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org/cm Comments
A Comparison of the Stochastic and Deterministic Approaches in a
Nucleation−Growth Type Model of Nanoparticle Formation
Cite This: Chem. Mater. 2021, 33, 5430−5436
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F or the last two decades, the research group of Richard
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Finke has been developing fairly general kinetic models of
nanoparticle formation,1−11 which can be viewed as initial
attempts at a rational control of nanoparticle size distribution.
The general approach of the lumped kinetic models used by
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Finke and co-workers was criticized in this journal by James
Martin,12 and a response was published by the Finke group.13
The present comment has been written to address a point that
was brought up by both authors12,13 in some form. Martin12
called for a consideration of single nucleation events, for which
stochastic kinetics is the appropriate method. Finke, White-
head, and Watzky13 explicitly called for using the stochastic
approach in really quantitative models. The problem in the
background is that classical (deterministic) chemical kinetics
works with concentrations as continuous functions of time at
the macroscopic or ensemble level, whereas in reality matter is
composed of particles and all molecular events actually occur
atomistically or molecularly between discrete particles. A
mathematical approach to handle this problem, called
stochastic chemical kinetics, has already been developed
during the last 100 years and is in common use for solving
certain kinetic problems,14−16 yet its general application seems
to be surprisingly rare.
In detailed, nonlumped models of nanoparticle formation,
the number of different species is usually extremely large as
each nanoparticle of a particular size should be considered as a
chemical entity on its own, whose reactivity differs at least
slightly from nanoparticles of identical chemical compositions
but different sizes.17−22 Given the very high number of
different species in the system, it is natural that the amounts of
substances for most of them are very low. These are exactly the
conditions under which considerations based on deterministic
kinetics, where amounts of substances and concentrations are
considered to be continuous variables, may be misleading or
entirely erroneous.16 It should be noted that the appearance of
such problems is possible in such cases but not inevitable.
There are a number of examples where the stochastic kinetic
approach yielded insightful results including autocatalytic
processes,23 autocatalytic extinction,24 chiral symmetry break-
ing,25−27 a mechanism-based interpretation of the Soai
reaction,28 the origins of biomolecular chirality29 and the
effect of parity violation in it,30,31 an analysis of the Frank
model,32 and details of single-enzyme catalysis.33−36
It is clear that the best way of addressing the concern raised
about the single-event nucleation by Martin12 is to compare
the results of deterministic and stochastic kinetic calculations
in the same chemical model. Indeed, Finke’s response13 noted
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sı Supporting Information
that a stochastic simulation of nucleation is necessary and then
a possible expansion of the simulation to the deterministic
limit (where the experimental evidence is almost exclusively
gained) could lead to a realistic model of any mechanism.13
Such a stochastic−deterministic comparison has well-known
theoretical foundations:37,38 Kurtz’s theorem16,37 states that
the usual deterministic kinetic approach is the infinite volume
limit of the continuous time discrete state (CDS) stochastic
approach, which is most commonly used and will be employed
here. However, Kurtz’s theorem has two limitations. First, it is
not valid for open systems.32 This is not relevant for the
present analysis because the model here at least formally
describes a closed nanoparticle formation system. More
importantly, it is typically the expectation (or mean) of the
stochastic approach, which is basically the same as an average
but defined with mathematically precision,16 that can be
compared directly with results from the deterministic
calculations. The problem lies in the fact that the stochastic
expectation is occasionally a very unlikely or even impossible
state in a single experiment.16,39 Phenomena similar to this are
known in the description of autocatalytic reactions, too.24,25
The kinetic models of nanoparticle formation are often
described as autocatalytic1,2,6,7,10 which might give some
reason for concern in this respect.
The present comment directly addresses the issue of the
connection between the stochastic and the deterministic
approaches to kinetics specifically for the nucleation−growth
type mechanisms of nanoparticle formation. Results from the
two approaches will be compared in two different systems: one
for which the exact analytical solution was reported recently
(eq 1 below)21 and another one for which a method to find the
numerical deterministic solution was developed specifically in
this work (eq 10 further on). In both cases, the stochastic
description is based on Monte Carlo simulations,16 which
consider the models at the single nucleation event level.
Received: December 8, 2020
Revised: May 7, 2021
Published: June 25, 2021
https://doi.org/10.1021/acs.chemmater.0c04688
5430 Chem. Mater. 2021, 33, 5430−5436
Chemistry of Materials

■
pubs.acs.org/cm Comments

THE NUCLEATION−GROWTH TYPE KINETIC

i yz
kg − 2k n

lnjjjj −k g[M]0 t z
z
⟨r ⟩ = r0
z
MODEL AND THE DETERMINISTIC APPROACH 2k gk n + k g(k g − 2k n)e−k g[M]0 t

In the nucleation−growth type model1,5,17 considered here, M
will denote a single monomeric unit of the nanoparticle,
whereas Ci will stand for a nanoparticle containing exactly i
monomeric units. The two reactions in the model are second
order nucleation (kn) and also overall second order particle
growth (kg,i), whose rate constant is directly proportional to
the number of monomeric units in the particle (i).
kn
2M → C2 rn = k n[M]2
kg, i
Ci + M → Ci + 1 i≥2
In this equation, ri denotes the rate of the corresponding
reaction step. This model was primarily developed to interpret
the time dependence of the average particle size in a simplified
but fully quantitative manner in solution systems. Unfortu-
k 2k n + (k g − 2k n)e {
3 kg
−kn +
2(k g − 2k n)(1 − e−k g[M]0 t ) (4)
Parameter r0 here is a reference size: the hypothetical sphere-
equivalent size of a single monomeric unit as a nanoparticle.
So the deterministic kinetic approach to the chemical model
in eq 1 leads to a full solution in the form of analytical formulas
for the concentration and particle sizes. Equation 2 gives the
system of simultaneous ordinary differential equations that
follows from the model, whereas eqs 3 and 4 show the
analytical solutions. It should be noted that it is highly
rg, i = ikg[M][Ci] exceptional that this analytical solution could be found for eq
2.21 Normally, such analytical solutions are only available for
(1)
the simplest systems.43 Unlike in the typical cases of
deterministic kinetics, the numerical solution of eq 2 is
impossible by the usual integration methods43 because it has
an infinitely high number of coupled dependent variables (i.e.,
concentrations).

nately, the kinetics of nanoparticle formation is not studied
with a sufficient time resolution in the majority of the relevant
articles, but the usefulness of the model was still demonstrated
in various systems including the formation of zirconiumox-
oalkoxy nanoparticles,40 the formation of amino-PEG covered
gold nanoparticles41 (the interpretation itself is given in a later
article for these two sets of data21), and the formation of TiO2
nanoparticles from the hydrolysis and condensation of
titanium(IV)-bis(ammonium-lactato)dihydroxide under basic
conditions.42 These three examples imply that the model itself
could be a general one for solutions.
The system of simultaneous ordinary differential equations
that describes the investigated chemical model takes the
following form:
∞ ∞
d[M]
= − 2rn − ∑ rg,j = −2kn[M]2 − kg[M] ∑ j[Cj]
dt j=2
d [C 2 ]
= rn − rg,2 = k n[M]2 − 2kg[M][C2]
dt
d[Ci]
= rg, i − 1 − rg, i = (i − 1)kg[M][Ci − 1] − ikg[M][Ci]
dt
Brackets mean concentrations here (amount of substance
divided by volume). The typical initial conditions of
nanoparticle formation are such when, at time t = 0, the
initial concentration of the monomeric unit is [M]0, whereas
all of the nanoparticles are absent, i.e., [Ci]0 = 0. In our
previous work,21 detailed mathematical derivations showed
that the concentrations of individual species in the model can
be given exactly as a function of time as follows:
[M]0 kg e−k g[M]0 t
[M] =
2k n + (kg − 2k n)e−k g[M]0 t
[M]0 2kgi − 2k n2(i − 1)! (− 1)i − 1(e−k g[M]0 t − 1)
[Ci] = i
■
THE STOCHASTIC APPROACH: METHODS
In this section, the stochastic kinetic approach to the model
described in eq 1 will be developed. As usual in the continuous
time discrete state approach,16 the system will be described
using discrete molecule numbers instead of continuous
concentrations, and the connection between the two models
will be made using the full volume (V) of the system.16
The number of monomeric unit molecules in the initial state
will be denoted n. Symbol c1(t) will mean the number of
monomeric units at time t, whereas the number of nano-
particles with exactly i monomeric units in it will be designated
ci(t). It is seen that the maximum value of i is n (i.e., no
individual nanoparticle can contain more monomeric units
than the overall number of monomeric units in the system).
j=2 Because of mass conservation, the following equation holds at
any time instant:
n
i>2 ∑ ici(t ) = n
i=1 (5)
(2)
Counting the number of possible solutions for eq 5 gives the
number of states (M) in the stochastic model of the process. In
a classical subfield within combinatorics, this is called the
partition problem.44 The number of solutions of eq 5 is called
the partition function of number theory and is abbreviated
p(n).44 No closed form expression is known for calculating
p(n). For example, the known value of the partition function
for n = 10 000 (ten thousand) is approximately 3.6 × 10106
(exact value is given in the Supporting Information), which
renders it hopeless to handle all possible states by simply
increasing the computational power.
The full form of the CDS approach sets up a master
equation that is equivalent to the rate equation,16 which has

k n(j 2 − 1) ijji − 1 yzz

[2k n + (kg − 2k n)e−k g[M]0 t ] ∏ j = 2 (2k n − kgj − kg) the form given in eq 2 in the present case. In the master
jj z(− 1) j
j − 1z{
i
equation, the probability of a given state (and not the
j = 2 (2k n − kgj − kg)j k
+ [M]0 ∑
ÄÅ ÉÑ
ÅÅ ÑÑ
probability of individual concentrations or molecule numbers)
ÅÅij yz g ÑÑ
ÅÅjj z ÑÑ
is given in a linear, first order set of differential equations. In
ÅÅjj zz ÑÑ
ÅÅjj 2k + (k − 2k )e−k g[M]0 t zzz
k j /(2k n − k g)

ÑÑ
kg
ÅÅk n ÑÑ
the model of eq 1, even stating this master equation in a
ÅÅÇ { ÑÑÖ
− 1
g n concise form runs into substantial difficulties because of the
(3)
complicated and exceptionally large state space described in
The cube-root number-average size of the nanoparticles could the previous paragraph. Despite our attempts, no way to use
also be obtained analytically: the master equation in any meaningful way was found.
5431 https://doi.org/10.1021/acs.chemmater.0c04688
Chem. Mater. 2021, 33, 5430−5436
Chemistry of Materials
In such complicated cases, it is still possible to run Monte
Carlo simulations based on CDS kinetics,45−49 an approach
widely known as the Gillespie algorithm.16 In this method, the
time-dependent propensity pi (or infinitesimal transition
probability) of each step is defined analogously to the
deterministic rates:
kn k n c1(t )[c1(t ) − 1]
2M → C2 p1 (t ) =
NAV
kg, i
Ci + M → Ci + 1 i≥2
ikg
pi (t ) = c1(t )ci(t )
NAV
Note that the number of different reactions and propensities
cannot exceed n, as the highest possible nonzero molecule
number is cn. In these formulas, NA is Avogadro’s constant and
V is the volume of the reactor. The inclusion of these
parameters is necessary for connecting the deterministic and
stochastic approaches.16
The essence of the simulation is that, in each step, two
independent, uniformly distributed random numbers are
generated between 0 and 1; these are rnd1 and rnd2. The
first random number is used to increment the time according
to the following equation:
ln rnd1
t new = t old − n
∑ j = 1 pj (t old)
The second random number is used to decide which of the
steps with nonzero propensity occurs. Step i occurs if and only
if the following inequity is satisfied:
i−1 i
∑ j = 1 pj (t old) ∑ j = 1 pj (t old)
≤ rnd 2 <
n
∑ j = 1 pj (t old)
n
∑ j = 1 pj (t old)
The occurrence of step i causes the following changes in the
molecule numbers:
c1(t new ) = c1(t old) − 2; c 2(t new ) = c 2(t old) + 1
if i = 1
c1(t new ) = c1(t old) − 1; ci(t new ) = ci(t old) − 1;
ci + 1(t new ) = ci + 1(t old) + 1 if i > 1
These steps are repeated until c1 = 0, which means that all the
propensities are zero, i.e., an unchangeable final state is
reached.
A high number of simulations from identical initial
conditions and parameters were done (repetitions) in order
to approximate probability distributions when necessary. The
initial number of molecules (n) was usually selected to be
between 106 and 108. This is small compared to the usual
number of monomeric units in any realistic cases but was
computationally manageable and already gave highly con-
clusive results for the comparison of the stochastic and
deterministic approaches. Most simulation were done at kn/kg
≪ 1 (slow nucleation compared to particle growth), because
otherwise the particles remain very small.21
■
pubs.acs.org/cm Comments
THE STOCHASTIC APPROACH: RESULTS AND
COMPARISON
For maximizing the information content of the graphs
presented here and reducing the number of parameters, the
results will be shown with scaled variables.43 This technique
also facilitates comparisons of stochastic and deterministic
results. Instead of time, scaled time will be used here: in the
deterministic approach, scaled time can be calculated as
2 tkg[M]0, whereas the corresponding formula is tkgn/(NAV) for
the stochastic approach. Similarly, the scaled concentration of
the monomeric unit is [M]/[M]0 in the deterministic approach
and c1/n in the stochastic approach. Finally, the scaled particle
size is r/r0 in both types of calculations. It should also be noted
(6) that, with the introduction of these scaled parameters, the final
results will depend only on the dimensionless rate constant
ratio of kn/kg and not on the individual values of the rate
constants. Therefore, the displayed results fully characterize
the entire meaningful parameter space, so they cover all
possible values of the two rate constants (kn or kg) and the
single initial concentration ([M]0) that can be reasonably
encountered in reality.
Figure 1 shows the results for the time dependence of the
scaled concentration of the monomeric unit from five
(7)
Figure 1. Scaled concentration of the monomeric unit in five
(8)
repetitive simulation runs and the deterministic expectation for the
same process for the system of eq 1. Parameters: n = 106, kn/kg = 10−6.
randomly selected stochastic simulation runs and the
corresponding deterministic curve at the fixed values of kn/kg
= 10−6 and n = 106. As expected, the individual Gillespie
simulations are noticeably different, and the deviations are very
much in line with the known time dependence of simple
(9) autocatalytic processes.50 It is also clear that some of the
simulation runs are faster, whereas others are slower than the
deterministic expectation. Two more figures showing how the
simulations depend on the values of n and kn/kg are found in
the Supporting Information as Figures S1 and S2.
From the same five simulation runs, the time dependence of
the scaled average size was also determined. These results are
shown in Figure 2 along with the deterministic curve. When
viewing this figure, it should be kept in mind that the size of a
particle is proportional to the cube root of the number of
monomeric units in it, so a scaled size of 40 actually implies
64 000 monomeric units in the particle. The comparison of the
runs with each other and the deterministic predictions is very
similar to the one shown in Figure 1 for the scaled
concentration of the monomeric unit. A close inspection of
the stochastic results shows that some of the curves are not
entirely monotonic. The overwhelming trend is an increase in
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Chem. Mater. 2021, 33, 5430−5436
Chemistry of Materials
Figure 2. Scaled average size as a function of scaled time in five
repetitive simulation runs and the deterministic expectation for the
same process for the system of eq 1. Parameters: n = 106, kn/kg = 10−6.
average size as time passes, but occasionally short periods of
decrease can also be seen. This phenomenon has no parallel in
the deterministic calculations and is caused by single
nucleation events. Whenever a new nucleus is formed, it has
a very small size (two monomeric units form a nucleus), so it
may decrease the average somewhat.
To characterize the magnitude of the deviations expected
because of the stochastic nature of the process, simulation runs
were started from exactly the same initial state 100 times.
Drawing a graph similar to Figure 1 or 2 in this case is not
feasible with 100 runs. Instead, the distribution of a selected
property, the monomeric unit half-life (i.e., the time necessary
for the concentration of the monomeric unit to fall to one-half
of the initial values), is shown in Figure 3. It is to be noted that
Figure 3. Cumulative distribution of half-lives for the concentration of
the monomeric unit for the system of eq 1. Parameters n = 108; kn/kg
= 10−7.
this is not analogous to the half-life of first order processes,
which is independent of the initial concentration,43 but can still
be used for comparison purposes here as the graph only shows
different repetitions of simulation from exactly the same initial
conditions. Also, it is an important observation in stochastic
kinetics that comparisons of distributions should be done using
the cumulative distribution function rather than the probability
density function.16,25,28,29,50 In nonexpert use, the probability
density function is often preferred as it is the direct equivalent
of a histogram. However, histograms involve highly arbitrary
categorization of events, which is understood to fundamentally
influence the final picture drawn. The use of cumulative
distribution functions avoids these problems entirely. In the
present case, the ordinate of Figure 3 shows the cumulative
distribution functions F(t1/2), which is the probability of
obtaining a half-life shorter than t1/2 in a simulation. As already
5433
pubs.acs.org/cm Comments
mentioned, Figure 3 contains 100 points, which was the
number individual runs. In deterministic kinetics, the kinetic
curves are uniquely determined by the initial conditions, so the
half-life is a single value without any distribution. This single
value is shown by a gray vertical line in Figure 3. It is seen that
this line is very close to the time of 50% probability.
Furthermore, a red continuous curve is also included in the
graph, which shows the best fitting normal distribution to the
curve. This line fits the simulation points quite nicely. Small
fluctuations in stochastic kinetics are expected to follow normal
distribution because of the central limit theorem of probability
theory.16 The adherence of the distribution of half-lives to
normal distribution predicts that the relative fluctuations will
be a lot smaller as the initial number of particles is increased.16
It is quite noticeable that, even at a low particle number of 108,
no obvious deviations are seen from normal distribution. In
many cases where the stochastic effects are present even in
macroscopic systems, such deviations are very large at small
molecule numbers.16,25,28 In the Supporting Information, two
more graphs similar to Figure 3 are included as Figures S3 and
S4. They show the analogous distributions for different values
kn/kg (10−6 and 10−8). The expected half-lives under these
conditions are different from that shown in Figure 3, but the
general picture and the close adherence to the normal
distribution is the same.
As already mentioned in the introduction, one of the most
important descriptors of a nanoparticle synthesis method is the
size distribution obtained. This can be calculated for the final
state from both stochastic simulations and deterministic
formulas. A comparison is shown in Figure 4. As explained
Figure 4. Final particle size distribution in stochastic simulations and
the deterministic prediction for the system of eq 1. Parameters: n =
108; kn/kg = 10−6.
for Figure 3, a comparison like this should be done using the
cumulative distribution function and not the probability
density function. So the ordinate of Figure 4 shows F(r),
which is the probability that the size of a randomly selected
particle in the final mixture is smaller than r. Only three
simulations are shown in the graph as all three run very close
to each other (they are not even seen separately for most
regions of the figure). A much higher number of actual
simulation runs were done, but this unique distribution was
always reached as the final result. Furthermore, the distribution
obtained in the stochastic run matches very closely the one
predicted by the deterministic approach. Some deviations can
be seen above the scaled particle size of 60, but these are
arguably small artifacts connected to number representation
issues in calculating the alternately signed sum of large
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Chemistry of Materials pubs.acs.org/cm Comments

binomial coefficients in eq 3, a computational problem noted

in several previous works.17,30,31
It should be noted that the initial number of monomeric
units for calculating the results shown in Figure 4 was 108,
which is still a very small one in chemistry. The match of the
result of even a single stochastic run with the deterministic
prediction is very good here. Hence, the result presented in
this section proves that Kurtz’s theorem37 for the nucleation−
growth mechanism with autocatalytic phenomena already gives
practical agreement between the two approaches even at
consideration of just 108 monomers. This agreement will be
even better when a larger initial number of molecules is
considered.

■
Figure 5. Cumulative distribution of half-lives for the concentration of
the monomeric unit for the system of eq 10. Parameters n = 107; kn/kg
STOCHASTIC−DETERMINISTIC COMPARISON IN A = 5 × 10−8.
SECOND MODEL
As already pointed out, the full analytical deterministic solution
is not known for any other model, and numerical solutions
cannot be obtained either because the number of concen-
trations is infinitely large. However, we could develop a novel
numerical integration method that could be used for the case
when the growth rate constants are independent of the size of
the nanoparticle. The chemical model is the following:
kn
2M → C2 rn = k n[M]2
kg, i
Ci + M → Ci + 1 i≥2 rg, i = kg[M][Ci]
(10)
Figure 6. Final particle size distribution in stochastic simulations and
In this case, the ordinary differential equations are the deterministic prediction for the system of eq 10. Parameters: n =
d[M]
∞ ∞ 107; kn/kg = 5 × 10−7.
= − 2rn − ∑ rg ,j = −2kn[M]2 − kg[M] ∑ [Cj]
dt j=2 j=2

d [C 2 ]
= rn − rg ,2 = k n[M]2 − kg[M][C2]
dt
d[Ci]
= rg , i − 1 − rg , i = kg[M][Ci − 1] − kg[M][Ci]
dt
This system of differential equations was solved by a
specifically developed numerical method, which is described
in detail in the Supporting Information. It should be
emphasized that this method is only suitable for the system
shown in eq 11 and cannot be generalized.
The stochastic Gillespie simulations could be done very
similarly to the previous case. The only difference was that the
propensity function pi(t), originally defined in eq 6, had to be
calculated by a different formula:
kg
pi (t ) = c1(t )ci(t )
NAV
Similarly to the previous model, the deterministic and
stochastic predictions were compared systematically. Figure 5
shows the distribution of half-lives at kn/kg = 5 × 10−7. The
half-life values are understandably different from those
calculated in the previous model, but otherwise the graph is
very similar to Figure 3: the distribution obtained from 100
individual runs is described by a normal distribution quite well.
The same is shown for two different values of kn/kg in Figures
S5 and S6 in the Supporting Information.
The final distribution of nanoparticle sizes is shown for one
particular value of kn/kg (= 5 × 10−8) in Figure 6. Here n = 107
was selected, so the initial number of monomeric units was
even lower than for the analogous data shown in Figure 4. The
two different simulation runs agree with each other very well
and also agree with the deterministic prediction. The
i>2
(11) distribution itself is very different from the one shown in
Figure 4, no doubt because the two models are substantially
different. Yet the fact that stochastic and deterministic
predictions for the size distributions are within any reasonable
experimental limit is clear from both Figures 4 and 6.
■ SUMMARY
In response to the suggestion of James Martin,12 which called
for a consideration of single nucleation events, and then the
suggestion of Finke,13 which called for considering the
stochastic nature of those single nucleation events, in
nanoparticle formation models, a comparison of the stochastic
(12) (continuous time discrete state) and the more common
deterministic approaches was presented here in two
nucleation−growth type nanoparticle formation models.
Detectable fluctuations in reaction time were found, which
are very similar to those demonstrated in simple autocatalytic
reactions50 and are by no means specific to nanoparticle
formation. The results showed that even at initial monomer
molecule numbers as low as 10 7, the stochastic and
deterministic approaches predict almost identical particle size
distributions. This comparison validates the deterministic
kinetic approach and calculations for the size distribution in
such systems.
Rebeka Szabó
Gábor Lente orcid.org/0000-0003-2022-2156
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Chem. Mater. 2021, 33, 5430−5436
Chemistry of Materials
■
pubs.acs.org/cm
ASSOCIATED CONTENT
*
sı Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.chemmater.0c04688.
An example of the value of the combinatorial partition
function, a sample Matlab code used in implementing
Gillespie’s algorithm, and the four additional graphs
referred to in the text (PDF)
■
AUTHOR INFORMATION
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemmater.0c04688
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work was supported by the Higher Education Institu-
tional Excellence Programme of the Ministry of Human
Capacities in Hungary, within the framework of the first
thematic programme of the University of Pécs. The National
Research, Development, and Innovation Office of Hungary
also supported this work under Grant No. SNN 125739.
■
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