A method to capture the large relativistic and solvent effects on the UV-vis spectra of photo-activated metal complexes

We have recently developed a method based on relativistic time-dependent density functional theory (TD-DFT) that allows the calculation of electronic spectra in solution (Creutzberg, Hedeg{\aa}rd, J. Chem. Theory Comput.18, 2022, 3671). This method treats the solvent explicitly with a classical, polarizable embedding (PE) description. Furthermore, it employs the complex polarization propagator (CPP) formalism which allows calculations on complexes with a dense population of electronic states (such complexes are known to be problematic for conventional TD-DFT). Here, we employ this method to investigate both the dynamic and electronic effects of the solvent for the excited electronic states of trans-trans-trans-[Pt(N3)2(OH)2(NH3)2] in aqueous solution. This complex decomposes into species harmful to cancer cells under light irradiation. Thus, understanding its photo-physical properties may lead to a more efficient method to battle cancer. We quantify the effect of the underlying structure and dynamics by classical molecular mechanics simulations, refined with a subsequent DFT or semi-empirical optimization on a cluster. Moreover, we quantify the effect of employing different methods to set up the solvated system, e.g., how sensitive the results are to the method used for the refinement, and how large a solvent shell that is required. The electronic solvent effect is always included through a PE potential.


I. INTRODUCTION
Platinum (II) complexes are used in cancer treatment since the 1970s. The prototypical complex for cancer treatment is cis-[Pt(NH 3 ) 2 Cl 2 ], but several complexes with similar motifs are in use today. [2][3][4] Unfortunately, the treatments cause severe side-effects. 5 The side effects occur since cis-[Pt(NH 3 ) 2 Cl 2 ] reacts with other bio-molecules in the body than the target molecules inside the cancer cells. To circumvent these side effects it has been suggested to use a so-called pro-drug. 3 A pro-drug is inactive (and thus harmless for the body) until activation at the site of the tumor. Octahedral Pt(IV) complexes have been investigated as pro-drugs over the last few years. 3,4,6 These complexes are kinetically stable d 6 complexes until they are photo-activated. The use of photo-activation combined with a pro-drug has been coined photo-activated anti-cancer therapy (PACT). 6,7 Different octahedral Pt(IV) complexes have been investigated for use in PACT. A class of complexes that has received considerable attention is the diazido Pt(IV) complexes. 6,8 One of the most simple of these complexes is shown in Figure 1. The advantage of the diazido complexes is their inertness with respect to bio-reducing agents (such as glutathione) 9 .
The complexes are known to decompose after irradiation, but the mechanistic pathways of this decomposition are still not understood. 6 A more complete understanding of the photophysical properties of the Pt(IV) pro-drugs is the next step to further develop PACT.
Theoretical methods based on time-dependent density functional theory (TD-DFT) can help unravel photo-physical properties. 10 Investigations by Salassa et al. 11 employed this method to understand and characterize the UV-vis spectrum of cis-trans-cis-[Pt(N 3 ) 2 (OH) 2 (NH 3 ) 2 ]: They found that the excitations are mainly of ligand-to-metal-charge-transfer (LMCT) character, involving orbitals on azide ligands and platinum. The resulting excited states were found to be dissociative with respect to N -3 . Triplet states were also speculated to be involved in the decomposition. In a later paper by Sokolov et al. 12  Calculations of the excited state manifold of platinum complexes are generally expected to require relativistic effects. These effects have mostly been included with either scalar relativistic Douglas-Kroll-Hess (DKH) to second order 12 or effective core potentials (ECPs). 11 None of these methods include spin-orbit coupling (SOC) explicitly. In a recent investigation, we investigated the effect of SOC on calculated UV-vis spectra for the Pt(IV) complexes trans-trans-trans-[Pt(N 3 ) 2 (OH) 2 (NH 3 ) 2 ] and cis-trans-cis-[Pt(N 3 ) 2 (OH) 2 (NH 3 ) 2 ], employing a four-component linear response framework. 13 One of our main findings was that the SOC led to a much denser manifold of electronic states and many of these states were of mixed singlet-triplet character. Similar findings were also obtained in a recent study by Freitag and González, using a relativistic DMRG-SCF method to study the excited state dissociation reactions. 14 Thus, explicit inclusion of SOC is important to correctly access the excited state manifold of the Pt(IV) complexes used in PACT. Yet, even with inclusion of SOC, the solvent (usually water) employed in experimental work may also have a large impact on the excited states and UV-vis spectra. Accordingly, the next step is to investigate the effect of the solvent: Although we will not study the full dissociation mechanism here, we note that there are strong indications that the decomposition mechanisms of the Pt(IV) complexes are solvent dependent. [15][16][17] However, previous theoretical studies either ignored 12-14 the solvent or included it through continuum models 11 , which are known to be inaccurate for solvents prone to form hydrogen bonds.
Over the last years, we and others have developed models that explicitly include the solvent, employing a polarizable embedding (PE) model. [18][19][20][21][22][23] The PE model includes the environment classically with multipoles and polarizabilities, allowing mutual polarization between the quantum mechanical and classical subsystems. Within non-relativistic frameworks, the PE models have been shown to work well for electronic spectroscopy [24][25][26][27][28] . The PE models were only recently introduced to a relativistic framework 1,29,30 and applications of this methodology have therefore been rare. Initial calculations have demonstrated that the electronic solvent effect on trans-trans-trans-[Pt(N 3 ) 2 (OH) 2 (NH 3 ) 2 ] is substantial. 1 However, structural and/or dynamical effects of the solvent have not been investigated. In this investigation, we undertake a more systematic investigation of solvent effects for the trans-trans-trans-[Pt(N 3 ) 2 (OH) 2 (NH 3 ) 2 ] complex. We will mainly address how the structural changes in the environment influence the spectra by performing molecular dynamics simulations. The dynamics are obtained through classical simulations, but since no force field exists for the platinum complexes, we have constructed one based on calculated charges and the molecular Hessian. We have set up a method in which snapshots extracted from the classical simulation are refined by cluster calculations, employing first a semi-empirical method and then DFT. Part of this paper is also devoted to quantifying to what degree the calculated UV-vis spectra depend on the QM methods employed in this setup. Finally, we also investigate the effect of including water molecules explicitly in the QM region.

II. THEORY
In the PE model, the system is divided into a region that is treated using methods from quantum chemistry (QM), and a region treated classically. The classical region is parameterized by electrostatic multipoles and point-polarizabilties, calculated from a quantum mechanical method by fragmenting the solvent into individual molecules. The total energy expression is then where the first term is the QM energy expression, given as We have in Eq. (2) used a second quantization formalism. Thus, D pq is an element of the one-electron reduced density matrix, h pq is an integral over the kinetic energy and nuclear attraction one-electron operators, and j pq contains the Coulomb integral for electron Here, σ denotes the Pauli spin matrices, I 2 and 0 2 are 2 × 2 unit and zero matrices while c is the speed of light. Finally, V ext is an external potential that here is reduced to the nucleielectron attraction (see Refs. 30 and 1 for further details). As can be inferred from Eq.
to decouple the large and small component wave functions 33 . The decoupling in Eq. (4) allows us to focus only on the positive energy solutions, which reduces the computational cost significantly.
The energy E es in Eq. (1) accounts for the interaction between the electrostatic multipoles in the environment and the QM density, whereas the energy, E ind , accounts for mutual polarization of the QM and MM densities (the latter through the point polarizabilities).
These two energies can be represented by the operators,V es , andV ind that are added to the vacuum Kohn-Sham operator In this formalism, µ ind is a vector containing the induced dipole moments calculated as 34 The definition of R Relay can be found in the literature (see e.g. Ref 30) whereas E is the total electric field, here given for a specific site s in the environment The total electric field has components from nuclei in the QM region,Ê n , electrons in the QM region,Ê e , and the multipoles on the remaining sites,Ê es , where we again refer to the literature for details 35 . Below, we will use the short-hand formV ind for the term involving the induced dipoles.
In this work we employ linear response theory 36,37 to calculate UV-vis spectra. The linear response formalism is often denoted TD-DFT. In this formalism, we solve the equation X is a property gradient (here employing the dipole operator), S [2] the metric, κ z the solution vector, and E [2] is the electronic Hessian, defined as Expressions for the A and B terms can be found elsewhere: the vacuum forms, here denoted A vac and B vac , are provided by Salek et al. 38 We define the additional terms due to a PE environment below. Since regular linear response theory is known to suffer from problems in regions with a a high density of states (which is common on relativistic calculations 1,39 ), we will generally employ the complex polarization propagator (CPP). [39][40][41][42] For the CPP, we set where γ is a phenomenological (inverse) lifetime; regular linear response theory corresponds to setting γ = 0, i.e., z = ω. With z = ω + iγ we have access to the imaginary part of the frequency dependent polarizability tensor, Im[α], which is directly related to the cross-section σ(ω) of the signal in electronic spectroscopies The calculation of the signal cross section is done with an input-defined frequency, ω, meaning that the CPP method has the same cost in all frequency ranges. This is unlike traditional response solvers, which obtain the frequency by solving for a number of roots, starting from the lowest ones (thus the total number of roots may become very high for regions with dense population of electronic states).
We have previously shown how the modification of Eq. 7 due to the PE framework leads to modified linear response equations for both regular linear response 18,30 and the CPP model. 1,43 In short, these changes are, whereV es and V ind were defined in Eq. (5) andṼ ind is a transformed form of V ind (a more detailed derivation can be found in the literature). 1,30,38,44 The first term accounts for the effect due to the multipoles and the ground-state polarization. The second term accounts for the change in solvent response due to the change of electron density in the QM system during an electronic excitation.
Finally, we introduce effective external field effects (EEF) 45,46 . This contribution arises as the external magnetic field that induces an electronic transition, also induces a field, The last term, containing µ ind ext,X (ω k ) = R Relay E X (ω k ), is responsible for the EEF effect.

III. COMPUTATIONAL DETAILS
Static structures and potentials of trans-Pt complex in water: Since the structures obtained during the MD simulations are purely classical, we refine these structures through quantum mechanical optimizations on smaller clusters (more details are given in the next subsection). We initially employed a fast semi-empirical method for this refinement to save computer time. The structures were subsequently refined with DFT. We decided to employ a single structure to investigate the effect of the additional DFT refinement on the calculated UV-vis spectrum, before embarking on optimizing a large number of snapshots. Rather than employing a random snapshot from the classical MD, the structure was taken from our previously optimized solvated trans-trans-trans- (trans-Pt) complex 1 . We recapitulate the optimization here: we employed QM/MM in a box (35 × 35 × 35Å) of explicit (frozen) water molecules, optimizing only the trans-trans- complex. This optimization was followed by two subsequent optimizations. First, we made a cutout including the water molecules within 6Å from the platinum complex. Structure optimizations of this cluster were then carried out relaxing the platinum complex and all water molecules within 4Å, while the rest were kept frozen. This was done with the PBEh-3c 47 method. Next, we refined this optimization with the BP86 functional 48 and a def2-sv(p) 49,50 basis set. We chose this functional since it is computationally efficient and has been shown to provide structures similar to B3LYP in accuracy for transition metal complexes. 51 These calculations were done in ORCA. 52 Finally, the 6 A sphere was re-inserted into the original box and a 10Å sphere was cut out (see Figure   2 were the PBEh-3c systems are shown as examples  56 . The 6-31G* 57,58 basis set was employed for the ligands while the effective core potential SDD 59 was employed for the Platinum atom. Default radii were used for all atoms. A final adjustment of the force field parameters was done by setting the angle between the nitrogen atoms in the N − 3 ligands to 180 degrees, in order to ensure that they were kept linear during the simulations. Dynamics and polarizable embedding potentials: Using the constructed force field the complex was solvated in a box (10 × 10 × 10Å) of explicit TIP3P water molecules. A minimization was then done preceded by two MDs to ensure the platinum complex maintained a reasonable structure: first a MD for 20 fs at constant pressure with SHAKE. 60 After ensuring the integrity of the platinum complex, we continued this MD for 1 ns. Thereafter an equilibration simulation was done at constant pressure for 2 ns before the final production MD was done for 20 ns (also at constant pressure). All calculations were done in AMBER 16 61 . From the trajectory, 49 structures were extracted with a minimum time separation of 0.2 ns. After this, the same QM optimization procedure as for the first single structure (trans-Pt complex in water) was carried out on 6Å sphere cutouts from the structures, but no re-insertion into the original box was done. Thus, the final systems are all 6Å, which (as we show below) is sufficient. Selected structures as well as the force-field parameters are provided as a zenodo repository. 62 Embedding potentials were calculated for the snapshots described above, using the Polarizable embedding (PE) was included in the calculations using the PeLib library (which is interfaced to DIRAC), moreover, effective external field calculations (EEF) were included.
All calculations employed the dyall.v2z 69 basis set for the platinum atom, while the ligands employed a def2-sv(p) basis set. For a few snapshots, we additionally carried CPP calculations with B3LYP (and the same double-zeta basis sets as above) or with CAM-B3LYP and triple zeta basis sets (the results from these calculations are shown in Figures S4 and S5).
The basis sets were always used uncontracted.
We will in the following not discuss the non-relativistic results, since they (as expected) were quite different from the X2C calculations.

IV. RESULTS AND DISCUSSION
We first discuss the effect of optimizing the Pt(IV) complex in a small cluster of water molecules after the initial solvation. We next compare the spectra (and solvent shifts) resulting from employing the X2C and scalar relativistic Hamiltonians for PE regions of different sizes. We additionally investigate the effects of extending the QM region with selected water molecules. These initial investigations will serve to justify the method used for the dynamics, which is done in the last subsection.

A. Structural solvent effect from method employed in refinement.
We start by comparing the spectra obtained from a PBEh-3c optimized structure to those optimized with BP86. To properly separate structural and electronic solvent effects, we first compare the two spectra without a PE description of the environment, i.e., a vacuum calculation on the two structures (Figure 3a). Since we previously showed that the electronic effect due to PE can significantly change the spectrum, we repeated the comparison while including a PE environment within 6 and 10Å spheres (Figure 3b). Yet, both vacuum and solvated UV-vis spectra show that the spectra obtained for the BP86 optimized structure are significantly red-shifted in comparison to the PBEh-3c spectra (peak positions for the individual calculations are given in Table I): in the vacuum case, the red-shifts are 0.61 and 0.41 eV, respectively. When including the electronic solvent effect with PE, the corresponding shifts are both 0.48 eV for the 6Å system, whereas they are 0.41 and 0.54 eV for the 10Å system. The absorption cross sections also change significantly from vacuum to solvent and this is discussed further in next subsection. Here we only note that for the absorption cross sections in vacuum, the first peak is 0.24 a.u. higher for the PBEh-3c structure compared to the first peak of the BP86 structure, while the second peak of PBEh-3c is 0.42 a.u. lower than that of BP86 (see Figure 3a and Table I). When including the 6Å environment, similar changes are observed, with the first peak from the PBEh-3c structure being 0.56 a.u. higher and the second peak 0.26 a.u. lower when comparing to the peaks of the spectra from the BP86 structure ( Figure 3b and Table I). For the 10Å environment, the PBEh-3c structure again has a higher absorption cross section for the first peak (0.52 a.u.), and lower (0.29 a.u.) for the second peak compared to BP86 (Figure 3b and Table I).
In conclusion, both the underlying structure and the electronic contribution of the solvent have large effects on the resulting UV-vis spectra. These large effects prompted us to investigate the underlying structures. These are shown as overlays in Figure 4. In this figure, some of the water molecules can be seen to overlap exactly and these corresponds to the ones kept frozen in the optimizations. However, both water molecules close to the trans-Pt complex and the complex itself show significant structural changes after optimization with BP86. One of the goals of employing a semi-empirical method for the refinement was to investigate whether the snapshots obtained from the classical dynamics can be refined in a computationally cheap manner. Unfortunately, the changes in the structures combined with accompanying shifts in both energies and cross sections strongly indicate that this is not the case. Thus, we here employ the higher level of theory, e.g., BP86. We note for the particular structure employed here, the highest peak of the BP86 result in Figure 3b is only 0.03 eV off from the experimental peak at 4.35 eV 70 , while that of PBEh-3c predicts a peak that is 0.58 eV (33 nm) shifted from the experiment. One of the peaks in the vacuum spectrum of PBEh-3c is also at 4.38 eV, but seeing that the results shift to 4.93 eV due to the electronic effect of the solvent, this result is likely fortitous. In fact, we show in a section below, that the result from BP86 (including PE) also is likely to be fortuitous, since including dynamical effects will move the result slightly away from the experimental maximum.  with PBEh-3c and BP86 (the corresponding spectra are given in Figure 3). The absorption cross sections, σ(ω), are given in parantheses.

B. Solvent shifts with different choices of Hamiltonian
In the next series of calculations, we compared the environmental effect obtained by different choices of the underlying Hamiltonian: we either included only scalar relativistic effects (SR) or employ X2C. Systems with both 6Å and 10Å solvation spheres are investigated (but we exclusively use the structure refined with BP86). The resulting UV-vis spectra are shown in Figure 5 (a)-(b) and the peak positions are provided in Table II. From vacuum to solvent, it is seen that the inclusion of PE yields a significant change in the spectra, but this change is qualitatively similar for SR and X2C Hamiltonians: the two distinct peaks in the vacuum spectra around 3.5-4.5 eV becomes a single peak, whereas a new peak appears at higher energies in the solvated spectra. Thus, we can conclude that the difference is not related to the inclusion of SOC, but exclusively an effect of the solvent. To understand the observed difference, we analyzed the transitions in the response vectors, employing the 10 A system. All peaks are LMCT transitions involving donor orbitals on the N -3 ligands and acceptor orbitals on the Pt center. The d-orbitals contributing to both peaks in the X2C spectra are along the Pt-N -3 bond axis. Meanwhile, the vacuum spectra have contributions from the d-orbital along Pt-OHaxis and a d-orbital in the N -3 -NH 3 plane. The difference between the contributing d-orbitals can explain the differences between vacuum and PE spectra (the SR and X2C calculations employ the same structure for the trans-Pt complex).
Due to the rather dramatic effect of PE on the spectra, it is not meaningful to compare the solvent shift from the vacuum to the PE environment of the SR and X2C Hamiltonians.
However, we can compare the final, solvated excitation energies and peak maxima: the excitation energies (taken as the energy of the peak maxima) are not very different between SR and X2C Hamiltonians. However, the absorption cross sections at peak maxima change between the Hamiltonians. For the 6Å system, the cross sections are 22%-25% lower for the X2C Hamiltonian. Interestingly, the inclusion of a larger environment does not induce any significant changes, as seen when moving from the 6Å to the 10Å solvation sphere, with only the second peak being slightly shifted with 0.07 eV and the absorption cross-section increasing around 4 %. We have also investigated how taking EEF effects into account changes the spectra (this investigation was only carried out for X2C). As expected, the excitation energies are not changed, while the absorption cross sections decrease with 9 and 13 % for the 10Å solvation sphere (see Figure 6 and Table II). For the 6Å solvation sphere, the corresponding changes in the absorption cross sections for the peaks are a decrease with 9 % with PBEh-3c and BP86 (the corresponding spectra are given in Figure 5). The absorption cross sections, σ(ω), are given in parantheses. FIG. 6: UV-Vis spectra calculated using CAM-B3LYP and X2C with and without EEF effects included.
The total system was the 10Å, using the BP86 refined structure. and 11 % when including EEF effects (see Table II). Thus, we conclude that we can safely employ a 6Å sphere to study the solvent effect, but an EEF should be included. In the next subsection, we will additionally attempt to include a few solvent molecules in the QM region.

C. Inclusion of water molecules in the QM region.
From the structure optimized with BP86, we included the five water molecules closest to the trans-Pt complex in the QM region (all water molecules within a 4.2Å distance from the Pt atom). The corresponding UV-vis spectra are shown in Figure 7(a) while the QM region is shown in 7(b). For the most intense peak, which is the only one seen experimentally, the effect of including QM water is much smaller than the effect of using a PBEh-3c refined structure. A slightly larger effect is seen for the higher energy peak, but the effect is still much smaller than the effect of using the refined structure. We carefully analyzed the response vectors to ensure that none of the excitations contained underlying transitions from the water molecules to the platinum complex (or vice versa). While this was not the case within the investigated frequency window, this will likely occur further into the high-energy region.

D. Dynamic effects: Conformations from MD
We have thus far only investigated the solvent effects for a single conformation. While this did provide insight into how a solvent can influence the features of UV-Vis absorption spectra, dynamic effects are required to mimic experimental conditions. From a series of snapshots obtained from a classical MD simulation with subsequent refinement through QM optimizations, we obtained 49 spectra with X2C. The spectra for the various snapshots can be seen in Figure S2; they generally have one peak (all peak positions are reported in Table   S3). We here show only the mean spectrum, as well as the spectra with peak maxima most red-and blue-shifted from the mean, respectively (Figure 8a). The corresponding absorption cross sections and excitation energies at peak maxima are provided in Table III. From the spectra that display the largest difference in the position of the peak maxima, the span of potential peak maxima ranges from 4.31 to 5.13 eV, i.e., 0.8 eV. This demonstrates the importance of dynamic solvent effects.
All spectra calculations were carried out both with and without EEF effects. We mainly consider the values including the EEF effects, but note that the absorption cross-section decrease with 24 % when we include the EEF effect. The mean spectra with and without EEF are shown in Figure 8(b).
Previous investigations employing range-separated functionals found that these calculations provide excellent agreement with experimental results for both the shape of the spectra and the energy at the absorption maximum 12,13 . However, these investigations were carried out without inclusion of dynamical and electronic solvent effect. In light of our present results, it is clear that benchmarking should include these effects. Yet, the inclusion of dynamics does not bring the computed spectra closer to the peak maximum of the experimental spectrum. The computed mean peak position is 4.79 ± 0.23 eV, compared to the experimental 4.35 eV. 70 Several underlying causes for this apparent discrepancy may be found: one of them being the choice of functional. To investigate this possibility, we computed the spectra for 5 structures using B3LYP, employing 5 randomly selected snapshots (see Figure   S4). We find that the peaks of the CAM-B3LYP spectra are blue-shifted compared to those of B3LYP. For three of the five snapshots used to compare B3LYP and CAM-B3LYP, we also investigated the effect of extending the basis set to triple-zeta quality, but this cannot explain the blue shift (see Figure S5).
We also note that some of the deviation from experiment in the present investigation may be caused by inaccuracies in the sampled structures from the subsequent restricted QM refinement. We investigated if the blueshift could be correlated with a simple structural parameter. In the supporting information ( Figure S6), we show how the peak maximum depends on the Pt−N 3 bond distance for the considered snapshots. This distance was chosen due to LMCT nature of the transition and the involvement of orbitals located on the azide ligands. The peak maxima are indeed sensitive to this distance, and distances smaller than the average usually result in transitions energies above the average. However, since we do not have a reference structure, it is not possible to isolate the blueshift to be an issue caused by the structure alone. We therefore leave this matter here. A reference structure may be obtained from ab initio MD, although it will come at the price of reduced sampling time or significantly increased computational demands. Despite the blueshift compared to experiment, our present results serve to quantify the importance of environment interactions on calculations of molecular properties, and therefore further emphasize the need for an explicit treatment of the environment.
Finally, we discuss whether our results are converged with respect to the sampling of solvent configurations. We have investigated the convergence in Table S2, where the average peak maxima and excitation energies are compiled in blocks of 10, 20, 30 (and so forth) snapshots. The calculated mean excitation energies and absorption cross sections are converged after 20 snapshots. Thus, we do not expect significant errors due to the employed sampling method.  The mean maximum peak position displayed together with the peak positions of the average spectra and the spectra for the structures that deviate the most from the mean maximum peak position (seen in Figure 8b). All reported values include EEF effects. resulting spectra, and we chose here the theoretically best method (BP86). Thus, the following analyzes employ structures obtained at the BP86 level. We also find that the spectrum computed without electronic solvent effects is rather different, compared to those including PE. However, extending the environment from 6Å to 10Å only has a minor effect on the spectra, leading to the conclusion that the smaller solvation sphere of 6Å is sufficient.
Extending the QM region by including the nearest five water molecules likewise has only a benign effect on the calculated spectrum.
Regarding the inclusion of dynamics (with subsequent QM optimizations), we find that the individual snapshots lead to rather different spectra. While this emphasizes that explicit treatment of the environment is required, the resulting average excitation energy (taken as the average peak maxima positions) is somewhat blue-shifted, compared to the experiment.
Yet, the excellent agreement with experiment in previous investigations with range-separated functionals 12,13 is in light of our present results likely to be somewhat fortuitous due to the lack of dynamic (and electronic) solvent effects. Indeed, employing global hybrid functionals such as B3LYP yield spectra that are systematically red-shifted compared to CAM-B3LYP.
This shows the importance of including a realistic solvent environment in functional benchmarking. Finally, EEF effects significantly alter the absorption cross sections and should be included.

CONFLICTS OF INTEREST
There are no conflicts of interest to declare.