The Impact of IV Acetaminophen on Postoperative Pain in Women Undergoing Pelvic Organ Prolapse Repair: A Double-Blind Randomized Placebo Controlled Trial
Phase: PHASE4
Conditions: Pelvic Organ Prolapse
Sponsor: Halina M Zyczynski, MD

Identifiers: NCT02155738   Unique Protocol ID: PFD-C-14-009  
Brief Title: IV Acetaminophen for Postoperative Pain After Pelvic Organ Prolapse Repair 
         Protocol Date:  2/20/18 
 
BACKGROUND 
POP is common with approximately 200,000 inpatient surgical procedures performed each year to treat this 
condition.1 Older women tend to seek care more often than their younger counterparts, and it is estimated that 
women 70-79 generate 10 times more consults per 1000 woman years compared to younger women. 2 This is 
particularly relevant since the world population is rapidly aging, with 27% of the population estimated to be >60 
years of age, with women representing 55% of the population by the year 2050.3 With such a significant 
number of elderly women projected to undergo surgical repair of POP, it is of particular importance to safely 
and effectively treat postoperative pain.   
 
Preemptive analgesia involves introduction of pain medication regimens prior to a noxious stimulus, such as a 
surgical incision, in order to prevent amplification of pain by the nervous system.4 Although NSAIDs would be 
ideal for this indication due to their reduction in pain and inflammation, they are not routinely used 
preoperatively in elderly patients because of interference with platelet and kidney function.5 Opioids are the 
standard of care for postoperative pain management in most practices; however, these narcotics pose a risk of 
constipation, nausea, urinary retention, sedation and mild cognitive impairment that can be especially 
problematic in an elderly population.6 Additionally, these side effects may lead to longer hospital stays and 
reduced patient satisfaction. There is no current standard of care for preemptive analgesia in POP surgery.  
 
IV acetaminophen, approved for use in the United States in 2010,7 has demonstrated safe and effective 
postoperative analgesia across a wide variety of surgical procedures including gynecology, general surgery, 
orthopedics and ophthalmology.8,9 However, it has not been well studied as preemptive analgesia and has 
demonstrated conflicting results about its efficacy for this indication. In two double-blind randomized placebo 
controlled studies of women undergoing abdominal hysterectomy, one study demonstrated significantly lower 
postoperative pain with preemptive IV acetaminophen compared to placebo,10 while the other study 
demonstrated similar pain scores.11 Interestingly, both of these studies reported significantly lower 
postoperative opioid narcotic consumption in the IV acetaminophen group compared to placebo.10,11 Ultimately, 
the efficacy of preemptive IV acetaminophen has yet to be established, especially in an elderly population of 
women who may benefit immensely from a reduction in postoperative narcotics.  Therefore, the overall goal of 
this study is to quantify the change in postoperative pain scores and narcotic requirements in women receiving 
preemptive analgesia with IV acetaminophen prior to POP repair. The central hypothesis is that women 
receiving preemptive IV acetaminophen prior to surgical correction of POP will have improved postoperative 
pain scores and reduced narcotic requirements. To test this hypothesis, we propose a double-blind 
randomized controlled trial of IV acetaminophen compared to placebo with the following aims: 
 
Aim 1: Quantify the impact of IV acetaminophen on 1a) postoperative pain scores and 1b) analgesic 
requirements.  1a) To achieve this aim, we will measure the degree of postoperative pain using visual analog 
scales (VAS) at specified time points throughout the postoperative period, and compare results between IV 
acetaminophen and placebo groups. 1b) We will use equianalgesic dosage tables to convert intra- and 
postoperative narcotics into morphine equivalents to compare narcotic requirements for the first week after 
surgery. We hypothesize that those patients receiving preemptive IV acetaminophen will have lower 
postoperative VAS scores and reduced narcotic requirements compared to placebo.   
 
Aim 2: Determine the effect of IV acetaminophen on patient satisfaction, mood, and interference with 
activities. To determine the impact of pain control on patient centered outcomes such as satisfaction, mood, 
and mobility, subjects will be asked to complete the American Pain Society Patient Outcome Questionnaire 
(APS-POQ-R) on postoperative day (POD) #1. Interference of pain with physical, mental and social activities 
will be measured by the Patient Reported Outcomes Measures Information Systems-Pain Interference–Short 
Form 8a (PROMIS PI-SF-8a) completed on POD#7. We hypothesize that women receiving preemptive IV 
acetaminophen will have improved patient satisfaction, mood, and quicker return to activities as evidenced by 
lower APS-POQ-R and PROMIS PI-SF-8a scores compared to placebo. 
 

Aim 3: Compare side effects of IV acetaminophen and placebo.  We will assess postoperative nausea, 
pruritus, dizziness and drowsiness using the APS-POQ-R questionnaire.  We will assess constipation and time 
to first bowel movement with postoperative bowel diaries.  We hypothesize that all of these side effects will be 
reduced or eliminated in those patients receiving preemptive IV acetaminophen compared to placebo due to a 
reduction in opiate requirements.   
 

RESEARCH STRATEGY 
Significance 
This research is significant since preemptive IV acetaminophen may demonstrate improved postoperative pain 
and quality of life (QOL) in patients undergoing POP surgery compared placebo.  If efficacy is demonstrated in 
women undergoing repair of POP, this will lead to improved implementation of IV acetaminophen as 
preemptive analgesia in this population of elderly women who are particularly susceptible to the side effects of 
narcotic pain medications.  Additionally, if preemptive analgesia with IV acetaminophen is effective in reducing 
postoperative narcotic use, this may lead to a reduction in side effects commonly seen with narcotics including 
nausea, pruritus, cognitive impairment, and constipation.  Reducing these side effects may lead to increased 
patient satisfaction, faster postoperative recovery and expedited hospital discharge. 
 
Innovation 
Although IV acetaminophen has shown efficacy as postoperative analgesia, studies on its use as preemptive 
analgesia are lacking.  Previous studies of preemptive analgesia with IV acetaminophen in Turkish and South 
Korean women undergoing total abdominal hysterectomy have been of low methodological quality and have 
shown conflicting results in reduction of postoperative VAS pain scores.10-11 Furthermore, this study aims to 
include patient centered outcomes such as patient satisfaction, mood and interference with activities, which 
have been lacking in prior studies of preemptive IV acetaminophen. If found to be effective in reducing 
postoperative pain and improving patients satisfaction, preemptive IV acetaminophen may become part of 
routine preoperative care for patients undergoing POP surgery. 
 
APPROACH 
Overview: This randomized double-blind placebo controlled multi-center trial will determine the efficacy of 
preemptive IV acetaminophen in reducing postoperative pain scores and narcotic requirements in women 
undergoing surgical repair of POP. 
 
Setting: This study will be conducted at Magee Womens Hospital (MWH) of the University of Pittsburgh 
Medical Center (UPMC), UPMC Passavant, Hamot Hospital of UPMC, West Penn Hospital of the Allegheny 
Health Network (AHN), and Jefferson Hospital of the AHN. Subjects will be recruited from multiple clinic sites 
throughout the UPMC and AHN networks.  These are high-volume referral center where women with POP are 
treated with surgical and non-surgical options.. 
 
Recruitment: Women will be recruited from the hospital based clinics and satellite sites of UPMC Magee, 
UPMC Hamot, UPMC Passavant, Jefferson Hospital and West Penn Hospital.  All potential participants for this 
study will be identified through standard clinical visits (either at initial consultation, follow-up, or preoperative 
appointment). As is our current standard of care, all new patients undergo a comprehensive history and 
physical exam.  If a woman has prolapse and is considering surgical repair, she may be eligible for the study. 
The study will be introduced by the patient’s physician.  If the patient would like to discuss the study further, 
she will be approached by a member of the study team to be screened. If she meets inclusion/exclusion 
criteria, she will be offered participation and informed consent will be obtained.  
 
Study eligibility 
Inclusion Criteria: Women ≥ 18 years of age scheduled to undergo surgery for POP via a vaginal or minimally 
invasive (laparoscopic/robotic) route and anticipated to have a hospital stay ≥24 hours will be eligible.  
Subjects must be able to speak and read English.   
Exclusion Criteria:  Women with (1) an allergy/intolerance to acetaminophen, (2) hepatic dysfunction, or (3) 
significant alcohol use – defined as patient reported consumption of more than 7 standard drinks per week 
and/or 3 drinks per day, will be excluded.  
 
Data collection 
Baseline assessment: (Table 1).The baseline visit will occur on the same day of enrollment. If the patient 
meets inclusion/exclusion criteria and consents to enrollment, baseline information will be obtained including 
age, race/ethnicity, general medical history, parity, tobacco use, prior hormone replacement therapy use, and 
baseline VAS pain score. Objective measurements including height, weight, BMI, and prolapse stage will be 
collected from the electronic medical record (EMR). Intraoperative data from the EMR will include surgical 
route (vaginal vs laparoscopic/robotic), concomitant procedures, estimated blood loss, and operative time. 

 
Table 1. Timeline of data collection 
 
Time of Data Collection/Evaluations 
Data 
Baseline Intervention 
 
Surgery 
Postoperative assessment 
7-day 
follow-up 
4h 8h 12h 16h 20h 24h 
VAS pain score 
x 
 
 
x 
x 
x 
x 
x 
x 
 
Narcotic requirements 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
Patient satisfaction and 
mood (APS-POQ-R) 
 
 
 
 
 
 
 
 
x 
 
Interference with activities 
(PROMIS PI-SF-8a) 
 
 
 
 
 
 
 
 
 
x 
Demographic factors 
x 
 
 
 
 
 
 
 
 
 
Intraoperative factors 
 
 
x 
 
 
 
 
 
 
 
Side effects (APS-POQ-R) 
 
 
 
 
 
 
 
 
x 
 
Bowel movements 
 
 
 
 
 
 
 
 
 
x 
Adverse events  
 
x 
x 
 
 
 
 
 
x 
x 
 
Intervention: Study drug and placebo will be prepared by the operating room pharmacist and placed in 
identical appearing 250cc glass bottles. Each bottle will contain either acetaminophen 100 mL or sodium 
chloride 0.9% 100 mL. Preoperative nurses will administer the study medication (either 100 cc of 
acetaminophen (1000mg/100mL) or 100 cc of normal saline) intravenously 10-30 minutes prior to anesthesia 
induction in the preoperative area on the day of surgery. The administered medication will be recorded in the 
EMR as “investigational drug” so that blinding will be maintained. Participants will be randomly allocated in a 
1:1 ratio using computer-generated fixed blocks of four, stratified by surgical route (vaginal vs 
laparoscopic/robotic). Allocation concealment will be maintained by the operating room pharmacist who will be 
in charge of preparing the study drug/placebo. The investigators, surgical team, anesthesia team, and nursing 
staff will be blinded to the randomization sequence.  Patients will be randomized in the preoperative area on 
the day of surgery to prevent randomization of patients who may go on to cancel or postpone surgery.  The 
UPMC Magee Investigational Drug service will maintain the randomization sequence.  Pharmacists at 
Passavant, Hamot, West Penn and Jefferson will contact the Magee Pharmacy on the day of surgery to obtain 
the treatment assignment. 
 
Follow-up:  Subjects will be followed for a total of 7 days (Table 1). Postoperatively, subjects will be asked to 
mark their pain on a VAS scale administered every 4 hours for a total of 24 hours. This will be performed by 
nurses at the time of routine vital sign assessment every 4 hours. Twenty-four hours after surgery, patients will 
be asked to complete the APS-POQ-R questionnaire. Doses of narcotic and nonnarcotic pain medications will 
be abstracted from the EMR.  After discharge, subjects will be given a 7-day diary on which they will record the 
time and dosage of all pain medications used (narcotic and non-narcotic) and time and date of all bowel 
movements. They will be asked to mail this questionnaire back to the office in a self-addressed stamped 
envelope. Participants will also be asked to complete the PROMIS PI-SF 8a questionnaire on POD#7. Based 
on participant preference, paper or electronic copies of this questionnaire will be provided. Paper copies will be 
mailed back with self-addressed stamped envelopes.  Electronic access will be granted through the NIH 
PROMIS Assessment Center via a secure link emailed to participants interested in electronic completion. All 
patients will be called and reminded to fill out this survey 1 week following surgery. Surgical and post-operative 
complications will be extracted from the EMR for a period of 7 days post-operatively by research staff.  
Specifically, readmissions or telephone calls to the office for poor pain control or constipation will be extracted.  
Of note, the study coordinators at AHN and UPMC will ensure proper data collection and will be in charge of 
data extraction at their respective sites.  
 
Variables and measures 
Postoperative pain 
Visual Analog Scale (VAS) pain: The primary outcome for this study is pain at 24 hours postoperatively. Pain 
will be measured every four hours following surgery (4, 8, 12, 16, 20, and 24 hours) by VAS pain scales. VAS 
pain scales are unidimensional measures of pain intensity that are easily completed and scored.12 Subjects 
place an “X” on a 10 centimeter (cm) VAS line at the point that represents their pain intensity. The score is 
calculated by measuring the distance in millimeters (mm) along the 10 cm line where 0 represents “no pain” 

and 10 represents “worst pain.” Scores range from 0-100mm. They have been widely used in diverse 
populations to assess pain, and specifically have been used to measure postoperative pain in many prior 
studies of IV acetaminophen.8 VAS pain scores will be used as the primary outcome measure in this study 
because they are easy to complete, which is essential in a predominantly elderly population, and because they 
are easily compared to prior studies of preemptive IV acetaminophen.  
Narcotic requirements 
Morphine equivalents: Doses of narcotic pain medications administered to subjects during the intra- and 
postoperative period will be abstracted from the EMR.  Narcotics will be converted to morphine equivalents, in 
grams, using an equianalgesic dosage table.13 Narcotic use following hospital discharge will be measured by a 
7-day diary, which will also be converted to morphine equivalents. Morphine equivalents have been widely 
used in the study of postoperative pain and specifically those investigating the efficacy of preemptive and 
postoperative IV acetaminophen.8,10,11  
 
Patient satisfaction and mood 
APS-POQ-R: The APS-POQ-R is a validated questionnaire used to assess QOL and satisfaction with pain 
control over the 24 hours following an operation. It is preferred over more global measures of QOL since it is 
validated for acute pain in the setting of recent surgery. This questionnaire was designed to assess satisfaction 
with pain control and impact of pain on mood and emotional well-being. It contains twelve items across six 
subscales: pain severity and relief, impact of pain on mood/emotions, adverse effects, satisfaction, 
participation in decision making, and non-pharmacological methods of pain management.14 We are specifically 
interested in the impact of pain on satisfaction (item 9), mood/emotions (item 5 a-d) and adverse effects (item 6 
a-d, see below). These subscales use a 0-10 rating scale. This measure has good internal consistency 
(alpha=0.85) and validity. 
 
Pain interference 
PROMIS PI-SF-8a: This questionnaire is a short form of the PROMIS PI item bank, designed to assess the 
interference of pain on an individual’s physical, mental and social activities. It is a patient reported outcomes 
measure and is validated for both computer and paper administration by the NIH. Specifically, it queries the 
interference of pain over the last week across 8 items.  It has shown excellent reliability (alpha=0.90-0.95) and 
validity.15 Based on participant preference, paper or electronic copies of this questionnaire will be provided. 
Electronic access will be granted through the NIH PROMIS Assessment Center, with questionnaires emailed to 
participants via a secure link. 
 
Side effects 
APS-POQ-R: The APS-POQ-R questionnaire contains four items on the side effects of pain medication 
including nausea, drowsiness, itchiness and dizziness (Items 6a-d). Respondents use a rating scale 0-10 to 
indicate the severity of each side effect.  Psychometric properties of this questionnaire are discussed above.   
 
Bowel diaries: Because the APS-POQ-R questionnaire does not query constipation, patients will be asked to 
provide the date/time of all bowel movements during the first postoperative week.  Validated measures of 
constipation are complicated by the fact that most are validated for chronic constipation.16 Therefore, we chose 
to survey constipation through the use of a self-reported bowel diary through POD#7. 
 
Data management plan 
After informed consent is signed, de-identified demographic and objective data from the baseline visit will be 
abstracted from the EMR into an excel file which will transferred into a SPSS (Armonk, NY) document for 
analysis. Data exchange between AHN and UPMC will be done through secure password protected servers.  
No protected health information will be exchanged between the two sites. The APS-POQ-R questionnaire will 
be administered on paper. Based on participant preference, paper or electronic copies of the PROMIS PI-SF-
8a questionnaire will be provided. Paper copies will be abstracted by members of the study team and 
electronic copies will be automatically downloaded. All files will be stored on a password protected network 
drive within the health system firewalls.  Security will be maintained by limiting login access to members of the 
study team. Data security will be monitored at weekly research meetings.  
 
Data analysis 

Aim 1: Quantify the impact of IV acetaminophen on 1a) postoperative pain scores and 1b) analgesic 
requirements. The primary outcome is VAS pain score at 24 hours. VAS scores will be measured on a scale 
of 0-100mm with higher scores indicating worse pain. Linear mixed models will be used to compare pain 
scores at baseline, 4, 8, 12, 16, 20 and 24 hours postoperatively between IV acetaminophen and placebo 
groups. Patient effects will be treated as random with fixed effects for group, time and group*time. Narcotic 
requirements measured in morphine equivalent grams will be compared by T-tests (and Wilcoxon rank-sum 
tests if non-parametric). Since route of surgery likely contributes to the amount of postoperative pain, we plan 
to stratify our analysis by vaginal and laparoscopic/robotic surgery. Both VAS pain scores and narcotic 
requirements will be compared in an intention to treat analysis. Heterogeneity of treatment effects will be 
analyzed by racial subgroups and menopausal status. Multivariable logistic regression analysis will be used to 
identify independent risk factors that predict pain at 24 hours postoperatively. We plan to adjust for operating 
time, estimated blood loss, and concomitant procedures, as all of these may predict worse postoperative pain.  
Anything found to be different at baseline will also be included as covariates. Age may affect postoperative 
pain through alteration of the pain response or differences in pain medication metabolism. For this reason, we 
plan to explore whether age moderates postoperative VAS scores.   
  
Aim 2: Determine the effect of IV acetaminophen on patient satisfaction, mood, and interference with 
activities. T-tests (and Wilcoxon rank-sum tests if non-parametric) will be used to analyze results of APS-
POQ-R rating scales and PROMIS PI-SF-8a scores. Individual analysis of APS-POQ-R questionnaire items 5 
and 9 is planned to determine the impact of IV acetaminophen on mood and satisfaction respectively. 
 
Aim 3: Compare side effects of IV acetaminophen and placebo.  The severity of individual side effects 
(nausea, drowsiness, itchiness, and dizziness), as measured by the APS-POQ-R adverse effects subscale 
(items 6a-d), will be compared between IV acetaminophen and placebo groups using T-tests (and Wilcoxon 
rank-sum tests if non-parametric).  Linear regression analysis is planned to quantify the effect of narcotics 
(measured in morphine equivalent grams) on side effect severity.  Constipation, measured in time (hours) 
since surgery to first bowel movement, will be compared between the groups and will be included in the 
multivariable regression model to determine the effect of narcotics on constipation. 
 
Sample size and power analyses 
There is a paucity of information on mean VAS scores on POD#1 following gynecologic surgery. Mean ± 
standard deviation 24 hour VAS scores following robotic sacral colpopexy have been published (44.0 ± 
20.8mm).18 VAS pain scores at 24 hours following vaginal prolapse repair are also available (19.3±14.8mm).19  
Previous studies of adult emergency department patients demonstrate a minimally clinically significant 
difference (MCSD) in VAS pain scores of 9mm, 12mm, and 18 mm.20-22 Unfortunately, MCSD have not been 
calculated in a gynecologic or urogynecologic surgical population. For this sample size analysis, we have 
chosen a MCSD in VAS pain score of 12 mm, as this is the median value of previously published values.  
Since we desired to power this study to detect a difference in VAS pain scores in women undergoing both 
vaginal and laparoscopic/robotic surgery, we performed separate sample size analyses using the larger of the 
two standard deviations (20.8mm) from previously published studies of robotic and vaginal surgery.18,19 
Assuming a two-sided alpha of 0.05, 96 women in each group would provide 80% power to detect a clinically 
significant difference in VAS scores after surgery in those receiving IV acetaminophen compared to placebo. 
After adjusting for a 5% loss to follow-up rate, we would need to randomize 102 women undergoing 
laparoscopic/robotic surgery and 102 undergoing vaginal surgery for a total of 204 subjects. 
 
Potential issues and solutions 
Patients that do not undergo surgery after enrollment: To prevent non-adherence to the study intervention, we 
will not randomize subjects until the day of surgery in the preoperative area. Once randomized, all participants 
will be followed and analyzed in an intention to treat analysis. Subjects who are lost prior to randomization, for 
example those that cancel surgery or are not medically cleared will be excluded from analysis. 
 
Competing events: We plan to exclude those women with severe dementia that will be unable to accurately 
complete study questionnaires/VAS pain scores.  Because patients with terminal diseases or those expected 
to have poor follow-up do not usually receive elective POP surgery, these events should not occur in a high 
percentage of subjects, if at all.   
 

Missing data: Subjects with missing VAS pain scores or those that do not complete/return questionnaires and 
diaries will still be included in the final analysis. To reduce the chance of missing data, members of the study 
team will call subjects or personally visit them in their hospital room to provide reminders for completion of VAS 
pain scales and APS-POQ-R questionnaires. Study nurses will call the patient at 1 week to remind them to 
complete and return their PROMIS PI-SF 8a questionnaire, pain diary and bowel diary. We will also emphasize 
the importance of the data and need for completeness with subjects at the time of enrollment. We will account 
for missing data at the onset of the study by increasing the sample size by 5%. By keeping data collection 
short (limited short forms with study participation ending on POD#7), we will not overburden the subjects.  
 
Adverse events: We will proactively monitor for allergic reaction to IV acetaminophen and hepatotoxicity 
throughout the first 24 hours following surgery. Hospital readmission will be proactively monitored through 
POD#7. Because postoperative pain medications containing acetaminophen are routinely given following 
surgery, we will audit the EMR on POD#1 to ensure that the maximum dose of acetaminophen (4000 mg) has 
not been exceeded in the 24 hour period following surgery.  Because the standard dose of IV acetaminophen 
is 1000 mg, acetaminophen containing medications will not be given to any participant (regardless of 
intervention group) within the first 6 hours of surgery. This will appear as an alert in the patient chart to ensure 
that the pharmacy does not dose acetaminophen containing medications during this window.   
 
Alternative strategies 
We initially considered comparing preemptive IV acetaminophen to ‘usual care’ rather than placebo. However, 
IV acetaminophen is occasionally administered intraoperatively by the anesthesiology team, and due to 
concerns for acetaminophen overdose, this medication would have to be prohibited.  We also considered an 
unblinded study without a placebo-controlled group in order to avoid the investigational drug costs associated 
with assembly of the identical appearing intervention/placebo bottles.  However, lack of blinding may bias 
patient reported pain scores and/or physician prescribing of narcotics.    
 
Benchmarks for success  
Project benchmarks of success will include: (1) achievement of overall subject accrual goals; (2) attainment of 
primary outcome for all subjects (VAS pain scores and narcotic requirements); (3) high-profile presentations 
and papers; (4) achievement of short-term career objectives; (5) implementation of clinical intervention as 
standard of care (if found to be effective).  
 
Feasibility data 
The Magee Womens Center for Bladder and Pelvic Health is a large referral center with five urogynecologists 
and two urologists specializing in female pelvic medicine. The Allegheny Health Network is a large referral 
center with three urogynecologists. Therefore, attaining a sample size of 204 in the span of one year is 
certainly feasible.  We have formally presented the study protocol to members of our division at monthly 
research meetings and have built consensus amongst the five urogynecologists in our division.  All have 
pledged their support for recruitment and believe our sample size is attainable.  Additionally, we have not made 
our inclusion/exclusion criteria overly-strict to enhance our ability to recruit subjects. 
 
Time table and plan for completing project in established timeframe 
This study is anticipated to be concluded by the end of the one-year award period (Table 2).  After a short 
period of research staff training, we anticipate that recruitment of the 204 participants will be concluded by the 
end of the 3rd quarter of year one.  The 4th quarter of year one will be reserved for data analysis and manuscript 
drafting.  We aim to submit the manuscript for presentation at the 2017 American Urogynecologic Society 
(AUGS) meeting. 
 
Table 2. Timeline 
 
 
Year 1 
Year 2 
Q 1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 
Train research staff 
 
 
 
 
 
 
 
 
Baseline data collection 
 
 
 
 
 
 
 
 
Follow-up data collection  
 
 
 
 
 
 
 
Analysis 
 
 
 
 
 
 
 
 
Write manuscript 
 
 
 
 
 
 
 
 

Disseminate findings 
 
 
 
 
 
 
 
 
 
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