Conditions: Arthropathy of Knee Joint
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 24
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine whether or not giving a lower dose of antibiotics (Vancomycin) in the area where it is needed (the knee joint) is more effective at obtaining adequate tissue levels of the antibiotic than the current standard dose which is given intravenously (IV) through a wrist vein. The use of intraosseous regional administration (IORA) of vancomycin requires the use of a tourniquet for the duration of the procedure. Many surgeons prefer to perform the surgery with tourniquet use minimised or without a tourniquet at all. The aim of this study is to evaluate whether IORA vancomycin can achieve effective tissue concentrations with tourniquet use minimised.

Detailed description:
Patients are assigned to one of two groups by chance (like a coin toss):

GROUP A - Will receive 15mg/kg based on actual body weight (maximum of 2g) of vancomycin via the systemic route at a rate of 15mg/kg as per hospital guidelines. Systemic IV vancomycin is given via a forearm vein, given over an infusion timed to finish immediately prior to surgery.

GROUP B - Will have the limb exsanguinated and an above knee tourniquet inflated to 300 mmHg. Immediately following tourniquet inflation, Group B will receive 500mg of vancomycin, via an EZ-IO intraosseous cannula. The vancomycin would be administered in 150ml of saline solution. The intraosseous cannula would be placed into the epiphysis of the proximal tibia. The tourniquet will be left inflated for 10 minutes following completion of the IORA injection then deflated.

Both Groups will receive weight-based dose of systemic cefazolin ( or alternative antibiotic if allergic to cefazolin 15 minutes prior to inflation of tourniquet. This ensures all patients in the study receive effective antibiotic prophylaxis regardless of randomization. Both groups of patients would then undergo routine prep and draping For both groups, Total knee replacement would then be carried out as normal and the tourniquet will be inflated for cementation of the implants.

TISSUE SAMPLES Ten (10) tissue samples will be taken from each patient, 6 'fat' samples and 4 'bone' samples. Each sample is very small, around the size of a pinhead. Bone samples will be taken from the femur only to ensure no direct contamination from the site of injection (tibia) In addition, drain samples will be taken from the intra-articular drain site to measure vancomycin concentration the morning following surgery.

Three blood samples will be taken in both groups, intraoperatively, in recovery, and the following morning.

These samples are frozen and sent to a lab for analysis.

Arms:
arm 1: Will receive 15mg/kg based on actual body weight (maximum of 2g) of vancomycin via the systemic route at a rate of 15mg/kg as per hospital guidelines. Systemic IV vancomycin is given via a forearm vein, given over an infusion timed to finish immediately prior to surgery. arm 2: Will have the limb exsanguinated and an above knee tourniquet inflated to 300 mmHg. Immediately following tourniquet inflation, Group B will receive 500mg of vancomycin, via an EZ-IO intraosseous cannula. The vancomycin would be administered in 150ml of saline solution. The intraosseous cannula would be placed into the epiphysis of the proximal tibia. The tourniquet will be left inflated for 10 minutes following completion of the IORA injection then deflated.

Interventions: intervention 1: Vancomycin
Intervention descriptions: intervention 1: Antibiotic

Protocol document:
Prot_SAP_000.pdf: 
 
 
Regional Prophylactic 
Vancomycin with Restricted 
Tourniquet Time in Primary 
Total Knee replacement 
 
NCT# 03506347 
 
November 8, 2018 


 
1 
Regional Prophylactic Vancomycin with Restricted 
Tourniquet Time in Primary Total Knee replacement 
Protocol Date: 7/8/17 
Revised 07/17/2018 
Current Version 11/8/2018 
Simon W Young, Henry D Clarke, Mark J Spangehl 
 
 
Project Summary 
 
Resistance to cefalosporins in Staphylococcus Aureus (SA) and Coagulase negative 
Staphylococci (CoNS) isolates is increasing, and vancomycin has been suggested as 
an alternative prophylactic agent in TKA1.  Recently, we have investigated 
prophylactic vancomycin via intraosseous regional administration (IORA) in primary 
TKA2, which allowed the use of a lower dose (500mg) while still achieving tissue 
concentrations 4-10 times higher than systemic administration.  
The use of IORA vancomycin requires the use of a tourniquet for the duration of the 
procedure. Many surgeons prefer to perform the surgery with tourniquet use 
minimised or without a tourniquet at all.  The aim of this study is to evaluate whether 
IORA vancomycin can achieve effective tissue concentrations with tourniquet use 
minimised.  
 
Based on a power calculation using previous IORA data, 26 patients undergoing 
primary TKA for osteoarthritis will be enrolled in a prospective, randomized, 
controlled trial. Patients will be randomized into two groups. Group A would receive 
a weight based dose of 15mg/kg systemic IV vancomycin via a forearm vein, given 
over a 1-2 hour infusion timed to finish immediately prior to surgery. Group A would 
have a tourniquet used for cementation only. Group B would receive 500mg 
vancomycin via IORA into a proximal tibial cannula, after tourniquet inflation and 
immediately prior to skin incision. In group B, the tourniquet would be inflated for a 
total of 10 minutes after completion of IORA injection, then deflated, then reinflated 
for cementation only. In addition, patients in both groups would receive standard IV 
systemic prophylaxis with a cephalosporin.  


 
2 
: 
 
 
Vanc dose 
Route 
Tourniquet 
Group A 
1g 
IV 
Inflate for cement only 
Group B 
500 mg 
IORA 
Up 10 min, down, up for cement 
 
 
Primary TKA would then be carried out as normal, and during the procedure ten 
tissue samples (6 subcutaneous fat, 4 bone) will be taken at set time intervals. These 
samples would then be processed using a previously validated technique involving 
high performance liquid chromatography (HPLC) to determine the tissue 
concentration of vancomycin. Samples would be stored in a -80C freezer in the 
laboratory at Mayo Arizona, before being sent as one shipment to a laboratory in 
Christchurch, New Zealand for processing. Tissue concentrations would then be 
compared between the two groups. 
 
 
 
 
 


 
3 
Introduction 
 
Total knee Arthroplasty (TKA) remains one of the most successful interventions in 
medicine.  Patients who are facing lifelong, crippling pain due to knee arthritis now 
have the opportunity to return to near normal function.   
 
The cost of treating an established infection is estimated at $US107,000 per case3-5, 
and even after successful treatment results in a significantly compromised functional 
outcome for the patient.  
 
Prophylactic antibiotics are currently the most effective measure available to prevent 
deep infection following knee replacement, but increasing antibiotic resistance is 
reducing their effectiveness6-10.  In particular, resistance to the most commonly used 
cephalosporin agents among Staphylococcus Aureus (SA) and Coagulase negative 
Staphylococci (CoNS) isolates continues to rise1,11. Vancomycin, which retains broad 
efficacy against such organisms, has been suggested as an alternative prophylactic 
agent in TKA1,12.   
 
However, systemic vancomycin requires a prolonged administration time, risks 
promoting further antibiotic resistance, and can cause systemic toxicity. Regional 
administration of medication using a tourniquet achieves higher tissue concentrations 
than systemic administration, by limiting distribution of the drug to the targeted limb. 
Recently, we have investigated prophylactic vancomycin via intraosseous regional 
administration (IORA) in primary TKA2,12, which allowed the use of a lower dose 
(250mg or 500mg) while still achieving tissue concentrations 4-10 times higher than 
systemic administration.  This low-dose IORA method optimizes timing of 
vancomycin administration, and minimizes potential side effects. In addition, greater 
efficacy of the IORA technique has been demonstrated in an animal model of TKA 
infection.13 
 
Regional administration however requires the use of a tourniquet during the procedure, 
which may have negative effects including increasing post-operative pain14, 
upregulating inflammatory enzymes15, and reducing quadriceps strength16. For this 


 
4 
reason, many surgeons prefer to minimise the use of the tourniquet during the 
procedure17.  
 
It may be possible to perform IORA with the tourniquet inflated for a short period of 
time following intraosseous injection, as the depot effect may mean tissue 
concentrations remain high for the remainder of the procedure. The aim of this study 
is to evaluate whether IORA vancomycin can achieve effective tissue concentrations 
for the duration of the procedure with tourniquet use minimised in primary TKA.  
 
 
 
 
 
From Kurtz et al, JBJS 2007 
 
 
Potential Benefits of Regional Vancomycin Administration 
 
Regional administration of vancomycin has the following potential advantages: 
 
1) Lower risk of toxicity 


 
5 
 
Vancomycin carries the risk of toxicity to other organs. In particular, higher systemic 
concentrations on vancomycin have been associated with a greater risk of 
nephrotoxicity.2,12,18,19 Because regional administration restricts all of the medication 
to its site of action, lower doses may still provide effective tissue concentrations while 
minimising the risk of systemic toxicity.  
 
2) More effective prophylaxis 
 
As well as the advantage of more effective coverage of resistant organisms with 
vancomycin, by using regional administration the antibiotic stays in the area where it 
is needed. Therefore a higher tissue concentration of the antibiotic can be achieved, 
even with a lower dose.  This is relevant as higher concentrations of vancomycin have 
been associated with greater efficacy in a clinical setting.18-20 In addition, greater 
efficacy of the IORA technique has been demonstrated in an animal model of TKA 
infection.13 
  
3) Ease of administration 
 
Vancomycin is normally given systemically over one hour, as high systemic 
concentrations can cause histamine release and a subsequent ‘red man syndrome’, 
caused by dilation of blood vessels secondary to the histamine release.  The timing of 
prophylactic antibiotics is extremely important, and the dose should be given within 
the 60 minutes preceding the surgical incision.2,12,21,22 Due to the long infusion time 
vancomycin is normally given, achieving optimum timing as a prophylactic antibiotic 
is difficult to achieve in a busy operating room. In a review of 18,342 arthroplasty 
procedures, vancomycin was given with appropriate timing in only 22% of cases, 
compared to 77% of cases given a cephalosporin3-5. 
 
The lower doses of vancomycin used with regional administration and the fact that its 
distribution is limited to the limb reduces the risk of ‘red man syndrome’.  This allows 
for more convenient administration of the antibiotic thus ensuring correct timing of 
administration. 
 


 
6 
4) Less resistance pressure 
 
Development of resistance to antibiotics relates to both duration and dosage of the 
antibiotic, which applies a ‘selection pressure’ to bacteria promoting the emergence of 
resistant organisms.  The advantage of regional administration over systemic is that a 
lower overall dose can be used, while still maximizing the effectiveness of the 
antibiotic at its site of action.  
 
 
Aim 
 
The aim of this study is to evaluate whether IORA vancomycin can achieve effective 
tissue concentrations with tourniquet use minimised in primary TKA.  
 
Patients and Methods 
 
Patients under undergoing revision total knee replacement would be eligible for 
enrolment in a prospective, randomized trial.   
 
Inclusion Criteria 
 
Primary TKA for osteoarthritis 
Informed consent given 
 
Exclusion Criteria 
 
Current or treatment with IV Vancomycin within preceding 7 days 
Previous hypersenstivity to vancomycin 
Significant cardiac or respiratory abnormality 
Patient has contraindications to IO vascular access using the  EZ-IO 
 
 
Both groups would receive weight-based dose of systemic cefazolin (or 
alternative antibiotic if allergic to cefazolin) 15 minutes prior to tourniquet 


 
7 
inflation – either 2g for patients between 80-120kg or 3g for patients over 120kg. 
This ensures all patients in the study receive effective antibiotic prophylaxis 
regardless of randomisation. Both groups of patients would then undergo 
routine prep and draping Group B will have the limb exsanguinated and an 
above knee tourniquet inflated to 300mmHg. 
 
Group A would receive 15mg/kg based on actual body weight (maximum of 2g) 
of vancomycin via the systemic route at a rate of 15mg/kg as per hospital 
guidelines (acceptable to give 2g over 2 hours). Systemic IV vancomycin is given 
via a forearm vein, given over an infusion timed to finish immediately prior to surgery.  
 
Immediately following tourniquet inflation, Group B will receive 500mg of 
vancomycin, via an EZ-IO (Teleflex Medical, San Antonio, Texas) intraosseous 
cannula. This system has been well validated in multiple studies6-10, showing high 
user satisfaction and low complication rates.  The vancomycin would be administered 
in 150ml of saline solution following the recommendations of Waisman et al.1,11. The 
intraosseous cannula would be placed into the epiphysis of the proximal tibia as 
previously described 1,12.  
 
In group B, the tourniquet will be left inflated for 10 minutes following completion of 
the IORA injection then deflated.  
 
Total knee replacement would then be carried out as normal and the tourniquet will be 
inflated for cementation of the implants in both groups. A fat sample will be taken 
immediately after skin incision, and then bone and fat samples with be taken at set 
intervals during the surgery, including immediately prior to closure. Each patient will 
have a total of 10 tissue samples taken intraoperatively. In addition, drain samples 
will be taken from the intra-articular drain site to measure vancomycin concentration 
the morning following surgery. Three blood samples will be taken in both groups, 
intraoperatively, in recovery, and the following morning.  
 
A timeline for each group is presented below. Samples will be taken at specific steps 
during the procedure, and actual times will be recorded with each sample as the 


 
8 
duration of the surgical procedure may vary.  Times given below in italics represent 
approximations only.   
 
Group  B 
(Intraosseous) 
Group A 
(Systemic) 
-90 minutes 
 
1g systemic Vancomycin infusion  
-10 minutes 
1g systemic Cefazolin (or alternative 
antibiotic) injected 
1g systemic Cefazolin (or alternative 
antibiotic) injected 
-1 minute  
Routine prep and draping 
Routine prep and draping  
0 minutes 
Exsanguination & Tourniquet inflation for 
10 minutes 
----------------------- 
(No Tourniquet inflation) 
1 minute 
 
500mg intraosseous Vancomycin injected 
into tibial cannula 
---------------------- 
Surgery Commences 
2 minutes 
Skin incision  
Skin incision 
Post incision 
2 minutes 
1st sample – subcutaneous fat 
Blood Sample 1 
1st sample – subcutaneous fat 
Blood Sample 1 
Distal Femoral Cut 
(10-15 minutes) 
2nd and 3rd samples – fat and bone 
Tourniquet deflated at 10 minutes 
2nd and 3rd samples – fat and bone 
Tibial Cut  
4th and 5th samples – fat and bone 
4th and 5th samples – fat and bone 
15-25 minutes 
 
 
Implant Trialling  
(25-45 minutes) 
6th and 7th samples – fat and bone 
 
6th and 7th samples – fat and bone 
 
Implant Cementing 
(45-60 minutes) 
Tourniquet inflation pre-cementing 
8th and 9th samples – fat and bone 
Tourniquet deflation post cementing 
 
Tourniquet inflation pre-cementing 
8th and 9th samples – fat and bone 
Tourniquet deflation post cementing 
 
Prior to Closure 
60+ minutes 
10th Sample - fat 
10th sample - fat 
Surgery Complete 
 
 
Recovery 
Blood Sample 2 
Blood Sample 2 
Next Morning 
Drain Sample 
Blood Sample 3 
Drain Sample 
Blood Sample 3 
 
 
 
 
 
 
 


 
9 
Samples 
 
Ten tissue samples will be taken from each patient, 6 ‘fat’ samples and 4 ‘bone’ 
samples.  Each sample will be approximately the size of a pinhead.  Bone samples 
will be taken from the femur only to ensure no direct contamination from the site of 
injection (tibia).  Where possible, both bone and fat samples will be taken from tissue 
which is normally discarded during the course of a total knee replacement procedure, 
otherwise samples will be taken from tissue that is already exposed with no further 
incisions or invasive procedures required.  Due to the small size of the samples it is 
anticipated that there will be no detrimental effect on the patient.  Samples will be 
stored the Mayo Clinic Hospital lab at -90°C, before being transported to 
Christchurch, New Zealand for analysis using a previously validated technique2,12. 
Bone samples will be crushed with pliers, finely cut further with a scalpel, then 
weighed and immersed in phosphate buffered saline pH 7.3 for 15 h at 4C. The fat 
samples will finely cut with a scalpel, and then treated in a same way as the bone 
samples. The immersed bone or fat tissue suspension will be vortexed for 30 seconds 
and centrifuged at 15,000 g for 10 min. The supernatant will be transferred to a clean 
tube and perchloric acid added to precipitate the proteins. After centrifugation at 
15,000 g for 5 min, 50 uL of clear supernatant will be analysed. Drain fluid samples 
will be processed by the Mayo Clinic laboratory by being centrifuged at 2500rpm 
for 10 minutes.  The supernatant will be placed in a 1.8ml cryovial.  The 
remaining supernatant and cell pellet will be discarded.  The drain fluid samples 
will be stored at -90°C until they are shipped with the other samples to 
Christchurch, New Zealand.  
 
 
 


 
10
Power Calculation 
 
Data from a previous randomized trial comparing (IORA) of 500 mg vs. systemic 
administration of 1g vancomycin provide AUC of concentrations during the 
procedures.   The following table provides the information of AUC and standardized 
AUC (AUC/length of procedure).  
 
 
 
AUC  
 (AUC/procedure 
mins)  
(mean)  
AUC  
( AUC/procedure 
mins) 
(median)  
AUC  
(AUC/procedure 
mins)  
(STD)  
AUC  
(AUC/procedure 
mins  
(Min)  
AUC  
(AUC/procedure 
mins)  
(Max)  
Bone 
  
  
  
  
  
IO 
1236 (15.3)  
1190 (13.2)  
561 (7.1)  
542 (7.6)  
2151 (29.1)  
Systematic 
259 (3.2)  
221 (3.0)  
185 (1.9)  
87(1.0)  
697(7.4)  
Fat 
 
 
 
 
 
IO 
2398 
1652 
1913 
617 
6846 
Systematic 
194 
190 
56 
126 
315 
Blood 
 
 
 
 
 
IO 
1236 
1158 
280 
863 
1638 
Systematic 
2547 
2684 
782 
1454 
3554 
 
 
Using AUC 
The standardized area under the curve is 30.5 (STD: 26.6) in the IO arm, and 2.4 
(STD: 0.6) in the systematic arm. To achieve 90% statistics power with type I error 
rate of 0.05, 12 patients will be required for each group after accounting for 10% 
missing data.  
 
While data on pharmacodynamics of vancomycin for prophylaxis are lacking, in 
treatment models of infection, the area under the concentration-time curve divided by 
the Minimum Inhibitory Concentration (MIC, a parameter that reflects the sensitively 
of a bacterial strain to a given antibiotic) is the pharmacokinetic-pharmacodynamic 


 
11
parameter most predictive of efficacy. Therefore, further increases in tissue 
vancomycin concentrations are likely to enhance the effectiveness of prophylaxis, 
particularly in organisms with MICs of 1g/L or more such as MRSA and CoNS20; this 
suggests the differences used in our power analysis are clinically relevant. 
 
 
Statistical analysis 
 
Means, standard deviations, and the 95% confidence limits will be calculated for the 
concentrations in the different samples. Different tissue samples were pooled 
according to surgical steps. Coefficient of variations (CV) of concentration level will 
be summarized at each surgical step for the comparison between two arms. Repeat 
measure analysis of variance will be used to compare the average level of 
concentration across time between groups adjusted by BMI, age, and length of 
surgical procedure; Shapiro-Wilk test will be used to assess the normality of the 
residuals.  Adverse event will be recorded by contingency table.  
 
 
 


 
12
Safety of the intraosseous route 
 
The technique of intraosseous regional administration of antibiotics has been 
evaluated in humans in two randomised controlled trials 2,12.  No complications 
related to the use of the technique were found. 
 
The use of the intraosseous route for administration of both fluids and medications is 
well established. In 1947, Heinld4 reported on the use of the intraosseous route in over 
1000 paediatric patients, reporting a 95% success rate in administering fluids, blood 
products, and a variety of medications. The technique has been more popular in 
paediatric patients because intravenous access is more difficult; however intraosseous 
administration is equally as effective in adult patients. A summary of more current 
literature is included below, and a copy of a comprehensive review article recently 
published by Tobias7 is attached.  
 
Of particular relevance to the current study, 3 papers have investigated the regional 
(with tourniquet on) intraosseous delivery of antibiotics in horses.  Scheuch27 
compared intraosseous versus intravenous infusion of amikacin (an antibiotic) and 
found similar tissue levels of antibiotic in 21 horses. Mattson28 found effective tissue 
concentrations of gentamicin after intraosseous regional delivery in 12 horses, and 
recommended this as a form of treatment for infection.  Similarly Rubio29  compared 
regional intravenous versus intraosseous administration of vancomycin in 12 horses 
and found equivalent tissue perfusion for both routes.  None of the above studies 
reported any complications with the intraosseous route. 
 
The use of regional (with tourniquet inflated) intraosseous infusions of medications 
has also been investigated in humans. Waisman11 on 109 patients who were given 
local anaesthetic agents through the regional intraosseous route, in both the upper and 
lower limbs, to allow surgical procedures to be performed on the limb with the patient 
awake.  The procedure was successful in 106 of 109 patients, with 3 failures.  In one 
patient the needle was incorrectly positioned, and two patients had inadequate 
anaesthesia which  the authors attributed to an insufficient amount of medication 
infused.  No other complications were reported.  This paper is a useful reference as it 
has a very similar concept to our study (substituting the intraosseous route for 


 
13
intravenous in the regional delivery of medications) and provides evidence of the 
safety of the technique in a large number of patients.  
 
There are 4 main complications of intraosseous infusion that have been reported in 
adults. All relate to technical errors or prolonged infusions in an emergent setting, and 
are therefore extremely unlikely to occur in the single, controlled injection proposed 
in this study.  
 
1) Extravasation of fluid (due to incorrect needle placement) 
This complication occurs when a needle is not place correctly (outside the bone), and 
infusion of fluid or medication is commenced. With modern intraosseous needles this 
complication is reduced by closely monitoring the patient, particularly at the IO 
needle insertion site, and using appropriate length IO needles to prevent over 
penetration through the bone.  The reported success rates for the EZ-IO needle used in 
the current study range from 94-100%, and it is anticipated that as the needle will be 
placed by a trained orthopaedic surgeon in a controlled theatre environment the 
chance of incorrect needle placement will be very low. 
 
2) Compartment Syndrome 
Compartment syndrome again relates firstly to incorrect needle placement, and has 
been described rarely in a isolated case report following intraosseous infusions30. It 
occurs if the tip of the needle is placed into soft tissues rather than bone, then 
prolonged infusion of fluids commenced and the situation is not recognised. Large 
published series of intraosseous infusions have not reported this complication 
suggesting it is very rare.7 It is extremely unlikely to occur in the context of this study 
as the needle is left in situ for a very short time, and fluid is injected as a single bolus 
so needle malposition or fluid leakage into the tissue will be immediately recognised.  
 
 
3) Fracture 
There have been isolated reports of fracture following intraosseous needle placement 
in the literature. This is thought to relate to the use of excessive force with manual 
needle placement, and to our knowledge has not been reported with the powered 
needle driver used in the current study.  


 
14
 
4) Infection / osteomyelitis 
A meta-analysis of 4359 intraosseous insertion attempts reported an incidence of 
infection of 0.6%7.  It is anticipated that as the insertions in our study will take place 
in a full sterile environment and antibiotic will be injected through the needle the 
incidence of infection is likely to be even lower.  
The above complications will be outlined in the patient information sheet.  
 
Vancomycin and ‘Red Man Syndrome’ 
Vancomycin has been administered successfully via the intraosseous route in both 
human12 and animal studies29,31. One advantage of using the regional technique 
outlined in this study is the potential to use lower doses to achieve high local 
concentrations, and thus minimize systemic side effects such as ‘Red Man Syndrome’. 
 
Red man syndrome is an anaphylactoid reaction caused by the degranulation of mast 
cells resulting in histamine release. It is not an allergic reaction and is independent of 
preformed immunoglobulin E. It occurs in 30% to 90% of healthy volunteers given 
vancomycin32, and symptoms are usually mild and alleviated by use of an 
antihistamine. Incidence is related to both dosage and rate of infusion; Polk et al.33 
observed the reaction during systemic infusion of 1 g vancomycin in 82% of 
volunteers, but no reaction occurred when a 500-mg dose was used. Healy et al.34 
noted symptoms in eight of 10 volunteers (80%) given 1 g vancomycin over 1 hour 
but in only three of 10 volunteers (30%) given the same dose over 2 hours. In a recent 
trial of TKA patients 500mg vancomycin was given using the same IORA protocol as 
this in study, and no cases of red mean syndrome were seen12. This is likely due to 
both the lower vancomycin dose and the depot effect of the high tissue concentration, 
that causes antibiotic to be released gradually into the systemic circulation after 
tourniquet deflation29.  
 
As a precaution, the patients receiving IORA vancomycin in this study will be 
monitored closely after tourniquet deflation and an antihistamine will be available if 
clinical signs of red man syndrome are seen. 
 
 


 
15
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2. 
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