American Journal of Transplantation 2008; 8: 15–20
Blackwell Munksgaard
Minireview
Alemtuzumab (Campath-1H) in Kidney Transplantation
G. Ciancio∗ and G. W. Burke III
Department of Surgery, Division of Transplantation,
University of Miami Miller School of Medicine,
Miami, FL
∗ Corresponding author: Gaetano Ciancio,
gciancio@med.miami.edu
Kidney transplantation has become the treatment of
choice for both the quality of life and survival in pa-
tients with end-stage renal disease (ESRD). However,
the immunosuppressive regimen which allows opti-
mal kidney transplant outcome remains elusive. One of
the more promising induction agents, Alemtuzumab,
was introduced to kidney transplantation by Calne in
the late 1990s with low dose cyclosporine A monother-
apy, with the hope of establishing ‘prope’ or near tol-
erance. Subsequent pilot studies with Alemtuzumab
alone or monotherapy (DSG, Rapa) demonstrated high
rates of acute rejection (AR) along with occasional hu-
moral components that lead to abandoning the con-
cept of Alemtuzumab as a ‘magic bullet’ to achieve
tolerance, prope or otherwise. A number of programs
(including our own) has since modified maintenance
immunosuppression using low dose tacrolimus, and
shown acceptable rates of AR, with relatively low inci-
dence of viral infection and lymphoproliferative disor-
ders along with cost benefit. However, there are only
three prospective, randomized studies which are small
with one year or less follow-up, and most published
series utilize historical control groups with relatively
short follow-up. As extrapolation from short-term data
is far from secure, long-term, prospective, randomized
studies with Alemtuzumab will be necessary to deter-
mine the optimal immunosuppressive regimen.
Key words: Acute rejection, Alemtuzumab, induc-
tion therapy, mycophenolate mofetil, renal allograft,
sirolimus, tacrolimus
Received 27 July 2007, revised 19 September 2007 and
accepted for publication 28 September 2007
Introduction
Progress in the development of immunosuppressive regi-
mens has reduced the incidence and severity of acute re-
jection (AR) after renal transplantation. This has resulted
in improved short-term (primarily 1 year) outcomes (1–3),
but with less marked effects on long-term graft survival
(4). This is due in part to the nephrotoxicity of calcineurin
C 2008 The Authors
Journal compilation 
C 2008 The American Society of
Transplantation and the American Society of Transplant Surgeons
doi: 10.1111/j.1600-6143.2007.02053.x
inhibitors (CNIs) (5), the alloimmune component of trans-
plant glomerulopathy (6), and other less well-defined pro-
cesses (7). Regimens that can yield similar short-term re-
sults but with less long-term deterioration (8,9) continue to
be sought, perhaps even eventually allowing the develop-
ment of immunologic tolerance (10,11).
New biologic agents such as (chimeric or humanized) mon-
oclonal antibodies with longer half-lives have been intro-
duced as induction therapy (2). The resulting prolonged
biologic effect may allow lower dosages of (nephrotoxic)
CNIs, both short- and long-term, and perhaps lower doses
or avoidance of corticosteroids. One such agent is Alem-
tuzumab, a humanized CD52-specific complement fix-
ing (cytotoxic-lymphodepleting) IgG1 monoclonal antibody
first introduced in hemato-oncology by Waldmann and Hale
(12), then in renal transplantation by Calne (13). The hu-
man CD52 antigen is found in variable concentrations on
all peripheral blood mononuclear cells. Alemtuzumab pro-
foundly depletes T cells from peripheral blood for several
months with effects, albeit less marked, on B cells, natural
killer cells, and monocytes, (in descending order) and with
the least effect on CD34+ (immature) hematopoetic stem
cells. (see review 14).
Alemtuzumab is currently not indicated for organ transplan-
tation and thus patients should be informed of its off-label
use and its evolving experimental nature.
Alemtuzumab in Kidney Transplantation
Early experience
The Cambridge group performed the first series of human
deceased donor renal transplants using Alemtuzumab in-
duction therapy as prophylaxis against rejection in com-
bination with low dose cyclosporine monotherapy (13).
The pilot trial (Table 1) of 31 patients utilized two doses
of Alemtuzumab, 20 mg each, given on the day of the
transplant and the following day. Cyclosporine monother-
apy was used posttransplant with trough levels in the range
of 100–150 ng/mL. There were six episodes of steroid-
responsive rejection with one case of an almost acellular
vasculitic rejection also treated with steroids. With 5-year
follow-up (15), the incidence of AR which had been lower
initially in the Alemtuzumab treated group (13), equaled
that of the control group (contemporaneous kidney trans-
plant recipients all but five of whom were treated with
triple maintenance therapy without induction) and was ap-
proximately 30% due to an increase in late (1–3 years post
15
Ciancio and Burke III

Table 1: Published effects of Alemtuzumab was used in higher doses and without subsequent im-
Yes No Possibly References munosuppression in this report (17), the possibility of
autoimmune phenomena including thyroiditis associated
Tolerance induction
Alemtuzumab alone × 16 with Alemtuzumab, should be recognized.
Alemtuzumab with early DSG × 19
Prope (near) tolerance induction Alemtuzumab with short-term deoxyspergualin
Alemtuzumab with CyA × 13,15 monotherapy: This same group (19) investigated whether
monotherapy Alemtuzumab and deoxyspergualin (DSG) monotherapy
Effective with non-CNI would induce tolerance in humans. Five recipients of
maintenance therapy live donor kidneys were treated perioperatively with
Sirolimus mono therapy × 22,23 Alemtuzumab and DSG in a pilot trial and followed post-
Sirolimus/MMF × 24
operatively without maintenance immunosuppression.
Alemtuzumab serially/MMF × 25
Alemtuzumab was used for peripheral and nodal T-cell
Effective with CNI therapy
Steroid reduction/ ×1 26,29–31, depletion; DSG was chosen for (1) the demonstration
sparing 33–35 of tolerance when added to a T-cell depletion model in
Spaced weaning (Tacro) ×1 27,28 nonhuman primates (20) and for its inhibitory effect on
Effective for treatment of ? 36,37 monocyte/macrophage activation (21). Despite profound
acute rejection T-cell depletion and DSG dosing, all patients developed
Role in future protocols ? reversible rejection that was similar in timing, histology
1 Short-term. and transcriptional profile to that seen in patients treated
CNI = calcineurin inhibitor; DSG = deoxyspergualin; MMF = My- with Alemtuzumab alone (16).
cophenolate Mofetil; Tacro = Tacrolimus.
Answer: No.

kidney transplant) episodes of AR. Furthermore, the serum

creatinine was the same in both groups at 5 years, de-
spite the hope that the lower cyclosporine A concentra-
tion in Alemtuzumab recipients would translate to reduced
nephrotoxicity. Importantly, the Alemtuzumab patients on
cyclosporine A monotherapy were ‘no more tolerant than
patients on triple therapy’ as judged by graft survival and
incidence of AR (13).
QU: Is Alemtuzumab tolerogenic?
Alemtuzumab alone: Kirk et al. (16) were the first to use
Alemtuzumab in a pilot trial designed to test the need for
maintenance immunosuppression in the context of multi-
ple doses of Alemtuzumab. Seven nonsensitized recipients
of living donor kidneys received Alemtuzumab without ad-
ditional immunosuppression. Alemtuzumab was adminis-
tered at 0.3 mg/kg per dose. Six patients received three
doses in the peritransplant period: four on days –5, –3
and –1 and two on days –3, –1 and +2. One received
four doses on days –1, +1, +3 and +5 (11,13). Profound
peripheral lymphocyte and monocyte depletion occurred.
Nonetheless, all patients developed rejection episodes
within the first month that were characterized by mono-
cytic (not lymphocytic) infiltrates with only rare T cells
in the peripheral blood or allograft. Most were reversed
with steroid therapy although one required OKT3 as well.
Sirolimus maintenance therapy was then initiated. There
were no late rejections.
Of note, one patient developed auto immune thyroid dis-
ease 3 years after transplant/Alemtuzumab induction while
receiving sirolimus monotherapy (17). Autoimmunity has
also previously been reported in multiple sclerosis patients
treated with Alemtuzumab (18). Although Alemtuzumab
QU: Is Alemtuzumab effective with non-CNI
maintenance therapy?
Sirolimus monotherapy: At the University of Wisconsin
(22), 29 patients received two doses of 20 mg each of
Alemtuzumab on day 0 and day 1. Twenty-four (living donor)
recipients then received maintenance sirolimus therapy.
Thirty percent in this pilot study experienced significant
rejection episodes, usually between 2–3 weeks postop-
eratively, which were typically of a humoral rather than
cellular nature. Some were difficult to control, requiring
a combination of plasmapheresis, cytomegalovirus (CMV)
IGm thymoglobulin, rituximab, steroid bolus, mycopheno-
late mofetil (MMF) and tacrolimus. Using a modification in
the protocol, the initial dose of Alemtuzumab was given
the day before transplantation followed by a dose of thy-
moglobulin 1.5 mg/kg on day 1 (patients 26–29). A 2-week
course of steroids was also added. Nevertheless, of five
patients, three experienced AR.
At 3-years, the pilot study included a 46% rate of rejec-
tion (humoral and/or cellular). Seven (54%) of these were
humoral, treated with the regimen described (23). How-
ever, graft and patient survival of 96% and 100%, respec-
tively, were achieved. Fifty percent of the patients were
maintained on monotherapy without serious infections and
there were no malignancies. Because of the high incidence
of early rejection, however, a brief course of a CNI was rec-
ommended (23).
Rapa/MMF; no CNI: Flechner et al. (24) in a pilot study
of 22 patients (14 living donor; 8 deceased donors)
used Alemtuzumab (30 mg, day 0 and 1) induction
with mycophenolate mofetil (500 mg b.i.d.) and sirolimus

16 American Journal of Transplantation 2008; 8: 15–20


(concentration controlled 8–12 mg/mL) maintenance in or-
der to avoid CNI and steroids. With a mean follow-up of
15.9 months, patient survival was (21/22) 96% and graft
survival (19/22) 87%. However, AR occurred in 8 (36.3%-
two humoral). Of 19 surviving grafts, 18 (95%) remain
steroid and 15 (79%) CNI free. Overall infection rates were
low, but two patients developed severe acute respiratory
distress syndrome (ARDS) at month 3 and 7, respectively,
resulting in mortality in one and graft loss in the other.
No cancer or posttransplant lymphoproliferative disease
(PTLD) was observed. The higher than expected rate of
AR, leucopenia and possible pulmonary toxicity raised con-
cerns regarding the efficacy and safety of this protocol.
Serial Alemtuzumab/MMF; no CNI/steroids: Gruessner
et al. (25) reported a nonrandomized study of 75 pancreas–
kidney and solitary pancreas recipients who received alem-
tuzumab (4 doses for induction and up 12 doses within the
first year) and mycophenolate mofetil (≥2 g/day) monother-
apy. Alemtuzumab, 30 mg IV, was given intraoperatively
as well as for maintenance dosing. The maximum number
of Alemtuzumab doses was limited to 10 within the first
year. In a 6-month follow-up, the results were compared
with a historical group of 266 consecutive pancreas recipi-
ents using thymoglobulin induction and tacrolimus mainte-
nance. Pancreas allograft survival at 6 months in the Alem-
tuzumab for SPK recipients was 81% (vs. 79%; p ≥ 0.66);
for PAK recipients, 91% (vs. 85%; p ≥ 0.59); and for PTA
recipients, 71% (vs. 84%; p ≥ 0.07). The incidence of a
first (reversible) rejection episode at 6 months in the Alem-
tuzumab versus control group for SPK recipients was 41%
(vs. 9%; p ≥ 0.0003); for PAK recipients, 14% (vs. 10%;
p ≥ 0.89); and for PTA recipients, 19% (vs. 26%; p ≥ 0.36).
Based on 6-month data, the combination of alemtuzumab
and MMF was associated with a high rejection rate (in SPK
recipients), but good (graft and native) kidney function; it
eliminated undesired CNI and steroid-related side effects.
Longer follow-up is necessary to evaluate both efficacy and
safety.
Answer: No
Is Alemtuzumab effective with CNI maintenance
therapy?
University of Wisconsin: After their initial experience with
Alemtuzumab and sirolimus monotherapy, the Wisconsin
group (26) reported a single center retrospective study
comparing patients who received two doses of Alem-
tuzumab at the time of renal transplant in combination
with a low dose of steroids (10 mg methylprednisolone
per day), mycophenolate mofetil and either tacrolimus or
cyc1osporine (n = 126) with those who received either an
anti-CD25 antibody (n = 799), thymoglobulin (n = 160) or
other antibody treatment (n = 156). The choice of induc-
tion antibody was made by the operating surgeon based on
‘perceived efficacy, side effect profile and cost’ (20). The
latter three groups were in combination with a CNI, my-
American Journal of Transplantation 2008; 8: 15–20
Alemtuzumab
cophenolate mofetil and higher dose steroids. The Alem-
tuzumab group overall experienced less rejection than
the other three groups: Alemtuzumab ∼22%, anti-CD25
∼30% and thymoglobulin ∼32% (from figure 2 in Ref.
20) (p = 0.037). The follow-up in the Alemtuzumab group
was 12 months versus 4–6 years for the other groups. A
subgroup with delayed graft function, treated with Alem-
tuzumab, experienced less rejection and improved graft
survival statistically p = 0.0096 and 0.0119, respectively,
than the control groups. The rate of AR in the Alemtuzumab
DGF group (n = 23) was 14%, anti-CD25 (n = 127) was
38% and in the thymoglobulin group (n = 41) 42% (fig-
ure 2 in Ref. 20). However, the follow-up was limited to
200 days for Alemtuzumab recipients with DGF (figure 2
in Ref. 20). There was no difference in infection or ma-
lignancies among the four groups. Further follow-up will
be necessary to assess outcome in the Alemtuzumab
group.
University of Pittsburgh: Reports from the University of
Pittsburgh (27) suggested lymphoid depletion with Alem-
tuzumab before rather than after kidney transplantation
would reduce the anticipated donor-specific response and
allow avoidance of high-dose steroids and multiple main-
tenance immunosuppressive agents. Three groups were
retrospectively compared: historical controls with no pre-
treatment (n = 152), thymoglobulin (5 mg/kg) pretreatment
group (n = 101) and Alemtuzumab (30 mg) pretreatment
group (n = 90). Patient and graft survival were not signif-
icantly different in either of the depleted groups versus
the historical controls. However, there were markedly dif-
ferent incidences and times to AR. In the thymoglobulin-
pretreated patients, the onset was earlier and the incidence
higher (40% at 6 months, ∼50% at 1 year (figure 2 in Ref.
27) (p < 0.001) than in either the Alemtuzumab or histor-
ical controls. The incidence of rejection during the first 6
months after Alemtuzumab pretreatment was 1%, how-
ever, by 12 months the AR rate increased to 20% (figure 2
in Ref. 27). Of note, 3-year graft survival in the thymoglobu-
lin group, which experienced the high rate of AR, was 70%
compared to ∼80% in the historical control group (figure 1
in Ref. 27).
Spaced weaning of tacrolimus was attempted in 91
(90.1%) of the 101 recipients of the thymoglobulin pretreat-
ment group. In 45% of these patients, daily maintenance
therapy was resumed because of AR. In view of the high
rate of AR and worse graft survival observed with space
weaning after thymoglobulin pretherapy, spaced wean-
ing was delayed for 1 year before being attempted in 83
(91.2%) of the 90 patients of the Alemtuzumab pretreat-
ment group. With follow-up of 12–18 months, 62 (74%)
of the 84 Alemtuzumab-treated patients were on spaced
weaning, 14% on daily monotherapy, with only 12%
receiving more than a single agent. However, further
follow-up of graft survival and change in creatinine is nec-
essary to evaluate the safety and efficacy of Alemtuzumab
in this trial.
17
Ciancio and Burke III
More recently this group has reported results in an LRD
kidney transplant protocol with Alemtuzumab and spaced
weaning of tacrolimus monotherapy (28). The 1-year ac-
tuarial patient and graft survival was 98.6% and 98.1%,
respectively. With larger numbers and better use of im-
munologic monitoring, the 1-year AR episodes were 6.8%.
They report no CMV or other infection, no DGF and PT DM
rate of.5% (28). However, longer follow-up will be critical
to assess the effectiveness of this approach.
The University of Miami: The Miami experience with
Alemtuzumab began with a pilot study in an attempt to
(1) reduce both early and long-term CNI nephrotoxicity,
and (2) eliminate steroids. Alemtuzumab (two doses, 30
mg each) was used as induction therapy in 44 de novo re-
nal allograft recipients (29). Maintenance Tacrolimus trough
levels were 5–7 ng/mL; with reduced MMF dosage (500
mg twice daily). With a median follow-up of 9 (range 1–
19) months, patient and graft survival were both 100%.
Biopsy-proven AR was diagnosed in four patients (9%).
Four patients (9%) developed infections that required hos-
pitalization. Thirty-eight (86%) remained off long-term cor-
ticosteroid therapy. In our experience, the combination of
Alemtuzumab, low dose tacrolimus and mycophenolate
mofetil, and avoidance of maintenance corticosteroid use
was safe and effective for kidney transplant recipients.
Later reports and our own experience, however, suggested
that a higher incidence of biopsy-demonstrated AR may ex-
ist in the African–American and Hispanic subgroups treated
with Alemtuzumab (30). This remains controversial be-
cause others, in a small, prospective randomized study,
showed equivalence in AR rates at 1 year comparing Alem-
tuzumab to thymoglobulin in an immunologically high-risk
group that included African–Americans and Hispanics (31).
Of note, the second randomized prospective study com-
paring Alemtuzumab with CyA (low dose) monotherapy
(n = 20) to triple immunosuppression (CyA, azathioprine
and steroids) without induction (n = 10) also reported
equivalence (32). However, the study was small with only
6-month follow-up, and the AR rate was already relatively
high: 25% (Alemtuzumab) versus 20% (standard immuno-
suppression).
Answer: Yes, but longer follow-up and randomized studies
are necessary to draw meaningful conclusions.
QU: Is Alemtuzumab better than other induction
agents?
Alemtuzumab versus thymoglobulin versus da-
clizumab: Our group (33) subsequently designed the first
randomized prospective trial using three different antibody
induction agents in 90 first renal transplant recipients
from deceased donors: thymoglobulin, Alemtuzumab and
daclizumab. Maintenance immunosuppression included
tacrolimus and mycophenolate in all three arms, and
methylprednisolone in the thymoglobulin and daclizumab
18
groups. The targeted trough level of tacrolimus was be-
tween 8 and 10 ng/mL for thymoglobulin and daclizumab
groups, with a targeted mycophenolate dose of 1 gm
twice daily. In the alemtuzumab treated arm, target
tacrolimus trough level was lower 4–7 ng/mL (to reduce
long-term nephrotoxicity,) with 500 mg twice daily doses
of mycophenolate and no steroids. AR rates at 1 year
were equivalent, that is 5/30 in all three groups (∼16.6%).
In the alemtuzumab group, there was slightly lower GFR
at 1 month, but no difference at 1 year.
In the Alemtuzumab group, 80% remained steroid-free at
1 year, with lower tacrolimus trough levels and mycophe-
nolate dosing. There were no differences in other adverse
events. No direct comparison among these three arms is
possible, because the maintenance regimens are different
(33). However, the efficacy of Alemtuzumab appears simi-
lar to that of the other two agents in this small, prospective
randomized study. Further follow-up is in progress.
Alemtuzumab versus basiliximab: A nonrandomized,
retrospective, sequential study comparing outcomes in kid-
ney transplant recipients induced either with Alemtuzumab
(n = 123) or basiliximab (n = 155) with a prednisone-free
maintenance protocol using tacrolimus and mycopheno-
late mofetil was reported from Northwestern (34). Mean
follow-up was 33 ± 23 months (range 30–42 months) for
Alemtuzumab and 47 ± 10 months (range 31–65 months)
for the basiliximab group, and ∼2/3 were living donors (33).
The 1-year actual patient and death censored kidney trans-
plant survival rates, Alemtuzumab versus basiliximab, were
96.8% versus 99.4%, and 99.2% and 99.4%, respectively
(p = n.s.). Although the rate of AR was lower in the Alem-
tuzumab group for the first 3 months, by 12 months, the
rate of AR for both groups was equivalent (Alemtuzumab
14.9%; basiliximab 13.5%). There was no difference in cre-
atinine concentration at 1 year and minimal change over
36 months. CMV occurred in 21% (Alemtuzumab) and 19%
(basiliximab) in the zero negative recipients, and in both
groups PTLD occurred in two patients. The Northwestern
team has also demonstrated reduced cost associated with
alemtuzumab induction (35).
Answer: It is possible to achieve excellent short-term
(1 year) results with Alemtuzumab. However, comparison
studies suffer from lack of (1) long-term follow-up and (2)
randomized, prospective controlled trials. The best induc-
tion protocol for the long-term remains to be defined.
Alemtuzumab for the Treatment of Acute
Rejection in Renal Transplant Patients
There are anecdotal reports describing the use of Alem-
tuzumab in the treatment of AR (36). There are no prospec-
tive studies. There appears to be a higher risk of infection
in patients treated with Alemtuzumab for AR (37).
American Journal of Transplantation 2008; 8: 15–20

Alemtuzumab: acute humoral rejection (AHR) in renal
transplant recipients
In kidney transplant patients who received Alemtuzumab
induction, AHR appeared to occur with higher frequency,
requiring an aggressive combination of plasmapheresis
and intravenous immunoglobulin, in addition to steroid ther-
apy (19,22,24). One case of AHR with an almost acellular
vasculitic rejection that was treated with steroids was re-
ported in Calne’s original study (13). It should be noted that
plasma cells do not express the CD52 epitope in detectable
concentrations and that memory T (and perhaps B lympho-
cytes) may also be somewhat more refractory to Alem-
tuzumab (38). Kirk et al. (16) reported no AHR, but a high
incidence of reversible AR with monocytic predominance
in the biopsy infiltrates. Notably, chemokine transcript lev-
els in these biopsies were consistently high, suggesting
the facilitation of infiltrating cells (19). All were respon-
sive to treatment followed by maintenance with steroids
or sirolimus or both. Hill et al. (39) reported an early severe
AHR (C4d+) resulting in renal allograft loss in a recipient
treated with Alemtuzumab induction therapy, cyclosporine
A, mycophenolate mofetil and steroids. This patient devel-
oped donor specific anti-class I antibody. The presence of
antidonor MHC antibodies or B cell crossmatch pretrans-
plantation is not detailed (39). It is clear that Alemtuzumab
induction, even with additional immunosuppressive agents
does not prevent AHR in renal allograft recipients.
Alemtuzumab/Tregs
Our group (33) reported significantly more leucopenia with
Alemtuzumab than thymoglobulin or daclizumab, but a
greater percentage of T regulatory cells as assessed by
number of Fox-P3 mRNA copies, by flow cytometry and
semiquantitative PCR analysis. This was in the context
of low dose mycophenolate mofetil and low dose/level
tacrolimus maintenance immunosuppression. However,
Noris et al. (40) using cyclosporine A as the CNI, not
tacrolimus, did not identify Tregs. In this study, Treg pheno-
type and function was monitored during immune reconsti-
tution in 21 renal transplant recipients treated with Alem-
tuzumab and MMF who received sirolimus or cyclosporine
as maintenance therapy. Three patients, one on sirolimus
and two on cyclosporine, experienced an AR episode that
responded to steroid therapy. In sirolimus treated patients,
hyporesponsiveness demonstrated in vitro was reversed
by Treg depletion. T cells from cyclosporine treated pa-
tients were anergic. Thus, in their study CD4+CD25 high
Treg expansion in renal transplant patients, appeared to
occur with sirolimus but not CyA maintenance immuno-
suppression. Translating this observation into a real clini-
cal benefit (41), because sirolimus protocols without CNI
have shown higher rates of AR, remains a challenge for the
future.
Conclusion
The use of Alemtuzumab as induction therapy in kidney
transplantation, has evolved over the past decade, typical
American Journal of Transplantation 2008; 8: 15–20
Alemtuzumab
of many novel therapeutic agents, from the initial response
of enthusiasm, to a realization that it is not a panacea.
The learning curve has been through tolerance, prope tol-
erance, mono/dual agent maintenance therapies to cur-
rent protocols, generally embracing low dose CNIs and
steroid sparing successfully. There are suggestions that
Alemtuzumab is particularly effective in delayed graft func-
tion, and that there are important cost savings with its use.
However, preventing AHR will be critically important. It may
be necessary to avoid the use of Alemtuzumab in those pa-
tients with B-cell positive crossmatches and/or antidonor
antibody. If the current experience showing low rates of
AR, with correspondingly low rates of viral infections, lym-
phoproliferative disorders and posttransplant diabetes at
1 year, can be validated in randomized, prospective, long-
term protocols, then Alemtuzumab will assume an impor-
tant role in kidney transplantation induction therapy.
Acknowledgment
The authors would like to express their appreciation to Ms. Maruja Chavez
for her perspicacious, prescient and perceptive perseverance in the prepa-
ration of this paper.
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