Antidepressant-like profile of action of two 4-amine derivatives of 10,11-dihydro-5H-dibenzo [a,d] cycloheptane in mice evaluated in the forced swimming test

Article abstract of DOI:10.1016/j.bmc.2006.12.014

This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for 10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzocycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In addition, putative underlying mechanisms of action are discussed.

Full text of DOI:10.1016/j.bmc.2006.12.014

Bioorganic & Medicinal Chemistry 15 (2007) 1645–1650
Antidepressant-like profile of action of two 4-amine derivatives of
10,11-dihydro-5H-dibenzo [a,d] cycloheptane in mice evaluated
in the forced swimming test
Filipe Silveira Duarte,a Paulo Roberto Codec¸o Martins,b Gilberto Alves Romeirob
and Thereza Christina Monteiro De Limaa,*
aLaboratory of Neuropharmacology, Department of Pharmacology, CCB, Universidade Federal de Santa Catarina,
Floriano´polis, SC 88049-900, Brazil
bDepartment of Organic Chemistry, IQ, Universidade Federal Fluminense, Campus do Valonguinho s/n, Nitero´i, RJ 24210-150, Brazil
Received 20 March 2006; revised 27 November 2006; accepted 11 December 2006
Available online 13 December 2006
Abstract—This study investigated the antidepressant-like effect of 4-amine derivatives of 10,11-dihydro-5H-dibenzo-alkylamine-
cycloheptane, 4-amine (3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADDCH1) and
1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2), in a validated experimental model of depression, the
forced swimming test (FST) in mice. Female adult mice were sub-chronically (three doses in 24 h) or repeatedly (once a day for
10 days) treated with either of the compounds and evaluated in the FST. The sub-chronic treatment promoted a dose-dependent
reduction in the immobility time in the FST with the doses of 50 mg/kg (ADDCH1) and 30 mg/kg (ADDCH2) ip being the most
effective (33% and 37% of reduction, respectively). A similar profile of action was observed in the animals repeatedly treated with
ADDCH1 50 mg/kg or ADDCH2 30 mg/kg ip (for 10 days) and there was no sign of motor impairment or locomotor activation as
evaluated in the rota-rod and open-field tests, respectively. These findings suggest that these amine derivatives of the system dibenzo-
cycloheptane have an antidepressant-like action which could be of clinical interest and, therefore, deserves further investigation. In
addition, putative underlying mechanisms of action are discussed.
ꢀ 2007 Elsevier Ltd. All rights reserved.
1. Introduction
besides a delay to the onset of beneficial clinical effects.3,4
For these reasons, at least, new therapeutic agents, per-
haps with fewer collateral effects and/or with innovative
mechanisms of action, which could reduce the delay in
the onset of antidepressant therapy, are highly desirable.
Depression is one of the most prevalent psychopatholo-
gies in the Western world with prevalence number be-
tween 9% and 18%1 affecting 1 in 10 men and 1 in 5
women in adulthood.2 Its clinical therapy is based on
classical antidepressant drugs such as monoamine oxi-
dase inhibitors (e.g., tranylcypromine) and drugs that
prevent the reuptake of catecholamines (e.g., imipra-
mine). Second generation drugs include compounds
such as the selective inhibitors of serotonin reuptake
(e.g., fluoxetine) and drugs with non-conventional mech-
anisms of action (e.g., trazodone, nefazodone and mirt-
azapine). These therapeutic tools are clinically effective
but all of them also present numerous side-effects
Previously, Jansen (1964)5 proposed that the compound
5-alkylamine 10,11-dihydro-5H-dibenzo[a,d]cyclohep-
tane should possess antidepressant activity due to its
structural similarity to other antidepressants such as
imipramine, although so far no studies were performed
to confirm this effect for this class of compounds.
Therefore, the present study examined the putative anti-
depressant-like activity of two 4-amine derivatives of
10,11-dihydro-5H-dibenzo[a,d]cycloheptane, 4-amine(3-
N,N-dimethylpropylamine)-10,11-dihydro-5H-dib-
enzo[a,d]cycloheptane-5-one (ADDCH1) and 1,2,3,4,8,
9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin
(ADDCH2), in a well-validated experimental model of
depression, the forced swimming test (FST).6
Keywords: Depression; Forced swimming test; Amine derivatives;
Dibenzocyclo heptane; Heterocyclic compounds.
*
Corresponding author. Tel.: +55 48 3331 9491; fax: +55 48 3337
5479; e-mail: thereza@farmaco.ufsc.br
0968-0896/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2006.12.014

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F. S. Duarte et al. / Bioorg. Med. Chem. 15 (2007) 1645–1650
2. Results
Sub-chronic treatment (3 doses in 24 h)
300
200
100
0
2.1. Evaluation of the antidepressant-like effect of the 4-
amine-dibenzocycloheptane derivatives after sub-chronic
treatment
Sub-chronic treatment with the compound ADDCH1 or
ADDCH2 promoted a dose-related decrease in the immo-
bility time in the FST, as depicted in Figure 1 (con-
trol = 210.65 4.37 s; ADDCH1(5mg/kg) = 220.22 5.19 s;
*
**
ADD CH1(15mg/kg) = 187.10 4.39 s; ADDCH1(30mg/kg)
169.31 13.72 s;
ADDCH1(100mg/kg) = 206.38 12.38 s;
=
ADDCH1(50mg/kg) = 132.00 21.03 s;
IMI(15mg/kg) =
138.33 12.76 s) (F(6,81) = 7.37; P < 0.0001) and
Figure 2 (control = 215.67 2.82 s; ADD CH2(1mg/kg)
215.00 9.48 s; ADDCH2(5mg/kg) = 197.00 7.35 s; ADD
-
(mg/Kg)
5
50
1
15
30
15
=
ADDCH2
IMIP
CONTROL
CH2(15mg/kg) = 186.57 13.66 s;
169.92 6.67 s; ADDCH2(50mg/kg) = 199.25
ADDCH2(30mg/kg)
=
14.51 s;
Figure 2. Effects of the sub-chronic treatment with 1,2,3,4,8,9-
hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2) and
imipramine (three doses in 24 h) on the immobility time in a 5-
min swim test. Each column represents the mean SEM of 7–15
animals. *P < 0.05 and **P < 0.01 versus control group (all
comparisons were made by ANOVA followed by Newman–Keuls’
test).
IMI(15mg/kg) = 137.33 23.43 s) (F(6,66) = 6.21; P < 0.0001).
The most effective antidepressant-like doses for ADD-
CH1 and ADDCH2 were 50 mg/kg and 30 mg/kg, respec-
tively, while the immobility time of animals treated with
the highest doses did not differ from control values.
2.2. Evaluation of the antidepressant-like effect of the
4-amine-dibenzocycloheptane derivatives after repeated
treatment (once a day for 10 days)
Repeated treatment (once a day for 10 days)
300
As shown in Figure 3, systemic repeated treatment with
ADDCH1 (50 mg/kg) or ADDCH2 (30 mg/kg) for
10 days reduced (13% and 15%, respectively) the immo-
bility time of mice in a similar way to that observed after
the acute treatment and imipramine treatment when
compared to control values (control = 218.25 6.62 s;
200
*
*
**
100
0
ADDCH1(50mg/kg) = 190.33 7.91 s; ADDCH2(30mg/kg)
186.40 11.12; IMI(15mg/kg) = 177.50 6.06 s) (F(3,21)
5.90; P < 0.01).
=
=
(mg/Kg)
-
50
30
15
IMIP
CONTROL ADDCH 1 ADDCH 2
Figure 3. Effects of the repeated treatment (10 days) with 4-amine-
(3-N,N-dimethyl propylamine)-10,11-dihydro-5H-dibenzo-[a,d]-cyclo-
heptane-5-one (ADDCH1) or 1,2,3,4,8,9-hexahydro-dibenzocyclo-
hepta[4,4a,5-ef]1,4-diazepin (ADDCH2) and imipramine on the
2.3. Evaluation of the effect of the 4-amine-dibenzocyclo-
heptane derivatives on the locomotor activity and motor
co-ordination after repeated treatment
immobility time in
a 5-min test. Each column represents the
mean SEM of 5–8 animals. *P < 0.05 and **P < 0.01 versus
control group (all comparisons were made by ANOVA followed
by Newman–Keuls’ test).
The spontaneous locomotor activity and the motor co-
ordination of the animals, as evaluated in the open-field
Sub-chronic treatment (3 doses in 24 h)
300
200
100
0
*
**
**
-
15
30
50
15
5
100
(mg/Kg)
CONTROL
ADDCH1
IMIP
Figure 1. Effects of the sub-chronic treatment with 4-amine-(3-N,N-dimethyl propylamine)-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptane-5-one
(ADDCH1) and imipramine (three doses in 24 h) on the immobility time in a 5-min swim test. Each column represents the mean SEM of 6–19
animals. *P < 0.05 and **P < 0.01 versus control group (all comparisons were made by ANOVA followed by Newman–Keuls’ test).

F. S. Duarte et al. / Bioorg. Med. Chem. 15 (2007) 1645–1650
1647
Table 1. Effects of the repeated treatment (10 days) with 4-amine-(3-N,N-dimethyl propylamine)-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptane-
5-one (ADDCH1) or 1,2,3,4,8,9-hexahydro-dibenzocyclohepta[4,4a,5-ef]1,4-diazepin (ADDCH2) and imipramine on the locomotor activity and
motor performance evaluated in the open-field and rota-rod tests, respectively
Drug
Dose
Open-field locomotor activity
Rota-rod
Number of animals
(mg/kg)
Number of falls
Time on the rotating bar (s)
Control
ADDCH1
ADDCH2
IMIP
—
50
30
15
84.12 4.98
91.33 4.59
81.20 13.10
82.83 9.25
0.75 0.31
0.50 0.34
0.40 0.24
0.83 0.40
57.85 0.82
59.50 0.50
58.60 0.98
58.11 0.87
8
6
5
6
Data are expressed as means SEM of 5–8 animals (all comparisons were made by ANOVA followed by Newman–Keuls’ test).
and rota-rod tests, respectively, were not affected by the
repeated treatment with both compounds ADDCH1
and ADDCH2, as shown in Table 1 (P > 0.05).
activity.15–17 The main differences between 4 -amine
(3-N,N-dimethylpropylamine)-10,11-dihydro-5H-dib-
enzo[a,d] cycloheptane-5-one and other drugs known to
be centrally active are the terminal groups which present
different electron density and the positions of their
nucleophilic moiety. These changes could endow the
molecule with different pharmacological properties such
as antidepressant-like (ADDCH1 and ADDCH2), or
antipsychotic-like (chlorpromazine) activity which is
not investigated in the present study.
3. Discussion
The compounds 4-amine(3-N,N-dimethylpropylamine)-
10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one
(ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocyclo-
hepta[4,4a,5-ef]1,4-diazepin (ADDCH2) clearly present
antidepressant-like profiles of action after sub-chronic
and repeated treatment, as shown by the significant
reduction in the immobility time recorded in the forced
swimming test (FST). A reduction in the immobility
time in the FST is exhibited by therapeutically useful
antidepressant drugs7,8 and is very well accepted as a
reliable indicator of this kind of pharmacological activ-
ity.9–11 However, a demonstration of effect under an
acute schedule of administration is not sufficient to
postulate an antidepressant activity since there have
been some false positive results for drugs such as caf-
feine, anticholinergic and antihistaminergic drugs.12
Nevertheless, the results obtained after the repeated
treatment with these 4-amine-dibenzocycloheptane
derivatives confirm their antidepressant-like profiles of
action since the effect is still present at the end of a
10-day treatment.
The mechanisms of action to support this antidepres-
sant-like activity, an effect on the NA and/or 5-HT sys-
tems, function in a similar way to some commercially
clearly structurally similar to typical tricyclic antidepres-
sants, besides also sharing similarities with CNS-acting
phenothiazines and histaminergics such as clozapine
and cyproheptadine.14 Therefore, based on the chemical
structures of ADDCH1 and ADDCH2, their putative
underlying mechanisms of action involving the catechol-
aminergic system are presently under investigation in
our laboratory.18
4. Conclusion
In conclusion, the present results showed a clear antide-
pressant-like effect of 4-amine(3-N,N-dimethylpropyl-
amine)-10,11-dihydro-5H-dibenzo-[a,d]-cycloheptane-5-
one (ADDCH1) and 1,2,3,4,8,9-hexahydro-dibenzocy-
clohepta[4,4a,5-ef]1,4-diazepin (ADDCH2). The under-
lying molecular mechanism of action is presently under
investigation but the findings shown here are very signif-
icant because they reveal a new potential tool for the
treatment of depression, an important medical field,
since this psychopathology is one of the most prevalent
throughout the world and is still in need of new and
perhaps better therapeutic approaches.19
Due to the fact that the FST is based on a motor
response of animals, it could be affected by changes in
their motor activity and/or performance. For this rea-
son, animals were evaluated in the rota-rod and open-
field tests. Sub-chronic and repeated treatment with
ADDCH1 or ADDCH2 did not alter the behavioral
performance of the animals which essentially depends
on their motor function. This observation strongly indi-
cates that the reduction in the immobility time is due to
a selective antidepressant-like effect of these 4-amino-
dibenzocycloheptane compounds, and not merely the
result of a general stimulation of the animal’s motor
activity.
5. Materials and methods
5.1. Drugs and solvents
Several drugs with central nervous system (CNS) activ-
ity possess two benzenoid rings fused to a six- or sev-
en-membered ring, in some cases aromatic, and to an
alkyl chain with terminal substituted nitrogens.13,14
The 10,11-dihydro-5H-dibenzo-alkylamine cyclohep-
tane system could exhibit several pharmacological ef-
fects including antidepressant5 and antipsychotic
The drugs and solvents used were: imipramine chlorhy-
drate, from Sigma Chemical Company (St. Louis, USA)
which and two 4-amine derivatives of dibenzocyclohep-
tane (ADDCH1 and ADDCH2), were synthesized in-
house according to the method described by Romeiro
and Martins (2001).13

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F. S. Duarte et al. / Bioorg. Med. Chem. 15 (2007) 1645–1650
5.2. Animals
carried out in
a
transparent Plexiglas arena
(30 · 30 · 15 cm). The apparatus floor, made from black
Plexiglas, was divided into nine equal squares and the
number of squares crossed in 5 min was counted. The
behaviour of each animal was assessed under red light
illumination (15 W). The field was thoroughly cleaned
with 10% ethanol solution between tests. All sessions
were videotaped using an infra-red video camera (Phil-
co, model PVC-4H10, Manaus, Brazil), to enable play-
back when necessary.
Female adult Swiss mice (25–35 g) were used in all
experiments. They were housed in groups of 20 animals
per plastic cage under controlled conditions of light
(from 07:00 to 19:00 h) and temperature (23 2 ꢁC).
The animals were allowed free access to standard labo-
ratory food and tap water, and to adapt to the laborato-
ry environment for at least one week before the
behavioural assessment. For each treatment, a different
group of experimental and control animals was used.
All animal testing was carried out according to interna-
tional standards of animal welfare recommended by the
Brazilian Society of Neuroscience and Behaviour (Act
1992) and approved by the local Committee for Animal
Care in Research (# 081/CEUA and 23080.001156//
2001-50/UFSC). The minimum number of animals and
duration of observation required to obtain consistent
data were employed.
5.5. Measurement of motor performance
Mice were placed on the horizontal rotating bar (diam-
eter 2.5 cm, 12 rpm) of the rota-rod apparatus on the
tenth day of treatment, immediately after the open-field
test. Total time spent on the bar during a 1-min session
was registered using a stopwatch, and the number of
falls during the session was also recorded.20
5.3. Measurement of immobility
5.6. Experimental procedures
To measure immobility, we essentially followed the
method proposed by Porsolt and colleagues
(1977,1978).7,8 Briefly, animals were submitted to a
swimming stress session for 15 min (pre-test), 24 h be-
fore being individually returned to the same plastic cyl-
inders (height 18.5 cm, diameter 12.5 cm) containing
13.5 cm of water at 25 ꢁC, for 5 min (test). In the test
session, animals were placed in the plastic cylinders for
just 5 min, 1 h after the last injection (sub-chronic or
repeated treatment). In both treatments, the behavioural
observation was performed for up to 5 min by an expe-
rienced observer, who was blind to the treatment condi-
tions. Animals were judged to be immobile when they
ceased struggling and remained floating motionless in
the water, making only those movements necessary to
keep their head above water.
5.6.1. Compound synthesis and features. Melting points
were determined using a Fisher-Johns melting point
apparatus and are uncorrected. The IR spectra were
recorded on a Perkin-Elmer 1420 spectrometer in potas-
1
sium bromide pellets. The H and 13C NMR spectra
were recorded on a 300 MHz Varian Unity spectrome-
ter, with TMS as an internal standard, coupling con-
stants are given in Hz. Low-resolution EI mass spectra
were recorded on a MAT 711A Finnigan instrument,
at 70 eV with the source at 200 ꢁC and an accelerating
voltage of 8 KV. The samples were heated and intro-
duced directly into the source area. Analytical thin-layer
chromatography (TLC) was performed on silica gel
plates, 60F-254 (0.25 mm, Merck).
5.6.2. General procedure for ADDCH1 and ADDCH2.
The first step in the synthesis of dibenzocycloheptane
derivatives is the introduction of the iodine atom in po-
sition 4 of the dibenzosuberone to give a iodinated com-
pound. A solution of the iodinated ketone and
appropriated amine was stirred under reflux for several
5.4. Measurement of locomotor activity
Animals were tested for their spontaneous locomotor
activity on the tenth day of treatment. The test was
b
O
N
H
N
a
ADDCH1
O
O
I
c
N
N
H
ADDCH2
Scheme 1. Reagents and conditions: (a) Thalium trifluoroacetate (TTFA)/trifluoroacetic acid (TFA)/KI/48 h; (b) N,N-dimethylpropylamine/reflux;
(c) ethilinediamine/reflux.

F. S. Duarte et al. / Bioorg. Med. Chem. 15 (2007) 1645–1650
1649
hours. The solution was cooled and chloroform was
added before washing three times with water. The
organic phase was dried with Na2SO4 and concentrated.
Column chromatography of the residue on silica gel
afforded the product as yellow oil (Scheme 1), which
was characterized by infrared, NMR and mass
spectrometry.13
N
N
H
Compound 1, 4-amine(3-N,N-dimethylpropylamine)-
10,11-dihydro-5H-dibenzo[a,d]cycloheptane-5-one (ADD-
CH1), was isolated with 55% yield. IR (film cmÀ1) 3391,
2941, 2815, 1596, 1573, 1505, 1462, 1277, 1242, 1158,
1101, 1080, 926, 781, 719, 665. EIMS (70 eV) m/z (%),
[M]+ 308.18881 (12), 237.11060 (20), 220.10434 (52),
149.01597 (10), 81.05897 (19). C20H24N2O HR. Calcd
Scheme 3.
5 min, as previously described. Imipramine (IMI,
15 mg/kg ip) was employed as the antidepressant stan-
dard drug using the same administration schedule. The
control group received 0.9% NaCl in a constant volume
by the same route and under a similar schedule of
administration.
1
308.18886; found: 308.18881. H NMR d (CDCl3, ppm)
1.83 (tt, J = 7.2 and 7.2 Hz, 2H), 2.25 (s, 6H), 2.39
(t, J = 7.2 Hz, 2H), 3.07–3.25 (m, 6), 6.44 (d, J = 7.2 Hz,
1H), 6.61 (d, J = 7.8 Hz, 1H), 7.17–7.39 (m, 4H), 7.73 (br
s, 1H), 7.98 (dd, J = 8.1 and 1.5 Hz, 1H). 13C NMR
(CDCl3) 26.93, 34.76, 35.65, 41.60, 45.30, 57.37, 109.78,
115.77, 121.57, 126.09, 128.81, 130.84, 131.52, 132.90,
139.92, 140.49, 143.11, 149.78, 197.52 (Scheme 2).
5.6.4. Evaluation of the antidepressant-like effect of the 4-
amine-dibenzocycloheptane derivatives after repeated
treatment (once a day for 10 days). Another group of
animals was treated for 10 days with ADDCH1
(50 mg/kg ip) or ADDCH2 (30 mg/kg ip) and tested in
the forced swimming test 1 h after the last drug admin-
istration. The control group received vehicle (0.9%
NaCl) in a constant volume by the same route and under
a similar schedule of administration.
Compound 2, 1,2,3,4,8,9-hexahydro-dibenzocyclohep-
ta[4,4a,5-ef]1,4-diazepin (ADDCH2), was isolated with
60% yield. IR (film cmÀ1) 3365, 3281, 3053, 2920,
2858, 1614, 1596, 1478, 1459, 1330, 1314, 1295, 1262,
1215, 1160, 1101, 1063, 1033, 994, 961, 894, 849, 804,
776, 759, 735, 700, 688, 642. EIMS (70 eV) C17H16N2.
m/z (%), [M]+ 248 (35), 247 (100), 220 (20), 204 (20),
189 (15), 178 (10), 165 (12), 115 (10), 1H NMR d
(CDCl3, ppm) 3.17–3.02 (m, 5H), 3,84–3.74 (m, 4H),
6,56 (dd, J = 7.5 and 0.9 Hz, 1H), 6,80 (dd, J = 8.1
and 0.9 Hz, 1H), 7,09 (dd, 7.5 and 1.5 Hz, 1H) 7,12 (t,
J = 7,8 Hz, 1H), 7.29–718 (m, 2H), 7,85 (dd, 7.2 and
2.1 Hz, 1H). 13C NMR (CDCl3) 32.60, 33.82, 49.24,
53.73, 118.01, 121.13, 125.99, 127.34, 129.09, 129.51,
129.62, 130.19, 137.88, 139.09, 140.14, 145.05. 172.51
(Scheme 3).
5.6.5. Evaluation of the effect of the 4-amine-dibenzocy-
cloheptane derivative on the locomotor activity and motor
co-ordination after repeated treatment. The locomotor
activity and motor co-ordination were assessed immedi-
ately before the forced swimming test. Imipramine
(15 mg/kg ip) was used as the antidepressant standard
drug following the same administration protocol.
5.7. Statistical analysis
Values are presented as group means and SEM. The
data were analysed by one-way analysis of variance
(ANOVA), and post hoc comparison of means was car-
ried out with Newman–Keuls’ test (sub-chronic and
repeated treatments), using GraphPad Prismꢂ version
3.0, with P < 0.05 being considered statistically
significant.
5.6.3. Evaluation of the antidepressant-like effect of the 4-
amine-dibenzocycloheptane derivatives after sub-chronic
treatment (three doses in 24 h). The compound ADD-
CH1 (5–100 mg/kg, ip) or ADDCH2 (1–50 mg/kg, ip)
was administered 1 and 18 h after the swimming stress
session and a third dose was administered 1 h before
the mice were tested in the forced swimming test for
Acknowledgments
F. S. Duarte is a recipient of a PhD scholarship from the
Brazilian National Research Council (CNPq) and T. C.
M. De Lima is a recipient of a research grant from the
Brazilian National Research Council (CNPq). The
authors thank Dr. Gareth Cuttle for the final English
revision of the text.
O
N
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