Original research article
A randomized, double-blind, placebo-controlled Phase II extended safety
study of two Invisible Condom® formulations in Cameroonian women
Francois-Xavier Mbopi-Keoua, Sylvie Trottierb, Rabeea F. Omarb, Ngoh N. Nkelec,
Séraphin Fokouac, Enow R. Mbud, Marc-Christian Domingob, Jean-Francois Giguèreb,
Jocelyne Piretb, Anthony Mwathae, Benoît Mâssee, Michel G. Bergeronb,⁎
aLaboratoire de Santé Hygiène Mobile, Ministry of Public Health and Faculty of Medicine and Biomedical Sciences, University of Yaoundé I,
bInfectious Diseases Research Centre and Faculty of Medicine, Université Laval, Centre Hospitalier Universitaire de Québec,
Centre Hospitalier de l'Université Laval, Québec, Québec, Canada G1V 4G2
cYaounde Gynaecologic-Obstetric and Pediatric Hospital, Yaoundé, Cameroon
dGynaecology Department and Faculty of Medicine and Biomedical Sciences, Central Hospital, University of Yaoundé I, Yaoundé, Cameroon
eFred Hutchinson Cancer Research Center, Seattle, WA 98117, USA
Received 20 April 2009; revised 30 June 2009; accepted 7 July 2009
Background: Invisible Condom® gel formulations being developed as microbicides to prevent the sexual transmission of HIVare advancing
through the phases of clinical trials. The objectives of this study were to evaluate, after 8 weeks of vaginal application, the extended safety
and acceptability of two Invisible Condom® vaginal gel formulations: (i) the polymer alone and (ii) the polymer containing sodium lauryl
sulfate (SLS) compared to placebo.
Study Design: This study is a randomized, doubled-blind, placebo-controlled Phase II extended safety study in healthy sexually active
women from Yaoundé, Cameroon. Women were randomized into three gel arms: (i) placebo, (ii) polymer alone and (iii) polymer/SLS.
Women applied gel intravaginally twice daily for 8 weeks.
Results: A total of 194 sexually active women applied placebo (n=41), polymer alone (n=76) and polymer/SLS (n=77). Invisible Condom®
gel formulations were well tolerated with no reported serious adverse events. The majority of reported adverse events were mild or moderate
and mostly similar in all three arms, except for pelvic pain that was 10% higher in the polymer and polymer/SLS arms compared to placebo.
Colposcopy showed neither genital ulceration nor mucosal lesions. Nugent score, H2O2-producing lactobacilli and vaginal pH were not
affected by the study products. The gel formulations and applicator were generally acceptable and comfortable.
Conclusion: This extended safety study showed that the Invisible Condom® gel formulations and applicator were well tolerated and
acceptable when applied intravaginally twice daily for 8 weeks. Thus, further phases of clinical development of Invisible Condom® as a
potential microbicide to prevent sexual transmission of HIV are warranted.
© 2010 Elsevier Inc. All rights reserved.
Keywords: Randomized; Double-blind; Placebo-controlled trial; Invisible Condom®; Women; Cameroon; Vaginal microbicides; HIV/STI prevention
Microbicides are promising female-controlled methods to
reduce the sexual transmission of HIV/STIs (for review, visit
www.microbicide.org ). Although AIDS vaccine and
microbicides are potentially powerful tools in HIV preven-
tion, their development has been hampered by candidate
products showing lack of protection against HIV/AIDS in
Phase III clinical trials [2–4]. Promising efficacy data on
PRO2000 (Karim CROI 2009 48LB) have recently raised
hopes that microbicides could be developed more quickly
than an AIDS vaccine . It is estimated that even a partially
effective microbicide could result in a 2.5 million averted
cases of HIVover 3 years . Social surveys in populations
Contraception 81 (2010) 79–85
⁎Corresponding author. Tel.: +1 418 654 2705; fax: +1 418 654 2715.
E-mail address: email@example.com (M.G. Bergeron).
0010-7824/$ – see front matter © 2010 Elsevier Inc. All rights reserved.
significantly hit with HIV/AIDS indicate that the use of
microbicides is well perceived . Therefore, the develop-
ment of a safe and effective microbicide could have a
significant impact on the HIVepidemic.
Besides the 33.0 million people who are presently living
with HIV/AIDS  and of whom 15.5 million are women,
WHO estimates that 340 million new cases of curable
sexually transmitted infections (STIs) occur annually [9,10].
Women are at high risk of getting HIV, and this number
increases continuously. In Cameroon, there are 1.6 times
more women aged 15 years and older than men of the same
age living with HIV/AIDS . Because of social, cultural
and gender power inequalities, it is often difficult for women
to initiate and control condom use with their partners.
Therefore, new HIV prevention methods under the control of
women such as microbicides are urgently needed.
We have developed two microbicide gel formulations
called the Invisible Condom®: (i) a polymer gel which is a
physical barrier that blocks the entry of pathogens into the
mucosa and (ii) the polymer with sodium lauryl sulfate (SLS)
which adds a chemical barrier that kills pathogens. We have
shown that the polymergel, SLS, and polymer gel containing
SLS were well tolerated and effective against HIVand herpes
simplex virus [12–16]. SLS was demonstrated to be effective
against human papillomavirus, a major cause of cervical
cancer . The polymer containing SLS is also effective in
preventing pregnancy in rabbits .
In a previous clinical trial , the gel formulation and
our vaginal applicator were well tolerated and acceptable.
The Invisible Condom® appears to be unnoticed by the
woman's sexual partner, which could empower women to
protect themselves. Furthermore, we demonstrated, using
magnetic resonance imaging technique, in women volun-
teers that the applicator with multiple apical and lateral holes
gives uniform distribution of the formulation covering the
vagina, cervix and posterior fornix . Moreover, the
product remains within the vagina between 4 to 8 h
following coitus .
We recently showed that the Invisible Condom®
formulations, placebo gel and the applicator were well
tolerated in 260 sexually abstinent and active Cameroonian
women after applying gel once, twice or thrice daily for
2 weeks . The present study was aimed at evaluating the
extended safety and acceptability of the Invisible Condom®
formulations, and the applicator in the target population of
200 sexually active HIV-uninfected women in Yaoundé,
Cameroon, after applying gel twice daily for 8 weeks.
2.1. Study design
This was a prospective randomized, three-arm, double-
blind placebo-controlled extended safety and acceptability
study of three vaginal gel formulations. Women were
recruited from Yaoundé, Cameroon, and were evaluated at
the Women Health Center “Clinic Tsinga”. Laboratory tests
were done at “Centre Pasteur” in Yaoundé and at the
“Laboratoire de Santé Hygiène Mobile” of the Ministry of
Public Health in Cameroon. Women aged between 18 and
49 years were randomized to one of three study arms:
placebo, polymer gel and polymer gel containing SLS
formulations. This study included sexually active women
who applied gel twice daily for 8 weeks. Women were
instructed to apply the gel formulation between menses (no
gel application during menstruation). Women were fol-
lowed up every 2 weeks during gel application. Investiga-
tors, participants and statistician were blinded regarding the
products or placebo used. The two products tested
(Invisible Condom® formulations) were (i) polymer gel
which is composed of a polyoxyethylene/polyoxypropylene
polymer (30%, w/w) suspended in 0.05 M citrate buffer
(formulation final pH 4.0±0.4) and (ii) the polymer gel
containing SLS formulation which is the same formulation
above plus SLS (2%, w/w). The universal placebo is
hydroxyethylcellulose that was developed for microbicide
trials and has been characterized previously [22,23]. The
two product formulations and placebo were prepared
according to current good manufacturing practices
(cGMP) and the filled applicators were provided in
individual blind-coded sealed pouches.
This study was approved by the Ethics committee of the
University Hospital (CHUL) in Quebec City as well as by
the Cameroon National Ethics Committee and was
authorized by Health Canada and the US-FDA as well as
the Cameroon Ministry of Public Health. Women signed an
informed consent before screening and enrolment. During
the screening visit, medical and gynecological histories
were taken. Vital signs, physical and gynecological
examinations, clinical laboratory and pregnancy tests, Pap
smear, STIs screening and baseline vaginal microbiologic
evaluation were performed. Concomitant medications were
also noted. To be included, women had to be healthy, have
normal physical, gynecological and colposcopic examina-
tions, at low risk of getting HIV/STIs and having one sexual
partner. All women had to have regular menstrual cycles.
Women had to have a minimum of four acts of vaginal
coital activity per 14 days of gel application. It was
recommended to apply the gel 1 h before planned sexual
intercourse. Exclusion criteria included clinically significant
laboratory findings, allergy to gel or applicator polymers,
history of vaginitis, urinary tract infection, HIV infection or
other STIs, and past history of toxic shock syndrome.
Women who were pregnant or had intrauterine device
Women who satisfied the eligibility criteria went through
their next menstrual period and came back to the clinic on
Days 5–10 from the beginning of their menstrual bleeding.
Women had seven study-related visits: screening (V1), first
day of gel application (V2), 2 weeks (V3), 4 weeks (V4),
6 weeks (V5), 8 weeks (V6) of gel use and close-out visit
(V7) about 2 weeks after end of gel visit. Nugent score ,
80 F.-X. Mbopi-Keou et al. / Contraception 81 (2010) 79–85
vaginal pH, adverse events (AEs) and gynecologic examina-
tions were evaluated at all visits. Colposcopy was performed
as previously described  at visits V1, V2, V4, V6 and
V7. Women were provided with enough male condoms
freely at each visit as well as counseling for reducing the risk
of HIV, other STIs and unintended pregnancy. Treatments of
active STIs were administered according to the guidelines of
Cameroon's ministry of health. STIs screening was
performed at visits V1 and V7 which included serology for
HIV, HSVand syphilis, and vaginal endocervical samples for
Neisseria gonorrhoea and Chlamydia trachomatis. Vaginal
samples were also analyzed for pH, Whiff test, wet mount
and Gram stain for Nugent scores , lactobacilli and
H2O2-producing lactobacilli [26,27]. Clinical laboratory
tests (hematology, clinical chemistry tests and urinanalysis)
were performed at visits V1, V2, V4 and V6.
At visits V2 through V5, participants received a diary
every 2 weeks (on first day and after 2, 4 and 6 weeks of gel
use) and rated symptoms and genital signs they experienced.
Participants also rated, on a daily basis during the product
application phase, their genital symptoms including vaginal
discharge with unusual odor, color or volume. Completed
diaries were collected at visits V3 through V6 every 2 weeks
(after 2, 4, 6 and 8 weeks of gel use) and reviewed by the
The acceptability was also assessed at the end of gel
application using a satisfaction questionnaire evaluating the
following: gel comfort, whether it dried up, was sticky,
leaked, soiled clothes, feeling offullness and effect on libido.
For the applicator, we asked participants about difficulty of
insertion, discomfort/pain at insertion, itching/burning at/
after insertion, if easy to use, if easy to remove membrane
and if easy to push plunger.
At each visit, the physician rated signs of genital
erythema, itching, edema, erosion, abrasion or ulceration
and any other signs present. The diagnosis of vaginitis was
based on history, physical and microscopic examination.
Bacterial vaginosis was diagnosed using Amsel's criteria
[24,28]. At baseline and after the last gel application, a
colposcopy was performed . Cervical Pap smears were
assessed according to the Bethesda classification .
2.2. Statistical considerations and analysis
The original study was designed to randomize 200
women to receive one of the three study products: placebo
gel, polymer gel alone or polymer gel plus SLS applied
intravaginally twice daily for 8 weeks using a 1:2:2
allocation ratio (40 women in the placebo gel arm and 80
women in each of the active gel arms). The power of the
study can be characterized as follows: if the true rate of
observing an AE is 5%: 40 and 160 women in the placebo
gel and active gel arms, respectively, would provide 80%
power to detect AE rates greater than 17% and 13%,
respectively. The study was not designed to provide
sufficient power for statistical pairwise comparisons of
product arms. Means, medians, counts and proportions were
used to describe cohort characteristics at baseline and
frequency of findings, AEs, product use, tolerance and
acceptability during follow-up.
A total of 349 volunteers were screened. Target popula-
tion to be randomized was initially set up at 200 participants.
However, we ended up by enrolling 220 women because 22
women who were randomized never came back for Visit 3
(Table 1). As we projected only 10% of replacement, we
replaced only 20 women. Those 22 women were assigned to
placebo arm (3 women), the polymer gel arm (12 women)
and the gel SLS arm (7 women). Four women had gel mix-up
and 194 randomized women were finally included in the data
analysis (Table 1). The mean age of women was 30 years
(range, 18–49). Age was well balanced across product arms.
All enrolled women were African black.
Certain number of women did not complete all the study
visits (i.e., relatively low retention rate). Of the 194
randomized women, 149 women completed gel applications
through V6 (Table 1) (retention rate of 77%) and 138 women
completed all study visits including the study exit visit (V7)
after the washout period of 2 weeks. There were 8
discontinuations (mainly because of pregnancy and other
medical reasons such as minor infection treated with
antibiotic), 31 dropouts (mainly due to nonadherence to the
provisions of the protocol, particularly not using all gel doses
or not respecting schedule for study visits), and 17 lost to
follow-up (mainly due to long travel or moving out of town).
Participants' accrual and retention
Day 1 (Visit 2)
Women enrolled41 100 76100 77100 194a
Week 8, end of gel (Visit 6)
Women retained24 58.566 86.859 76.6 149 76.8
∼2 weeks after (Visit 7)
Women retained22 53.763 82.9 5368.8138b
D, number of women discontinued (investigator decision to terminate
participant, normally for medical reasons); DO, number dropped out
(noncompliant subjects, e.g., did not use gel, did not come for a visit, or
withdrew herself); LTFU, number of women lost to follow-up, number of
women that are no longer reachable.
aTwenty-six eliminated (22 took product and never came back and 4
had gel mix-up).
bEight D, 31 DO, 17 LTFU (total of 56 noncompletion between Visit 4
and Visit 7).
81F.-X. Mbopi-Keou et al. / Contraception 81 (2010) 79–85
3.1. Sexual activity and gel use
Women reported sexual intercourse with condoms in
90%, 83% and 83% of the sexual acts for study arms
placebo, polymer gel alone and polymer gel plus SLS,
respectively. Gel use by women was relatively high in all
product arms ranging between 70% and 86% (Table 2).
Depending on study arm, about 80% of all gel applications
were unrelated to sex (Table 2). Because women applied
gel twice daily for 8 weeks (i.e., maximum of 112 gel
applications in 8 weeks) and had a minimum of four
vaginal intercourse per 2-week period (average of two to
three times of sex per week for a total of 16–24 times of
sex in 8 weeks), about 80% of gel applications was without
sex and only about 20% of gel applications coincided with
sex (Table 2).
3.2. Microbiology evaluation of vaginal flora and pH
The Nugent score  is a Gram stain scoring system of
vaginal swab sample to diagnose bacterial vaginosis; it
presents an overall picture of the vaginal flora. The
percentage of women in the placebo gel study arm and the
gel alone study arm showing a normal Nugent score
remained fairly stable (at an overall percentage of about
70% and 67%, respectively) across the study visits from
baseline to end of gel application. On the other hand, those in
the polymer plus SLS study arm showed some improvement
during product application from 61% to an overall
percentage of about 77% after up to 8 weeks of product
application. However, they showed some variation in H2O2-
producing lactobacilli across the various study arms. In the
three product arms, women with those lactobacilli seemed to
increase during gel application up to 4 and 6 weeks and then
came down to baseline value after end of gel application of
8 weeks. There was no difference in the vaginal pH of
women from the different study arms. The mean value was
fairly stable across the study visits and ranged between 4.7
and 5.0 across the three study arms placebo, polymer alone
and polymer plus SLS.
3.3. Adverse events and colposcopic evaluation
Table 3 shows the number of women (and %) with related
(possibly, probably and definitely related) AEs according to
the investigators. Overall, most of the AEs were mild or
moderate and transient in nature. Pelvic pain was higher in
the polymer alone and polymer SLS groups at 10%
compared to 0% for the placebo group. Itching was similar
in all 3 arms ranging between 10% and 14% (Table 3).
Vaginal bleeding and discharge were observed in 4% of
women in the polymer SLS arm only. Regarding abnormal
vaginal bleeding with gel use, one case was reported in the
polymer gel alone and three cases in the polymer gel plus
SLS group Among these four cases, one was assessed by the
investigator as the end of menses which was detected during
the planned visit. For two cases, the intermenstrual bleeding
were light, short, resolved spontaneously and did not involve
any change in the use of the gel products or in daily
activities. For one case, the intermenstrual bleeding was
assessed as heavy but resolved spontaneously. Colposcopic
evaluation did not show any abnormal change in the genital
epithelium for the three participants who experienced
intermenstrual bleeding. Even with normal genital and
colposcopic examinations, the contributory relationship
with gel alone or gel plus SLS cannot be excluded.
Consequently, the investigator assessed these three inter-
menstrual bleeding cases as probably related to the gel alone
(one case) or gel plus SLS (two cases). In fact, the level of
genital AEs was less than those reported for other vaginal
microbicides, namely, Tenofovir, BufferGel, Pro 2000 and
Carraguard in similar Phase I/II safety clinical trials [30–33].
Other AEs were abnormal Pap that was observed in 2% of
women in placebo arm and burning sensation that was felt by
2% and 1% of women in the placebo and polymer gel+SLS
arms, respectively. Bacterial vaginosis and candidiasis were
observed in 1–2% of women in all arms. Regarding
colposcopic changes, there was only one woman in the
polymer gel alone arm who had minor colposcopic changes
(pustule in the ectocervix and papule on the vaginal wall)
involving intact epithelia. Neither genital ulceration nor
mucosal lesions were reported with the use of the two studied
products or the placebo. In general, the Invisible Condom®
formulations and the placebo gel were all well tolerated
Sexual activity, gel use and condom use
% Gel application
% Sexual acts
Polymer gel alone
a% of women who used gel.
bThe percentage of women in first column who used gel without sex.
Number (and percentage) of women showing related genital AE
All women Gel formulation
Vaginal discharge/leucorrhea 0/41 (0.0%)
Pain at miction
5/41 (12.2%) 7/76 (9.2%)
82F.-X. Mbopi-Keou et al. / Contraception 81 (2010) 79–85
3.4. Acceptability of the gel formulation and the applicator
The acceptability of the gel formulations was high. On a
scale of gel comfort of 1 (intolerable) to 10 (very
comfortable), most women found it comfortable at a score
of 8 or 9 across the study arms. Following are the results
regarding gel formulations characteristics for placebo and the
study products (polymer gel and polymer gel plus SLS), and
applicator characteristics. The results revealed that 50% of
women believed that the placebo was never sticky, whereas
only 36% of women believed that the two product
formulations were never sticky. Thirty-three percent (33%)
of women reported that the placebo and the polymer plus
SLS did not soil clothes, whereas 52% of them reported that
the polymer alone did not soil clothes. Only 37% of women
reported that placebo never leaked before sex, whereas 65–
72% of them reported that gel alone and polymer plus SLS
never leaked before sex. Regarding gel leakage during sex, it
was similar for all three formulations where 66% of women
reported that formulations never leaked during sex. Simi-
larly, regarding polymer leakage after sex, 40–50% of
women said that formulations never leaked after sex. The
products did not affect libido. Moreover, the applicator also
had high degree of acceptability. It was reported that 73–
80% of women felt that it was often/always easy to insert,
73–88% of them said applicator never gave discomfort or
pain at insertion and 88–90% of women said that the
removal of the membrane sealing the reservoir was often/
always easy. The applicator assembly and its insertion were
considered always simple and easy. Forty to fifty-seven
percent (40–57%) of women found it was often/always easy
to push the plunger (to deliver the gel) and 31–57% found it
The study we are presenting here is a randomized, double-
blind, placebo-controlled Phase II trial that compares the
extended safety profiles of two formulations of the Invisible
Condom®, the polymer gel alone and the polymer gel plus
SLS, to a universal placebo formulation, after vaginal
application twice daily for 8 weeks.
The results of the study show that the polymer gel alone
and the polymer gel plus SLS were well tolerated and
acceptable by 194 healthy women from Yaoundé, Camer-
oon, at low risk of HIVinfection. Reported AEs were mostly
mild/moderate and transient. Itching/pruritus, pelvic pain,
vaginal discharge/leucorrhea and candidiasis were similar in
occurrence and severity in placebo and gel groups. Pelvic
pain was 10% higher in both the polymer gel alone and
polymer gel plus SLS arms compared to placebo arm.
However, it was generally transient, mild and not associated
with abnormal gynecologic or colposcopic findings. Further-
more, it did not result in product discontinuation. This AE
was judged as probably or possibly related to the products.
Regarding Nugent score, neither the placebo nor the two
formulations of the Invisible Condom® seemed to have any
harmful effect on the vaginal flora. On the contrary, polymer
SLS seems to improve Nugent score over study visits by 15–
20% during the 8 weeks of product application. Placebo
transiently decreased H2O2-producing lactobacilli after
1 week, but it returned to baseline at the end of gel
application. On the other hand, the polymer application
seems to improve H2O2-producing lactobacilli, whereas the
polymer SLS produced no effect on those lactobacilli.
Regarding vaginal pH, the mean value was fairly stable
across the study visits and arms and ranged between 4.7 and
5.0. Some investigators recognize that the pH of the normal
adult vagina can vary from 4 to 5 depending on the stage of
menstrual cycle . There were only three cases of bacterial
vaginosis diagnosed; one in each study arm.
Gel and male condom use together reported by all
women was high at rate of 71–86% and 83–90%,
respectively. Retention of study participants was relatively
low at 77% at the end of gel application period of 8 weeks.
One limitation of the study is the relatively low study
retention with product use (77% at Week 8) with retention
in the placebo arm much lower than the other two arms
(59% for the placebo arm vs. 87% and 77% for the two
active arms). We believe that this differential retention is
random since the study product blinding was kept
throughout the study and that we have used the universal
placebo which has been used in several microbicide trials
where no issues were reported in terms of toxicity and
acceptability. Reasons for the lost to follow-up in this study
were long travels and moving out of town. Although the
study retention is in the range of what has been achieved in
microbicide trials conducted in Africa (range of 70–91%)
and in feasibility and pilot studies prior to microbicide
trials with 12 weeks of follow-up (range of 63–94%), it
could impact the results by leading to underestimation of
AE and abnormality rates as well as overestimating
acceptability if participants leaving the study prematurely
did so because they experienced AEs or found the use of
the product unpleasant.
Although microbicides have been in development for
years, researchers faced a period of turmoil because of the
failure of three microbicide candidate products in Phase III
trials [2–4]. It is important to recognize that not all
products are the same, neither are all surfactants, as a
surfactant, PRO 2000, demonstrated for the first time the
promise of a vaginal microbicide gel for preventing HIV
infection in women (communicated at the 16th Conference
on Retroviruses and Opportunistic Infections Meeting held
in Montreal, February, 8–11, 2009). Each product should
be evaluated scientifically and clinically based on its
nonclinical and clinical safety and efficacy data.
The data obtained in the present study, regarding the
extended safety, tolerance, and acceptability profiles
strongly support the upcoming proof-of-concept clinical
trial of the Invisible Condom® gel formulations that is
83 F.-X. Mbopi-Keou et al. / Contraception 81 (2010) 79–85
being planned for the prevention of HIV transmission
during sexual intercourse.
Besides being developed as a vaginal microbicide, the
polymer containing SLS has also spermicidal activity as we
have found in vitro with fresh human sperm and we have
shown it to be effective in preventing pregnancy in rabbits
. Furthermore, postcoital test results, following planned
sexual intercourse, suggest that our microbicide polymer
containing SLS may also have spermicidal activity as 9 out
of 11 subjects had nonmotile spermatozoid .
We have designed a special vaginal applicator to
uniformly distribute the gel formulations over the vaginal
epithelium and cervical mucosae for maximal protection
against STIs. In the three arms, no accumulation of the
gel was observed over the 8 weeks by women regardless
of having sex or not. The polymer properties allows the
gel to adhere  to the vaginal and cervical mucosa for
several hours and to be slowly eliminated with normal
vaginal secretions , thus explaining why there was
minimal leakage and no feeling of wet underwear.
Moreover, as this gel is hydrosoluble, it is perceived as
natural vaginal secretions.
The two Invisible Condom® formulations and the special
applicator were comfortable and well tolerated by women
after 8 weeks of vaginal application. The applicator was easy
to use. One of the most attractive features of the Invisible
Condom® products tested is that it appears to be unnoticed
by the woman's sexual partner , which suggests that it
could further empower women and protect them in case men
refuse to wear male condoms. These results were submitted
to and reviewed by the independent Data and Safety
Monitoring Board, Health Canada and the US-FDA. They
were also presented at the Microbicides 2008 conference in
New Delhi, India.
This work was financially supported by a grant from the
Canadian Institutes of Health Research, Randomized
Controlled Trials. The authors would like to thank the
study participants, the research staff and Dr. Gerard Verna
for his advice.
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