2&%&2&@$
,/$+$
)&+>+9
"#&
/$
<$%$4&,+
*4
(-),&.&(-,&%'
&%
,/&+
+,;30
2-0
<$C
,*
+$$
-%
&2()*5$2$%,
*4
0*;)
+02(,*%+
4)*2
,/$
J
&%B$.,&*%
:&,/&%
*%$
:$$>
-4,$)
&%B$.,&*%9

*;)
(-),&.&(-,&*%
2-0
/$1(
,*
3$,$)2&%$
%$:
,)$-,2$%,+
4*)

-%3
9

*:$5$)
0*;
2-0
)$.$&5$
%*
<$%$4&,
4)*2
(-),&.&(-,&%'9
 
/$
4*11*:&%'
-1,$)%-,&5$
()*.$3;)$+
*)
,)$-,2$%,+
-)$
-5-&1-<1$
&4
0*;
./**+$
%*,
,*
(-),&.&(-,$
&%
,/&+
+,;30C
:-,./4;1
:-&,&%'
2$3&.-1
,/$)-(0
:&,/
-(()*5$3
3);'+
*)
+;)'&.-1
,)$-,2$%,9
 !"73'8"&	
&"'6
/$
&%5$+,&'-,*)
*)
+(*%+*)
2-0
3$.&3$
,*
+,*(
0*;
4)*2
,->&%'
(-),
&%
,/&+
+,;30
-,
-%0
,&2$9
 *;
.*;13
<$
)$2*5$3
4)*2
,/$
+,;30
4*)
)$-+*%+
)$1-,$3
*%10
,*
0*;
4*)
$=-2(1$
&4
0*;
2*5$
,*
-%*,/$)
.&,0
&4
0*;
3*
%*,
,->$
0*;)
+,;30
2$3&.-,&*%
*)
&4
0*;
/-5$
-
+$)&*;+
)$-.,&*%
,*
0*;)
+,;30
2$3&.-,&*%
*)
<$.-;+$
,/$
$%,&)$
+,;30
&+
+,*(($39
/$
+(*%+*)
&%5$+,&'-,*)
**3
-%3
);'
32&%&+,)-,&*%
*)
%+,&,;,&*%-1
$5&$:
*-)3
2-0
+,*(
,/$
+,;30
-,
-%0
,&2$9
	
"'6
/$
+,;30
&%5$+,&'-,&5$
()*3;.,+
&%B$.,&*%+
-%3
*)-1
2$3&.-,&*%+
-%3
-%$+,/$+&-
:&11
<$
()*5&3$3
-,
%*
.*+,
,*
0*;9
11
*,/$)
$5$%,+
-%3
()*.$3;)$+
-)$
.*%+&3$)$3
+,-%3-)3
*4
.-)$9

*;)
(-),&.&(-,&*%
:&11
%*,
-44$.,
,/$
:-0
0*;
%*:
(-0
4*)
2$3&.-1
.-)$
-,
,/$
9
*;
:&11
%*,
<$
(-&3
4*)
,->&%'
(-),
&%
,/&+
+,;309
/&+
&%+,&,;,&*%
3*$+
%*,
(1-%
,*
(-0
)*0-1,&$+
,*
0*;
&4
-
.*22$).&-1
()*3;.,
&+
3$5$1*($3
4)*2
<1**3
*)
,&++;$
*<,-&%$3
4)*2
0*;
3;)&%'
,/&+
+,;309

3'	6
4
0*;
$=($)&$%.$
-%0
&%B;)0
)$1-,$3
,*
0*;)
(-),&.&(-,&*%
&%
,/&+
)$+$-)./
+,;30
(1$-+$
.*%,-.,
)9
/)&+,*(/$)
9
2&,/
-,
#?68""#
&22$3&-,$109
$
:&11
()*5&3$
&%+,);.,&*%+
*%
/*:
,*
()*.$$39


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
9
	
9!3
*;)
+&'%-,;)$
*%
,/&+
.*%+$%,
4*)2
2$-%+
,/-,
0*;
/-5$
)$.$&5$3
,/$
&%4*)2-,&*%
-<*;,
,/&+
+,;30
-%3
,/-,
0*;
-')$$
,*
5*1;%,$$)
4*)
,/&+
)$+$-)./
+,;309
*;
:&11
<$
'&5$%
-
.*(0
*4
,/&+
+&'%$3
4*)2
,*
>$$(9

*;
-)$
%*,
'&5&%'
;(
-%0
*4
0*;)
)&'/,+
<0
+&'%&%'
,/&+
4*)29

	5$%
-4,$)
0*;
/-5$
+&'%$3
,/&+
4*)2
0*;
2-0
./-%'$
0*;)
2&%3
-,
-%0
,&2$9
1$-+$
.*%,-.,
,/$
+,;30
+,-44
&4
0*;
3$.&3$
,*
+,*(
,->&%'
(-),
&%
,/&+
+,;309
4
0*;
./**+$
%*,
,*
,->$
(-),
&%
,/$
)$+$-)./
*)
&4
0*;
3$.&3$
,*
+,*(
,->&%'
(-),
1-,$)
0*;)
<$%$4&,+
-%3
+$)5&.$+
:&11
+,-0
,/$
+-2$
-+
<$4*)$
,/&+
+,;30
:-+
3&+.;++$3
:&,/
0*;9

*;
:&11
%*,
1*+$
,/$+$
<$%$4&,+
+$)5&.$+
*)
)&'/,+9
/$
&%5$+,&'-,*)
	


-%3E*)
+*2$*%$
/$E+/$
-((*&%,+
&%
/&+E/$)
(1-.$
:&11
,)0
,*
-%+:$)
-11
*4
0*;)
A;$+,&*%+9
4
0*;
/-5$
A;$+,&*%+
*)
.*%.$)%+
-,
-%0
,&2$
*)
&4
0*;
%$$3
,*
)$(*),
-%
&%B;)0
)$1-,$3
,*
,/$
)$+$-)./
0*;
2-0
+($->
:&,/
-
2$2<$)
*4
,/$
+,;30
+,-44C
	


-,
#?68""#

/*;)+
-
3-09
$2<$)+
*4
,/$
%+,&,;,&*%-1
$5&$:
*-)3
4*)
-01*)
*11$'$
*4
$3&.&%$
-%3
44&1&-,$3
*+(&,-1+

.-%
-1+*
-%+:$)
0*;)
A;$+,&*%+
-%3
.*%.$)%+
-<*;,
0*;)
)&'/,+
-+
-
)$+$-)./
+;<B$.,9
 /$

*44&.$
%;2<$)
&+
#?
68G6"9
-11
,/$

*44&.$
&4
0*;
:*;13
1&>$
,*
+($->
,*
-
($)+*%
&%3$($%3$%,
*4
,/$
&%5$+,&'-,*)
-%3
)$+$-)./
+,-44
4*)
.*2(1-&%,+
-<*;,
,/$
)$+$-)./
&4
0*;
.-%%*,
)$-./
,/$
)$+$-)./
+,-44
*)
&4
0*;
:&+/
,*
,-1>
,*
+*2$*%$
*,/$)
,/-%
,/$
)$+$-)./
+,-449
%3$)
$3$)-1
$';1-,&*%+
,/$

$3&.-1
4-.&1&,0
+/-11
()*5&3$
%$.$++-)0
2$3&.-1
,)$-,2$%,
,*
0*;
-+
-
)$+$-)./
+;<B$.,
&%B;)$3
-+
-
)$+;1,
<0
(-),&.&(-,&*%
&%
-
)$+$-)./
()*B$.,
-(()*5$3
<0
-

$+$-)./
-%3
$5$1*(2$%,
*22&,,$$
-%3
.*%3;.,$3
;%3$)
,/$
+;($)5&+&*%
*4
*%$
*)
2*)$

$2(1*0$$+9
/&+
)$A;&)$2$%,
3*$+
%*,
-((10
,*
,)$-,2$%,
4*)
&%B;)&$+
,/-,
)$+;1,
4)*2
%*%.*2(1&-%.$
<0
-
)$+$-)./
+;<B$.,
:&,/
+,;30
()*.$3;)$+9
4
0*;
+;+,-&%
-%
&%B;)0
-+
-
3&)$.,
)$+;1,
*4
0*;)
+,;30
(-),&.&(-,&*%
2$3&.-1
.-)$
:&11
<$
()*5&3$3
<0
,/$
&./-$1
	9
$->$0

$3&.-1
$%,$)9
/$
$(-),2$%,
*4
$,$)-%+
44-&)+
3*$+
%*,
%*)2-110
()*5&3$
-%0
*,/$)
4*)2
*4
.*2($%+-,&*%
4*)
&%B;)09
*;
3*
%*,
:-&5$
-%0
1&-<&1&,0
)&'/,+
4*)
($)+*%-1
&%B;)0
<0
+&'%&%'
,/&+
4*)29
:"683'8&"3'6683"6"""&""3&
"83
36"'5:"
"8"&&
3866""86&"'


35&6"8"'*" &63 '6"&3'6'3";'
"
1
6"6*833
35#*6&&'

3&&

<+=-<0>-<0+."<+=-<0>-<?//5


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#?
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""

3$+.)&(,&*%
*4
,/&+
.1&%&.-1
,)&-1
:&11
<$
-5-&1-<1$
*%
/,,(CEE:::91&%&.-1)&-1+9'*5
-+
)$A;&)$3
<0
99
1-:9

/&+
:$<+&,$
:&11
%*,
&%.1;3$
&%4*)2-,&*%
,/-,
.-%
&3$%,&40
0*;9

,
2*+,
,/$
:$<+&,$
:&11
&%.1;3$
-
+;22-)0
*4
,/$
)$+;1,+9

*;
.-%
+$-)./
,/&+
:$<+&,$
-,
-%0
,&2$9


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8



	


	


 !"
	






	
	


	
	



	



	
 




!
"#"#""
&'%&%'
,/&+
.*%+$%,
4*)2
&%3&.-,$+
,/-,
0*;
/-5$
)$-3
,/&+
.*%+$%,
4*)2
*)
/-5$
/-3
&,
)$-3
,*
0*;
,/-,
0*;)
A;$+,&*%+
/-5$
<$$%
-%+:$)$3
,*
0*;)
+-,&+4-.,&*%
-%3
,/-,
0*;
5*1;%,-)&10
-')$$
,*
(-),&.&(-,$
&%
,/&+
)$+$-)./
+,;309

*;
:&11
)$.$&5$
-
.*(0
*4
,/&+
+&'%$3
.*%+$%,
4*)29
;<B$.,
-,$
 &,%$++
%5$+,&'-,*)
*)
$+&'%$$
<,-&%&%'
*%+$%,
-,$
-,$


D
#66"
+,-+,./
#" &",012,+0",.12,2,3455
-'$
#
*4
#

59
)*,*.*1
"8E#E#8

































































































































































2$%3
#"E6E#8
-+,
2$%32$%,C
##EE"#8